Culture

The onset date of the yearly rainy season reliably predicts if seasonal drought will occur in parts of Sub-Saharan Africa that are particularly vulnerable to food insecurity, and could help to mitigate its effects. Shraddhanand Shukla and colleagues at the University of California, Santa Barbara's Climate Hazards Center, present these findings in the open-access journal PLOS ONE on January 20, 2021.

Climate-driven seasonal drought can impact crop yields and is among major contributors to food insecurity, which can threaten people's lives and livelihoods. In the last five years, parts of Sub-Saharan Africa have experienced a significant rise in food insecurity, sometimes requiring emergency food assistance. Early warning systems that reliably predict conditions likely to lead to food insecurity could help drive timely actions to mitigate these effects.

Shukla and colleagues hypothesized that the onset date of the rainy season, as calculated from precipitation data, could serve as such a warning. To explore this possibility, they analyzed the relationship between the onset date, drought conditions observed via satellite images of vegetation cover, and the risks of food insecurity based on quarterly reports on food insecurity in across Sub-Saharan Africa from April 2011 through February 2020.

The analysis showed that a delay of about 10 days from the median date of onset of the rainy season was associated with a significantly higher likelihood of seasonal drought in regions with the highest risk of acutesevere food insecurity. A 20-day delay indicated a 50 percent chance of drought in those regions. Further analysis confirmed the predictive relationship between rainy season onset date and drought risk across Sub-Saharan Africa as a whole, and particularly in East Africa.

These findings suggest that the onset date of the rainy season could be an important component of an early warning system for droughts likely to lead to food insecurity in Sub-Saharan Africa. Further research could examine the relationship between onset date and other food insecurity indicators, such as high-resolution data on crop yields and prices or mid-season livestock prices.

The authors add: "Timing of rainfall onset can be tracked using remotely sensed observations and forecasted using climate models, and the results of this study show that it can be a reliable indicator of agricultural droughts, particularly in the most food insecure regions of Sub-Saharan Africa, which makes it a simple yet powerful tool to support effective early warning of food insecurity, thus saving lives and livelihood."

Fixed dose combinations of antibiotics are consumed in huge quantities globally, but 80 percent of combinations are not on the WHO Essential Medicines List, and 92 percent are not FDA-approved, - with inappropriate combinations risking inefficacy, toxicity, and selection for antimicrobial resistance

Attine ants are farmers, and they grow fungus as food. Pseudonocardia and Streptomyces bacteria are their farmhands, producing metabolites that protect the crop from pathogens. Surprisingly, these metabolites lack common structural features across bacteria from different geographic locations, even though the ants share a common ancestor. Now, researchers report in ACS Central Science they have identified the first shared antifungal compound among many of these bacteria across Brazil. The compound could someday have medical applications.

Attine ants originated as one species at a single location in the Amazon 50 million years ago. They have evolved to 200 species that have spread their farming practices throughout South and Central America. In exchange for food, bacteria at these farms produce small molecules that hold pathogenic fungi such as Escovopsis in check. However, these molecules differ from region to region, suggesting a highly fragmented and geographically limited evolutionary history for the bacteria. Monica T. Pupo, Jon Clardy and colleagues wanted to find out if any antifungal bacterial metabolites with broader distribution had been overlooked in prior investigations.

In a study of bacteria from ant nests at multiple sites in Brazil, the team discovered that nearly two thirds of Pseudonocardia strains produced a potent antifungal agent, which they called attinimicin. This discovery marked the first report of a specialized metabolite with broad geographic distribution produced by ant-associated bacteria. While this metabolite was safe for the fungal crop, it inhibited growth of fungal parasites, though -- unlike many antibiotics -- only in the absence of iron. It was also effective in fighting a Candida albicans infection in mice, comparable to azole-containing antifungal treatments that are used clinically, making it a potential drug candidate. The researchers ascertained attinimicin's structure and studied its evolutionary relationship to two similar bacterial peptides produced by Streptomyces -- oxachelin A and cahuitamycin A. The results suggest the associated genes in the two types of bacteria came from a common ancestor.

Boston, Mass. -- Renal cell carcinoma (RCC) is the most common form of cancer of the kidney. In 2018, there were an estimated 403,000 new cases of RCC and 175,000 deaths due to kidney cancer worldwide. Currently, the 5-year survival rate for patients with metastatic RCC is only about 12 percent. Current treatments include inhibitors of the VEGF and PD-1 pathways. However, resistance to therapy occurs in most patients and new combination treatments are still needed to enhance the efficacy of these current approaches.

Now, investigators have demonstrated that ACE2 expression is a good prognostic factor in RCC, that loss of ACE2 mediates resistance to classical treatments, and that in preclinical models, treatment with a drug that is downstream of ACE2 can improve tumor responses in RCC and significantly prolong survival. The team, led by Beth Israel Deaconess Medical Center's (BIDMC) Rupal Bhatt, MD, PhD, and University College Cork, Ireland's Thomas Walther, PhD, published their findings in the journal Science Translational Medicine.

"Our team reported that ACE2 is a new protective molecule for RCC, and building on this finding, we show that angiotensin-(1-7), a small peptide generated by ACE2, can be used to control tumor growth in preclinical models," said co-corresponding Bhatt, a medical oncologist at BIDMC and associate professor of medicine at Harvard Medical School. "Our findings suggest that angiotensin-(1-7) could be developed in clinical trials as a promising therapeutic option in patients with RCC in combination with current standard of care treatments and has a strong potential to improve overall survival."

ACE2 is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin II/AT1 receptor pathway. Interestingly, it is also the receptor for the SARS-CoV2 spike protein, and its downregulation by the virus leads to the often deadly progression of acute respiratory distress syndrome in COVID-19 patients.

Bhatt, Walther and colleagues show that higher ACE2 expression correlates with better overall survival in patients with RCC. They also demonstrated that VEGF receptor inhibitors such as sunitinib and axitinib down-regulate ACE2 expression in tumor cells in culture and in tumors in mouse models of RCC. Using novel and innovative methods and techniques, the authors generated multiple lines of evidence that this ACE2 down-regulation can be causative for the resistance to VEGF pathway inhibition, the inevitable consequence of this approved used class of drugs.

The authors also report that angiotensin-(1-7) is the likely mediator of this effect. The authors also showed that triple therapy of VEGF pathway inhibitors and anti-PD-L1 with angiotensin-(1-7) is superior to the actual standard treatment with VEGR and PD-1 pathway inhibition.

"Our work shows that angiotensin-(1-7) could provide a promising therapeutic option in patients with RCC in combination with VEGF-pathway inhibitors," said co-corresponding author Walther, Professor in Pharmacology at the University College Cork. "Resistance to VEGF-pathway inhibitors is a general problem in cancer treatment and therefore our findings have broader implications for VEGF-pathway inhibitor therapies that beyond RCC could be extended to other types of cancers."

Catnip and silver vine have been known as cat attractant plants. Cat lovers use dry leaves of these plants and toys stuffed with the leaves to give joy to their pet cats. But how does this work? What is the biological significance of the responsive behavior? A research group at Iwate University, Nagoya University, Kyoto University, and University of Liverpool found that the behavior had more practical reasons than getting euphoria.

"The first appearance of silver vine ("Matatabi" in Japanese) as a cat attractant in literature in Japan dates back to more than 300 years ago. A folklore Ukiyo-e drawn in 1859 shows a group of mice trying to tempt some cats with a smell of silver vine. Still, benefits of the cats' response had remained unknown." says Prof. Masao Miyazaki of Iwate University, a leader of the research project.

The research group first identified the active ingredient of silver vine that induces the response. They isolated substances from extract of silver vine leaves and administrated each of them to cats to examine the response. The experiment revealed that nepetalactol, a novel substance, most strongly induces the characteristic behavior.

"We applied nepetalactol to laboratory paper filters and tested with eighteen laboratory and seventeen feral cats. They displayed the typical response to silver vine. We also tested the substance with larger, non-domestic cats (jaguar, Amur leopard, and Eurasian lynx). They showed a similar reaction. We concluded nepetalactol is responsible for the typical feline reaction to silver vine," said Reiko Uenoyama, the paper's first author.

The second important finding by the researchers is the biological mechanism of the response by feline animals to silver vine. They hypothesized that the μ-opioid system, which is associated with euphoric effects in humans, is activated with the plant. "We tested β-endorphin levels before and after nepetalactol-induced response in cat blood. We found that silver vine activates the nervous system that is responsible for the euphorigenic reaction," said Miyazaki.

Does this mean cats play with silver vine to get euphoria? Alternatively, does silver vine has another function to cats? The research group believed that the plant has another biologically important function as the reaction was already shown in feline animals when they evolved from other species about 10 million years ago.

"On the basis of some reports that nepetalactone, the feline attractant in catnip, has mosquito repellent activity, we thought that the response allows cats to transfer plant's nepetalactol or nepetalactone on their fur for protection against mosquitoes. This led to a strong hypothesis when we found the mosquito repellent activity of nepetalactol." said Uenoyama.

To examine whether cats purposefully transfer nepetalactol, the research group placed paper filters with nepetalactol on different parts of the cat cage (floor, walls and ceiling). Although cats rubbed their faces and heads on the paper regardless of the place of the nepetalactol paper, they did not show the typical rolling when the paper was placed on a wall or ceiling. When cats rubbed against the nepetalactol paper, the substance was transferred to their faces and heads, indicating that the most important function of rubbing behavior is to apply the chemical to these parts of feline fur.

"Next, we tested the mosquito repellent property of nepetalactol on cats. We counted the numbers of mosquitoes landing on cat heads with and without application of nepetalactol. The mosquitoes landed less on the nepetalactol heads. To see whether mosquitoes react the same in a more natural setting, we compared the mosquito reaction between cats that responded to silver vine leaves and nonresponsive cats. Mosquitoes avoided the responsive cats. From these results, we found that the cats' reaction to silver vine is chemical defense against mosquitoes, and perhaps against viruses and parasitic insects. This was the most significant finding of our study," said Miyazaki.

Miyazaki and his colleagues see many possibilities to use the findings in research and practical application. "Why is this reaction limited to cats? Why don't non-feline animals react to the plant? To find answers, we want to identify the gene responsible for the reaction. The findings of this study may be used in various applications, including development of new mosquito repellant products."

Adding the arthritis drug tocilizumab to standard care for patients in hospital with severe or critical covid-19 is no better than standard care alone in improving clinical outcomes at 15 days, finds a new trial published by The BMJ today.

There was an increased number of deaths at 15 days in patients receiving tocilizumab, resulting in the trial being stopped early.

Today's results contradict earlier observational studies suggesting a benefit of tocilizumab. However, observational effects are limited by a high risk that they may be due to other unknown (confounding) factors - and some studies have not yet been peer reviewed or published in a medical journal.

A randomised trial assessing tocilizumab in critically ill patients with covid-19 (REMAP-CAP) published as a preprint earlier this month, found a beneficial effect of the drug on days free from organ support within 21 days and mortality. Reasons for these apparently contradictory effects, for example differences between patients' characteristics, need to be assessed in future analysis, say the researchers.

Tocilizumab blocks a specific part of the immune system (interleukin 6) that can go into overdrive in some patients with covid-19. Doctors think this might help lessen the body's inflammatory response to the virus and avert some of the more dire consequences of the disease, but its effects are not well defined.

To test this theory, researchers based in Brazil conducted a randomised controlled trial comparing tocilizumab plus standard care with standard care alone in patients admitted to hospital with severe or critical covid-19.

Their findings are based on 129 relatively young adults (average age 57 years) with confirmed covid-19 at nine hospitals in Brazil between 8 May and 17 July 2020.

Patients were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two chemicals linked to inflammation in their blood.

Patients were randomly divided into two groups: 65 received tocilizumab plus standard care and 64 received standard care alone.

Other potentially important factors, such as underlying conditions and use of other medication, were taken into account and all patients were monitored for 15 days.

By day 15, 18 (28%) patients in the tocilizumab group and 13 (20%) in the standard care group were receiving mechanical ventilation or died.

Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group.

The increased number of deaths in the tocilizumab group raised safety concerns and the trial was stopped early. In both groups, deaths were attributed to covid-19 related acute respiratory failure or multiple organ dysfunction.

The researchers point to some limitations including the small sample size, which affects the chances of detecting a true effect. However, results were consistent after adjusting for levels of respiratory support needed by patients at the start of the trial, suggesting that the findings withstand scrutiny.

As such, the researchers conclude that in patients with severe or critical covid-19, "tocilizumab plus standard care was not superior to standard care alone in improving clinical status at 15 days and might increase mortality."

And they say these results "raise questions about an anti-inflammatory approach in the treatment of covid-19 beyond corticosteroids."

What The Study Did: This observational study examined how COVID-19-related government-mandated closures and restrictions were associated with changes in mobility and the spread of COVID-19 in Nigeria.

Author: Daniel O. Erim, M.D., Ph.D., M.Sc., of Parexel International in Durham, North Carolina, 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.2020.32101)

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.

#  #  #

Media advisory: The full study is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.32101?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=012021

About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

What The Study Did: Researchers examined individuals' motivation to self-test and to distribute self-test kits given the urgent need to increase COVID-19 testing coverage and contact tracing.

Author: Cedric Bien-Gund, M.D., of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, 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.2020.34001)

Editor's Note: The article includes conflict 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.

#  #  #

Media advisory: The full study is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.34001?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=012021

About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

What The Study Did: This investigation analyzed U.S. county-level associations of income inequality, racial/ethnic composition and political attributes with COVID-19 cases and mortality.

Author: Tim F. Liao, Ph.D., of the University of Illinois at Urbana-Champaign, 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.2020.34578)

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.

#  #  #

Media advisory: The full study is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.34578?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=012021

About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

Researchers have developed an automated method that can track the development of harmful clumps of TAU protein related to Alzheimer's disease in the brain, according to work involving 443 individuals. The method revealed that TAU primarily emerged in an area of the brain called the rhinal cortex before spreading elsewhere, suggesting that targeting TAU here could potentially slow the progression of Alzheimer's disease. The buildup of toxic amyloid-beta and TAU proteins is responsible for many of the symptoms and damage to neurons seen in Alzheimer's disease. However, current therapies have shown reduced efficacy, at least in part because the therapies were administered long after the protein had spread throughout the brain. Developing more effective interventions therefore requires a better understanding of where TAU pathology originates and how it spreads. Justin Sanchez and colleagues designed an automated anatomic sampling method that uses PET imaging to track the presence of TAU in the brain. The team applied their technique to 443 adult participants - including 55 patients with Alzheimer's - and discovered that TAU deposits first emerged in the rhinal cortex independently from amyloid-beta before spreading to the temporal neocortex. A two-year experiment with 104 subjects showed that people with the highest initial levels of TAU or amyloid beta displayed the most spread of TAU throughout the brain by the end of the study. "These findings suggest that [the rhinal cortex] is a biomarker of downstream TAU spread ... with potential utility for therapeutic trials in which reduction of TAU spread is an outcome measure," the authors conclude.

A new Northwestern University study reaffirms the importance of getting a good night's sleep.

By examining fruit flies' brain activity and behavior, the researchers found that deep sleep has an ancient, restorative power to clear waste from the brain. This waste potentially includes toxic proteins that may lead to neurodegenerative disease.

"Waste clearance could be important, in general, for maintaining brain health or for preventing neurogenerative disease," said Dr. Ravi Allada, senior author of the study. "Waste clearance may occur during wake and sleep but is substantially enhanced during deep sleep."

The study will publish tomorrow (Jan. 20) in the journal Science Advances.

Allada is the Edward C. Stuntz Distinguished Professor in Neuroscience and chair of the Department of Neurobiology in the Northwestern's Weinberg College of Arts and Sciences. He also is associate director of Northwestern's Center for Sleep and Circadian Biology. Bart van Alphen, a postdoctoral fellow in Allada's laboratory, was the paper's first author.

Although fruit flies seem very different from humans, the neurons that govern flies' sleep-wake cycles are strikingly similar to our own. For this reason, fruit flies have become a well-studied model organism for sleep, circadian rhythms and neurodegenerative diseases.

In the current study, Allada and his team examined proboscis extension sleep (PES), a deep-sleep stage in fruit flies, which is similar to deep, slow-wave sleep in humans. The researchers discovered that, during this stage, fruit flies repeatedly extend and retract their proboscis (or snout).

"This pumping motion moves fluids possibly to the fly version of the kidneys," Allada said. "Our study shows that this facilitates waste clearance and aids in injury recovery."

When Allada's team impaired flies' deep sleep, the flies were less able to clear an injected non-metabolizable dye from their systems and were more susceptible to traumatic injuries.

Allada said this study brings us closer to understanding the mystery of why all organisms need sleep. All animals -- especially those in the wild -- are incredibly vulnerable when they sleep. But research increasingly shows that the benefits of sleep -- including crucial waste removal -- outweigh this increased vulnerability.

"Our finding that deep sleep serves a role in waste clearance in the fruit fly indicates that waste clearance is an evolutionary conserved core function of sleep," the paper's coauthors write. "This suggests that waste clearance may have been a function of sleep in the common ancestor of flies and humans."

Rubbing against catnip and silver vine transfers plant chemicals that researchers have now shown protect cats from mosquitoes. The results also demonstrate that engaging with nepetalactol, which the study identified as the most potent of many intoxicating iridoid compounds found in silver vine, activates the opioid reward system in both domesticated felines and big jungle cats. While nepetalactol had been previously identified, these studies directly illuminate its extremely potent effect on cats. And by revealing the biological significance of well-known feline behaviors, the study opens the door to further inquiry into how nepetalactol's twin effects - pest repellence and intoxication - may have driven the evolution of these behaviors. Catnip and silver vine are known to hold a special place in felines' hearts. When cats encounter these plants, they rub their heads and faces against them and roll around on the ground, displaying undeniable enjoyment. Afterward, the cats lounge around in a state of intoxicated repose. But while pet owners around the world gift their cats toys laced with catnip or silver vine leaves, the biological significance of these plants and the neurophysiological mechanism triggered when cats sniff and rub against them has not been known. To investigate, Reiko Uenoyama and colleagues tested how 25 laboratory cats, 30 feral cats, and several captive big cats, including an Amur leopard, two jaguars, and two Eurasian lynx, responded to filter paper impregnated with nepetalactol, finding that the cats showed a more prolonged response than they did with untreated control filter papers. In contrast, dogs and laboratory mice showed no interest in the nepetalactol-containing papers. Next, the researchers compared how 12 of the cats responded to each of the known bioactive iridoids, finding that nepetalactol is the most potent compound in silver vine leaves. To test whether feline responses to nepetalactol are regulated by the opioid system, they examined changes in plasma levels of ?-endorphin 5 minutes before and 5 minutes after 5 cats were exposed to nepetalactol, and later to a control stimulus, finding elevated endorphin concentrations only after exposure to the iridoid. When the researchers pharmacologically inhibited the cats' ?-opioid receptors, the cats no longer showed a rubbing response to the iridoid. Finally, they tested whether silver vine leaves repelled Aedes albopictus mosquitoes when cats rubbed against the plant, finding that significantly fewer mosquitoes landed on cats that exhibited this behavior. Uenoyama et al. note that nepetalactol might also be used as a repellent to protect humans from mosquitoes and suggest it could also repel the Aedes aegypti species, which transmits yellow fever, dengue, and Zika viruses.

Many patients with multiple myeloma, a type of blood cancer, eventually develop resistance to one treatment after another. That's in part because cancer stem cells drive the disease -- cells that continually self-renew. If a therapy can't completely destroy these malignant stem cells, the cancer is likely to keep coming back.

Researchers at University of California San Diego School of Medicine and Ionis Pharmaceuticals are taking a new, targeted approach to myeloma treatment -- silencing IRF4, a gene that allows myeloma stem cells and tumor cells to proliferate and survive. Past studies have shown that high IRF4 levels are associated with lower overall survival rates for patients with the disease.

In a study published January 20, 2021 in Cell Stem Cell, the team details their successes inhibiting IRF4 with an antisense oligonucleotide, an engineered piece of DNA specifically designed to bind the genetic material coding for IRF4, causing it to degrade. The oligonucleotide -- an investigational antisense medicine developed by Ionis and known as ION251 -- lowered disease burden, reduced myeloma stem cell abundance and increased survival of mice bearing human myeloma, according to preclinical study data.

Authors say the results support a Phase I clinical trial recently launched to assess the safety and efficacy of ION251 to treat humans with myeloma.

"As scientists, we don't usually have direct contact with patients, as a daily reminder of what our research could do, or why it's important," said co-senior author Leslie Crews, PhD, assistant professor in the Division of Regenerative Medicine at UC San Diego School of Medicine. "But I've been working with a local support group for patients with multiple myeloma. They inspire me. They ask the most insightful questions, and it really makes it personal. I hope this work will eventually give them new potential treatments to prevent relapse, and ultimately get better."

UC San Diego School of Medicine and Ionis Pharmaceuticals have a long history of collaborating on the development of investigational antisense medicines. Several Ionis antisense drugs have been commercially approved, including the U.S. Food and Drug Administration (FDA)-approved SPINRAZA, a therapy for spinal muscular atrophy. In addition, several other therapies are currently in clinical trials.

One challenge myeloma researchers face is that myeloma cells don't grow well in laboratory dishes. To study the disease and test new treatments, the best method, Crews said, is to transplant human myeloma cells into mice that lack an immune system and thus won't reject the human cells -- making avatars of each unique patient, in a way.

The team tested ION251 on these myeloma mouse avatars. Compared to untreated mice, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. What's more, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did. There were 10 mice in each treatment or control group and they received daily doses of ION251 or a control for one week, followed by three doses per week.

In separate experiments using human cells isolated from myeloma or healthy donor samples, doses of ION251 used were enough to eradicate the myeloma stem cells while sparing healthy blood cells.

"The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank -- in the treated mice, we couldn't find any myeloma cells left for us to study," said Crews, who is also associate member of the Moores Cancer Center and member of the Altman Clinical and Translational Research Institute at UC San Diego. "It makes the science more difficult, but it gives me hope for patients."

In addition to working on its own, the treatment improved myeloma tumor cell sensitivity to standard-of-care cancer therapeutics. The researchers also drilled down to the mechanisms at play and described the molecular effects of IRF4 inhibition -- information that both clarifies how myeloma forms in the first place, and how the treatment works.

"These proof-of-principle studies will enable rapid clinical development of anti-sense oligonucleotide-mediated IRF4 inhibition to prevent myeloma relapse driven by drug-resistant cancer stem cells," said co-senior author Catriona Jamieson, MD, PhD, Koman Family Presidential Endowed Chair in Cancer Research, deputy director of Moores Cancer Center, director of the Sanford Stem Cell Clinical Center and director of the CIRM Alpha Stem Cell Clinic at UC San Diego Health.

The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information is available at clinicaltrials.gov/ct2/show/NCT04398485.

"This collaboration exemplifies the power of combining Ionis' antisense technology to target previously un-druggable factors in cancer, with world-class academic, translational and clinical research from institutions such as UC San Diego to rapidly bring promising drugs to patients desperately in need," said co-senior author A. Robert MacLeod, PhD, vice president and franchise head of Oncology at Ionis Pharmaceuticals.

According to the National Cancer Institute, multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020 and a five-year survival of only 53.9 percent.

Simple vision tests can predict which people with Parkinson's disease will develop cognitive impairment and possible dementia 18 months later, according to a new study by UCL researchers.

The study, published in Movement Disorders, adds to evidence that vision changes precede the cognitive decline that occurs in many, but not all, people with Parkinson's.

In another new study published today in Communications Biology, the same research team found that structural and functional connections of brain regions become decoupled throughout the entire brain in people with Parkinson's disease, particularly among people with vision problems.

The two studies together show how losses and changes to the brain's wiring underlie the cognitive impairment experienced by many people with Parkinson's disease.

Lead author Dr Angeliki Zarkali (Dementia Research Centre, UCL Queen Square Institute of Neurology) said: "We have found that people with Parkinson's disease who have visual problems are more likely to get dementia, and that appears to be explained by underlying changes to their brain wiring.

"Vision tests might provide us with a window of opportunity to predict Parkinson's dementia before it begins, which may help us find ways to stop the cognitive decline before it's too late."

For the Movement Disorders paper, published earlier this month, the researchers studied 77 people with Parkinson's disease and found that simple vision tests predicted who would go on to get dementia after a year and a half.

Dementia is a common, debilitating aspect of Parkinson's disease, estimated to affect roughly 50% of people within 10 years of a Parkinson's diagnosis.

These longitudinal findings add weight to previous studies that were done at one time point, which had suggested that performance in vision tests, involving commonly used eye charts and skewed images of cats and dogs, was linked to the risk of cognitive decline.

The new study also found that those who went on to develop Parkinson's dementia had losses in the wiring of the brain, including in areas relating to vision and memory. The researchers used recently developed methods to analyse finely detailed MRI scans, enabling them to pick up the damage to the brain's white matter.

The researchers identified white matter damage to some of the long-distance wiring connecting the front and back of the brain, which helps the brain to function as a cohesive whole network.

The Communications Biology study involved 88 people with Parkinson's disease (33 of whom had visual dysfunction and were thus judged to have a high risk of dementia) and 30 healthy adults as a control group, whose brains were imaged using MRI scans.

In the healthy brain, there is a correlation between how strong the structural (physical) connections between two regions are, and how much those two regions are connected functionally. That coupling is not uniform across the brain, as there is some degree of decoupling in the healthy brain, particularly in areas involved in higher-order processing, which might provide the flexibility to enable abstract reasoning. Too much decoupling appears to be linked to poor outcomes.

The researchers found that people with Parkinson's disease exhibited a higher degree of decoupling across the whole brain. Areas at the back of the brain, and less specialised areas, had the most decoupling in Parkinson's patients.

Parkinson's patients with visual dysfunction had more decoupling in some, but not all brain regions, particularly in memory-related regions in the temporal lobe.

The research team also found changes to the levels of some neurotransmitters (chemical messengers) in people at risk of cognitive decline, suggesting that receptors for those transmitters may be potential targets for new drug treatments for Parkinson's dementia. Notably, while dopamine is known to be implicated in Parkinson's, the researchers found that other neurotransmitters - acetylcholine, serotonin and noradrenaline - were particularly affected in people at risk of cognitive decline.

Dr Angeliki said: "The two papers together help us to understand what's going on in the brains of people with Parkinson's who experience cognitive decline, as it appears to be driven by a breakdown in the wiring that connects different brain regions."

Dr Rimona Weil (UCL Queen Square Institute of Neurology), senior author of both papers, said: "Our findings could be valuable for clinical trials, by showing that vision tests can help us identify who we should be targeting for trials of new drugs that might be able to slow Parkinson's. And ultimately if effective treatments are found, then these simple tests may help us identify who will benefit from which treatments."

New study identifies a bizarre new species suggesting that giant marine lizards thrived before the asteroid wiped them out 66 million years ago.

A new species of mosasaur - an ancient sea-going lizard from the age of dinosaurs - has been found with shark-like teeth that gave it a deadly slicing bite.

Xenodens calminechari, from the Cretaceous of Morocco, had knifelike teeth that were packed edge to edge to make a serrated blade and resemble those of certain sharks. The cutting teeth let the small, agile mosasaur, about the size of a small porpoise, punch above its weight, cutting fish in half and taking large bites from bigger animals.

Dr Nick Longrich, Senior Lecturer at the Milner Centre for Evolution at the University of Bath and lead author on the paper, said: "66 million years ago, the coasts of Africa were the most dangerous seas in the world.

"Predator diversity there was unlike anything seen anywhere else on the planet. The new mosasaur adds to a rapidly growing list of marine reptiles known from the latest Cretaceous of Morocco, which at the time was submerged beneath a tropical sea.

"A huge diversity of mosasaurs lived here. Some were giant, deep-diving predators like modern sperm whales, others with huge teeth and growing up to ten meters long, were top predators like orcas, still others ate shellfish like modern sea otters - and then there was the strange little Xenodens.

"They coexisted with long-necked plesiosaurs, giant sea turtles, and saber-toothed fish. The new mosasaur adds another dangerous predator to the mix."

The discovery also adds to the diversity of marine reptiles in the late Cretaceous. This suggests their diversity peaked just before an asteroid hit 66 million years ago, wiping out marine reptiles and the dinosaurs.

"We're still learning how diverse the mosasaurs were," said Longrich. "And whenever we think we have them figured out, another one turns up."

The fauna lived in the million years before an asteroid hit the earth at the end of the Cretaceous period, ending the reign of the dinosaurs and wiping out 90 per cent or more of all species on Earth. The high diversity found in the new study suggests that the ecosystem wasn't in decline before the asteroid hit; instead the ecosystem seems to suggest that marine reptiles were expanding in diversity before they abruptly went extinct.

The teeth seen in Xenodens are unlike those of any other reptile. But Dr Longrich, who worked on fishing boats growing up in Alaska, had seen something similar before.

He said: "It reminded me of the teeth in the jaws of the sleeper sharks we'd sometimes catch while fishing halibut on my brother's boat. I remember seeing what those sharks could do- they'd carve huge bolts of flesh out of the halibut, almost cutting them in half."

The authors suggest that, similar to sleeper sharks and related dogfish sharks, the unusual jaws allowed the animal to punch above its weight, cutting small fish in half, carving pieces out of larger prey, and perhaps even scavenging on the carcasses of large marine reptiles.

But rather than being an extreme specialist, the teeth probably let Xenodens eat a huge range of prey - "They're like the knives sold on those old late night TV commercial- they'll slice through anything," said Longrich.

Anne Schulp, researcher at Naturalis Biodiversity Center in Leiden and Professor of Palaeontology at Utrecht University, and an author on the paper, said: "I'm blown away by the new discovery.

"I've been working on closely related mosasaurs for a decade or two now, and Xenodens shows this group managed to exploit yet another food source. They clearly were even more successful than we thought."

Dr Nathalie Bardet from the National Museum of Natural History in Paris said: "I have been working on mosasaurs for over 20 years and more specifically on those from the Maastrichtian Phosphates of Morocco which I am familiar with. I must admit that among the ten species that I know, this one has a so unusual and extraordinary dentition that at the beginning I thought it was a 'chimera' reconstructed with different fossils!"

Dr Nour-Eddine Jalil of the National Museum of Natural History in Paris and Universite Cadi Ayyad in Marrakech, said: "A mosasaur with shark teeth is a novel adaptation of mosasaurs so surprising that it looked like a fantastic creature out of an artist's imagination.

"Xenodens calminechari is further evidence of the extraordinary paleobiodiversity of the Phosphate Sea.

"It is as if nature is struggling to find all the combinations for an ever finer exploitation of food sources."