Culture

UC Davis MIND Institute researchers found an unexpected set of mental illnesses in patients with a spectrum of a rare genetic disorder. Their study revealed the need for clinicians to consider the complexities of co-existing conditions in patients with both psychological and fragile X associated disorders.

Double-hit fragile X spectrum cases

The patients had a "double-hit" condition that combined features and symptoms of fragile X syndrome and premutation disorder.

Fragile X syndrome (FXS), a rare single-gene disorder, is the leading inherited cause of intellectual disability. It is caused by a lack of the fragile X mental retardation protein (FMRP) resulting from a change, called mutation, in the FMR1 gene.

In most people, the CGG section of the FMR1 gene is repeated between 10 to 40 times. In some rare cases, individuals have premutation disorder when their FMR1 gene has 55 to 200 CGG repeats. When this section expands to over 200 repeats, there is a full mutation in the gene. This full mutation causes an inability to produce FMRP and leads to FXS.

The study presented 14 cases of male patients with FMR1-gene mutations and a variety of psychiatric disorders. These patients, ages ranging between nine and 58 years, had features resembling FXS and symptoms common among premutation carriers.

FXS symptoms include hand flapping, hyperactivity, recurrent ear infections, severe anxiety and tantrums. Individuals with FXS frequently have speech and language delays, behavior challenges and symptoms of autism spectrum disorder (ASD).

Premutation, on the other hand, is associated with the development of neurological problems associated with aging. One example of such age-related problems is Fragile X-associated tremor ataxia syndrome (FXTAS). FXTAS is a disease characterized by progressively severe tremor and difficulty with walking and balance. Premutation is also associated with medical and psychiatric problems such as migraines, hypertension, sleep apnea, restless legs syndrome, anxiety and depression.

Neurological and developmental problems

The study found that patients with premutation had a much earlier onset of neurological problems. Some even had earlier symptoms of neurodegeneration, particularly if they had developmental delay or ASD during their childhood. They also showed trouble with their emotional processing.

"Lower levels of FMRP can cause a range of emotional processing issues," said Andrea Schneider, associate research scientist in the Department of Pediatrics and at UC Davis MIND Institute and the lead author on the study. "Some of the common emotion-related disorders we found are mood disorders, anxiety and psychotic features."

The researchers called for more studies on the association of psychosis and lower FMRP levels - especially in patients with a double hit condition. The case series also highlighted the need for clinicians to consider additional possible diagnosis for FMR1 mutations in psychiatric patients.

"Clinicians need to be aware of the physical and mental toll on patients with a FMR1 mutation who also show symptoms of psychosis or early onset of neurological problems," said Paul Hagerman, professor of biochemistry and molecular medicine at UC Davis and co-author on the study. "This understanding helps develop treatment plans that address the multiple needs of these patients."

Hartford, Conn. -- Beverage companies spent $1.04 billion to advertise sugary drinks and energy drinks in 2018, a 26% increase compared to 2013, according to Sugary Drinks FACTS 2020, a new report from the Rudd Center for Food Policy & Obesity at the University of Connecticut. The report documents continued extensive targeted advertising of sugary drinks by beverage companies directed to Black and Hispanic youth, which contributes to health disparities affecting communities of color--the same communities that have been disproportionately impacted by COVID-19.

The report found that more than one-half of the total sugary drink advertising expenditures--$586 million--promoted regular soda and soda brands alone, an increase of 41% over 2013. By contrast, advertising spending for all diet and unsweetened drinks combined, including plain water and 100% juice, totaled $573 million. Advertising spending increased across a variety of sugary drink categories between 2013 and 2018--sports drink advertising increased by 24%, totaling $159 million in 2018, and advertising for sweetened iced tea almost tripled, from $38 million in 2013 to $111 million in 2018.

The report also found that companies continue to target sugary drink TV ads to Black and Hispanic youth, who have higher rates of sugary drink consumption compared to non-Hispanic White youth. Since obesity and other diet-related diseases disproportionately affect communities of color, targeted advertising of products that contribute to these negative health outcomes is especially problematic. Systemic and institutional barriers to health and opportunity also contribute to poorer health outcomes and persistent health disparities for these communities.

The report found:

In 2018, companies spent $84 million to advertise regular soda, sports drinks, and energy drinks on Spanish-language TV, an increase of 8% versus 2013 and 80% versus 2010.

Sports drink brands disproportionately advertised on Spanish-language TV, dedicating 21% of their TV advertising budgets to Spanish-language TV, compared to 10% on average for all sugary drinks.

Compared to White children and teens, Black children saw 2.1 times as many sugary drink ads and Black teens saw 2.3 times as many. Black youth exposure was particularly high for sports drinks, regular soda, and energy drinks.

"Our findings demonstrate that beverage companies continue to target their advertising to Black and Hispanic communities, which exacerbates ongoing health disparities affecting those communities" said Jennifer L. Harris, PhD, MBA, lead study author and senior research advisor at the Rudd Center. "Companies should not target communities of color with advertising that almost exclusively promotes unhealthy products and undermines efforts to improve the long-term health of young people."

Researchers used Nielsen data to identify brands in the soda, sports drink, energy drink, iced tea, fruit drink, and flavored water categories that spent at least $100,000 in advertising and that contained added sugar--excluding children's drinks previously examined in Children's Drink FACTS 2019 --and reported on diet soda and diet drinks in the same categories for comparison. Researchers collected data on the nutrition quality and advertising of sugary drinks and energy drinks by category, company, and brand, while also identifying categories, brands, and companies with TV advertising targeted to teens, Hispanic youth, and/or Black youth.

Additional top-level findings:

Teens remain a primary target audience for sugary drink advertising. From 2013 to 2018, teens' exposure to TV advertising increased for regular soda/soda brands (+1%) and iced tea (+68%), despite a 52% decline in time spent watching TV during the same time. Energy drinks and sports drinks targeted their TV advertising directly to teens, as evidenced by high ratios of ads viewed by teens versus adults.

Preschoolers' and children's exposure to sugary drink TV advertising is increasing. Preschoolers' saw 26% more TV ads for sugary drinks in 2018 than in 2013, and children's ad exposure increased by 8%. These increases occurred despite a 35% decline in average TV viewing times for preschoolers and a 42% decline for children during the same period.

Sugary drink advertising was primarily driven by PepsiCo and Coca-Cola brands. PepsiCo and Coca-Cola were responsible for 38% and 31% of all sugary drink advertising spending, respectively. PepsiCo sugary drink advertising spending increased by 28% from 2013 to 2018; Coca-Cola sugary drink advertising increased by 81% during that time period.

Four brands each spent more than $100 million to advertise sugary drinks in 2018: Coke, Pepsi, Gatorade, and Mtn Dew.

"Beverage companies have promised to take action to reduce the amount of beverage calories people consume, but at the same time they dramatically increased advertising for their full-calorie sugary drinks," said Fran Fleming-Milici, PhD, a co-author and director of marketing initiatives at the Rudd Center. "It's well past time for the industry to stop putting profits ahead of our kids' health and put their advertising dollars behind products that contribute to good health rather than undermine it."

The report authors include the following recommendations:

Beverage companies should commit to discontinue targeted marketing of sugary drinks to communities of color.

States and localities should enact excise taxes on sugary drinks and invest the resulting revenue in community-defined programs and services to reduce health and socioeconomic disparities.

The U.S. Food and Drug Administration (FDA) should establish regulations to address unclear labeling practices, such as requiring disclosures of added sugars, low-calorie sweeteners, juice, and caffeine content on the front of product packages.

States and local municipalities should prohibit the sales of energy drinks and shots to children under age 18 and require they be placed in low-visibility locations (such as behind counters).

Grassroots and other advocacy groups should develop campaigns to highlight excessive advertising of sugary drinks, especially advertising that disproportionately targets teens and communities of color.

Healthcare professional organizations should develop campaigns aimed at children and teens to raise awareness about these harms, especially for sugary drinks that are perceived to be healthier than soda (e.g., sports drinks, iced tea, and flavored waters) and energy drinks.

A group of researchers including scientists from the RIKEN Nishina Center for Accelerator-Based Science, University of Tokyo, Nagoya University, and the Japan Atomic Energy Agency (JAEA) used the spin-polarized Relativistic Heavy Ion Collider at Brookhaven National Laboratory in the United States to show that, in polarized proton-proton collisions, neutral pions emitted in the very forward area of collisions--where direct interactions involving quarks and gluons are not applicable--still have a large degree of left-right asymmetry. This finding suggests that the previous consensus regarding the generation of particle in such collisions need to be reevaluated.

Understanding the mechanism through which particles are created in collisions involving protons has relevance for understanding cosmic ray showers, where particles entering the earth's atmosphere from outer space create particle "showers" that help us learn about astronomical phenomena that take place in the extreme environment of the universe. However, it is very difficult to study how particles are created, as the force that binds protons in the nucleus and that bind quarks and gluons into protons--the strong interaction or nuclear force--is very strong compared to other forces such as the electromagnetic force and gravity. One avenue for exploring these important challenges has involved an attribute of protons called "spin," which can be understood by analogy to the way a toy top rotates on its axis. The spin of protons can be artificially aligned, in a process that is called "polarization".

In the 1970s, accelerator experiments at Argonne National Laboratory in the United States revealed that the pions generated toward the front of collisions involving polarized protons had large left-right asymmetry. The energy of the polarized protons used in these experiments was about 10 billion electron volts (GeV). Experiments at higher energies--including one at 200 GeV using the polarized proton beam at Fermi National Accelerator Laboratory (FNAL) in the United States and at RHIC at Brookhaven National Laboratory (BNL) in the United States, where two beams of 100 GeV protons moving in opposite directions were collided--showed that the left-right asymmetry persisted even with high-energy polarized protons. A consensus emerged that this asymmetry was caused by direct interactions among the quarks and gluons in the protons, based on a theory called perturbative quantum chromodynamics (QCD).

However, with additional experiments at the RHIC, findings began to emerge that challenged the consensus. According to Yuji Goto, one of the authors of the current work, "At the energy of RHIC, quarks and gluons are scattered, and various particles are generated in the form of a jet. When the left-right asymmetry of the jet generated forward of the collision position at RHIC was examined, it was found that, contrary to expectations, the overall jet and the pions contained in the jet did not show a left-right asymmetry. This suggested that the cause of the left-right asymmetry was not the direct scattering of quarks and gluons."

In order to further investigate, the researchers conducted experiments, published in Physical Review Letters, where they used an electromagnetic calorimeter detector previously used in the Large Hadron Collider at CERN--known as the LHCf experiment there and the RHICf experiment at RHIC--to take a detailed look at the gamma rays generated by pion decays at the very forward region of the collision. They found, however, that the left-right asymmetry in neutral pions persists even in that very narrow area.

According to Goto, "We found that the asymmetry continues to exist at a very narrow angle from right in front of the collision, and in fact increases as the angle moves away from zero. This result necessitates a reexamination of previous theoretical interpretations. The small forward angle of the asymmetry corresponds to the energy region in which the protons cause the excited state, and the contribution of other mechanisms--diffraction and resonance--may provide a hint to the mystery."

According to Minho Kim, an International Program Associate at RIKEN and graduate student at Korea University, who was the first author of the experiment, "It was great to be able to work with the new detector, and we plan to continue our work to understand the mechanism that generates the left-right asymmetry. This is sure to give us insights into cosmic ray showers and thus help us to understand phenomena that take place in the extreme environment of the universe."

In a heart attack, a series of biochemical processes leave the heart damaged, much like a car after an accident.

There is loss of tissue that needs to be rebuilt, proteins that get crushed, muscle damage, and interruptions to blood and oxygen flow to the heart. Because the heart is not very good at repairing itself, it is important to discover ways to minimize damage in the first place.

Researchers from San Diego State University's Heart Institute discovered how one key protein in the heart can act as the knight in shining armor, reducing the damage from the attack, which could improve survival rates and heart function in those who do survive.

"The more your heart is damaged, the worse the long-term prognosis, so that's where our research is focused," said Chris Glembotski, molecular cardiologist and director of the SDSU Heart Institute. "We study how to make the heart more resilient to the damage of a heart attack, which would improve patient's recovery."

After an attack, many patients have stents put in to open up blocked arteries, which helps in the long term. But the surge of oxygen has drawbacks as well.

"The oxygen surge that occurs as soon as the stent is implanted 'stuns' the heart cells and some of them die, which increases irreparable damage to the heart. We found a protein that can minimize the stunning," said Glembotski.

Glembotski and doctoral candidate Adrian Arrieta found that the protein, MANF (mesencephalic astrocyte-derived neurotrophic factor), acts much like an automobile collision specialist, correcting other proteins that have misfolded.

MANF is among roughly 20,000 proteins in the heart. After Glembotski discovered its potential several years ago, Arrieta was assigned to explore it further.

Arrieta tested genetically modified mice them by inducing a heart attack and observing how they did with and without the protein. They fared much better when MANF was present, acting as a regulator.

"This was our first clue about the importance of MANF in the heart," Arrieta said. "It has a protective effect, but we didn't know how it protects, because it is not structurally similar to proteins that we have previously studied."

Arrieta found evidence that the initial oxidative stress after a heart attack--the overabundance of oxygen--is followed by a potentially damaging opposite effect. Reductive stress is like an overreaction where oxygen is used by the heart so quickly that it can become depleted. Arrieta found MANF decreased reductive stress-induced damage in mice.

Preventive benefits if given in the ambulance

Eventually, the researchers anticipate this discovery could lead to the protein being administered as a drug that can be given to heart attack victims intravenously by first responders.

Immediately after a heart attack there is a 'golden period' when intervention to reduce the severity and damage can significantly boost chances of not only survival but also the level of functionality that the heart regains in recovery.

"One of our most interesting discoveries is our finding that MANF is a chaperone protein that keeps other proteins functional during stress," Arrieta said. "If we could give heart attack victims more MANF, they would have less damage after a heart attack, and they would recover more quickly."

Typically, proteins have a three-dimensional shape which enables them to do their job so the heart functions properly. If this shape is lost, heart function is impacted.

"Think of misfolded proteins like a salvage yard full of crushed automobiles," Glembotski explained. "They were beautifully structured and highly functional at one point, but they become this misshapen mass. In a way, the same thing happens to proteins, either when they're old, or when they experience stress, like a car in a collision."

Next, the researchers will study MANF in the larger hearts of pigs, which respond much like humans do after a heart attack. They will also search for optimal ways to deliver MANF to the heart, again in experimental animals, as this is a critical step in the development of MANF as a drug for humans.

CATONSVILLE, MD, June 23, 2020 - The weight loss industry in the United States is vast and generates about $20 billion each year from over 100 million dieters. Commercial weight loss programs design customer-focused program policies to shape and optimize satisfaction and development. These two metrics are tied to how well a program does and the success of the customers in that program. New research in the INFORMS journal Marketing Science finds one key to success is making sure you have the right role model for dieters.

There are plenty of dieters given the rates of obesity in the United States. According to the Centers for Disease Control and Prevention (CDC), the prevalence of obesity is 40% among young adults ages 20-39 years, 45% among middle-aged adults 40-59 years old, and 43% among adults age 60 and older.

The study, "Inspiration from the 'Biggest Loser': Social Interactions in a Weight Loss Program," conducted by Kosuke Uetake of Yale University and Nathan Yang of McGill University, finds weight loss among average-performing peers has a negative effect on an individual's weight loss, while the weight loss of the top performer among peers is positive.

The study looks at a weight loss database that tracks individual participants' meeting attendance and progress in a large national weight loss program.

"Not all peers are alike, and thus, each peer's impact on others within the group can't be the same. Social support from peers plays an important role in weight loss. We investigate the impact that peer weight loss has on an individual's weight loss success," said Uetake, a professor in the Yale School of Management.

The results show that the average weight loss among peers has a negative effect on an individual's own future weight loss. While in contrast, weight loss of the top performer has a positive effect on an individual's own future weight loss.

"These findings should impact how weight loss program employees should promote the past successes of their participants. The successes among average participants may act as a discouraging benchmark that roughly one-half of the participants will fail to reach, whereas the successes among top performers may act as an encouraging target that does not alienate as many of the participants," continued Uetake.

This work looks to implement policy changes to help dieters reach their goals. One way the study suggests doing that is by using the weight loss successes of top performers to provide inspiration to the group and perhaps avoid using the overall group's success as the benchmark.

The vast majority of Irish adults – 82% – are willing to download a contact tracing app to their smartphone to curb the COVID-19 pandemic, according to new research carried out by a team from Lero, the Science Foundation Ireland Research Centre for Software, University of Limerick (UL) and National University of Ireland Galway (NUI Galway). However, respondents also expressed several privacy concerns, including that the Government, tech firms or hackers might use the information gathered for other purposes after the pandemic.

In the survey, “A National Survey of attitudes to COVID-19 Digital Contact Tracing in the Republic of Ireland”, 98% of the more than 8,000 respondents stated that they understood the concept of contact tracing and 96% stated that informing the HSE of your close contacts is important if you develop COVID-19.

Lero’s Dr Jim Buckley said the response was very heartening considering that researchers from the University of Oxford estimated that, if 56% of people were to download an ideal contact tracing app in the UK, this would be enough to control the disease by itself.

It seems, Dr Buckley said, the primary driver for people’s willingness to download a public-health-backed, contact tracing app during the current crisis is a desire to help others and “for the greater good”. However, he noted, “studies in other jurisdictions have suggested that the actual adoption rate typically lags behind the take-up rate suggested by surveys performed in advance of contact-tracing apps’ launches. Therefore, there is no room for complacency and eliminating the disease requires a high degree of participation from the public and evidence-based app development.”

This Science Foundation Ireland funded research also shows 51% of respondents indicated they “definitely will install” the app if it becomes available, 31% indicated they “probably will install” the app. Ten per cent reported they “may or may not install” the app.

People preferred the idea of a Bluetooth app, with just 31% stating that they would prefer an app that uses geolocation technology. One of the survey authors Dr Michael O’Callaghan, general practitioner and researcher at the UL School of Medicine, said the results offer a good insight into people’s concerns relating to a contact tracing app.

“41% of respondents could see no reason not to install the app. The remaining 59% of respondents selected at least one option from a list of 10 options. ‘I worry technology companies will use this as an excuse for greater surveillance after the pandemic’ was selected by 41% of these, ‘I worry the government would use this as an excuse for greater surveillance after the pandemic’ was chosen by 33% and ‘I worry that my phone would be more likely to get hacked’ was selected by 1,742 (22%) of respondents. It is important, therefore, that those particular concerns be addressed if we are to ensure the greatest possible adoption of this technology,” Dr O’Callaghan said.

“Clear timelines on when this app would be wound down and how Bluetooth technology will allow information to be exchanged between phones are important messages that need to be communicated widely,” he added.

Dr O’Callaghan also said while the international evidence suggests that contact tracing apps are best employed as complementary to a manual tracing process, this study indicates a significant majority of the Irish general public are currently willing to download an app which aims to augment the contact tracing process.

Professor Liam Glynn, Professor of General Practice at UL’s School of Medicine and co-founder of #COVIDWATCHIRL, stressed that app download and ongoing use are two separate challenges. To ensure both occur, it will be essential to generate and communicate ongoing evidence to the general public and all other stakeholders that this app is useful to our country’s contact tracing efforts.

“It may be beneficial to keep the public informed on key data relating to the app, including downloads, active users and numbers of cases where the app has helped contact tracing efforts etc. People have indicated a clear willingness to help, but experience from other countries shows that intent to download does not always translate into actually downloading and using contact tracing apps. Allowing the general public to see in real-time the public health benefits of this app may help maintain public interest,” he said.

“Data from other countries suggest a significant response from early adopters, followed by a swift plateauing. However, these countries are reducing transmission and overall healthcare burden from COVID-19 effectively, so societal concern is likely to be declining. With the considerable uncertainty that prevails over the COVID-19 pandemic, it seems prudent for all countries to continue contact tracing app development and deployment,” he added.

According to Dr Jim Buckley of Lero and UL, analysis of free-text responses in the survey also yielded interesting insights.

“Concerns regarding battery life and Bluetooth led some respondents to suggest that a means to automatically enabling Bluetooth when users leaves their home or workplace should be integrated into the app. Another suggestion involved setting times for the app to be active, which could be entered by the user in advance according to their work, travel or shopping schedule,” he said.

The UK's definition of a 'close contact'--15 or more minutes within 2 metres of distance--used for its coronavirus track and trace system, should curb the spread of COVID-19 infection, indicates research published online in the Journal of Epidemiology & Community Health.

But this will be at the cost of having to trace many uninfected people. And its ultimate success depends on the rapid detection and isolation of the contacts traced, say the researchers.

Although focused on containing the early stages of the COVID-19 outbreak in the UK, the study findings have clear implications for the current use of the test and trace system, they emphasise.

Contact tracing is especially effective in the early stages of an outbreak when treatment options are limited, say the researchers. It has been used before in the UK: 2009 flu pandemic; Ebola virus in 2014; and monkeypox in 2018. And it has long been used to stave off onward transmission of sexually transmitted infections.

Contact tracing is known to curb the spread of infections that are symptomless and take some time to be passed on. But it's not clear how effective it might be for new pathogens that spread quickly, such as SARS-CoV-2, the virus that causes COVID-19 infection.

To explore this further, the researchers drew on information supplied by respondents to a survey, asking them to state how many encounters they had had with others on a given day, as well as the context and duration of those encounters.

For the purposes of this study, the researchers defined an encounter with another person as a face to face conversation or skin on skin touch within a distance of 3 metres.

In all, 5802 respondents reported over 50,000 separate encounters, enabling the authors to conclude that over a period of 14 days the average number of contacts was 217, although around 3% of respondents reported more than 1000 contacts during that time.

Of these, around one in four (27%; 59 contacts) met the UK definition of a close contact.

The researchers then used preliminary estimates of COVID-19 spread and the SEIR model, which captures the rate that people move from being Susceptible to infection, to Exposed to it, to Infectious, to Recovered, to predict the numbers of people in close contact with an infected person and traceable within two weeks.

They calculated that for every infected source person, an average of 36 (61%) close contacts could be identified and therefore traced, and that fewer than 1 in 6 infected people would generate any subsequent untraced infectious contacts.

But any one person is likely to have many encounters that are shorter than 15 minutes, such as when commuting or shopping, for example, and which would therefore fall outside the definition of a close contact. "Although unlikely to become infected [they] may pose a risk due to their greater abundance," warn the researchers.

And they predict that around 15% of infected cases would "generate at least one unidentified secondary case which would need detecting by other means" while 1 in 10 infected cases would generate "at least one person that couldn't even be identified.

"Similarly, we would expect around 3% of detected cases to not be able to identify their infecting individual," they write, but point out that these figures shouldn't be thought of as a failure of contact tracing; rather, a reflection of the uncertainties inherent in the approach.

Tightening the definition of a close contact to extend the time period could "dramatically lower" the number of contacts that would need to be traced, but would also increase the chances of infectious cases being missed, they explain.

A contact period of 4 or more hours would be unlikely to control an outbreak effectively, they suggest.

They acknowledge that their research has assumed that all primary infections start the process of contact tracing, which, given that many infected people don't have symptoms or seek medical care, is likely to be optimistic. And not all identified contacts will be traced sufficiently quickly to prevent further spread, they say.

But the current lower R number (reproductive ratio) and fewer contacts means that tracing doesn't have to be as effective to control the infection, they say.

And they conclude: "The current tracing strategy within the UK is likely to identify a sufficient proportion of infected individuals, such that subsequent spread could be prevented, although the ultimate success will depend on rapid detection of cases and isolation of contacts.

"Given the burden of tracing a large number of contacts to find new cases, there is the potential the system could be overwhelmed if imports of infection occur at a rapid rate," they warn.

Yale researchers have identified four drugs that may help minimize the long-term health effects of HIV infection, they report June 23 in the Journal of Clinical Investigation.

Antiretroviral therapy has proved to be a life-saving treatment for those infected with HIV. Yet even after treatment, most patients still harbor latent HIV in some immune system cells. The presence of inactive HIV in the genome can trigger chronic immune system activation, cause accelerated aging, and make patients more susceptible to cardiovascular problems and some forms of cancer.

"It's like diabetes. There are good treatments available but people still suffer adverse health consequences," said Yale's Ya-Chi Ho, assistant professor of microbial pathogenesis and medicine (infectious diseases) and senior author of the study. "Antiretroviral therapy alone is not sufficient to inhibit chronic immune system activation, and new drugs should be developed."

Ho's team looked for drugs that might help inhibit reactivation of HIV and reduce damaging immune system responses. The researchers screened 1,430 drugs approved by the U.S. Food and Drug Administration to assess their impact on human cells infected by HIV. They eventually zeroed in on four approved drugs that showed the most promise to both suppress activation of latent HIV and reduce damaging immune system response.

Two of the four drugs -- ruxolitinib, used in hematological disorders, and mycophenolic acid, used to inhibit organ transplant rejections -- were already in clinical trials to treat HIV infections. However, the researchers also found that filgotinib, which modulates immune response and is used to treat autoimmune diseases, and spironolactone, a hormone used to treat heart failure, also inhibited HIV reactivation and HIV-induced immune activation.
Ho said that these HIV-suppressing drugs might be used as a complement to antiretroviral therapy in the treatment of HIV infection to reduce chronic immune activation, which cannot be achieved by antiretroviral therapy alone.

Yale's Yang-Hui Jimmy Yeh is the lead author of the study, which was primarily funded by the National Institutes of Health and a Yale Top Scholar award.

LA JOLLA, CALIF. – June 23, 2020 – Scientists at Sanford Burnham Prebys Medical Discovery Institute have created a next-generation drug called Ciapavir (SBI-0953294) that is effective at reactivating dormant human immunodeficiency virus (HIV). The research, published in Cell Reports Medicine, aims to create a functional HIV cure by activating and then eliminating all pockets of dormant HIV--an approach called "shock and kill."

"What scientists have found with other 'shock' approaches is that they can be too hot and overactivate the immune system, or too cold and don't wake up the virus," says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and the study's lead corresponding and co-senior author. "Our research identifies a drug that works in the 'Goldilocks' zone--it reawakens the virus without activating the immune system. Our work also provides further evidence that this drug class, called Smac mimetics, is a promising approach to reactivating latent HIV."

Antiretroviral therapy (ART) has increased the life expectancy of people with HIV by decades--with many individuals now living as long as the general population. However, because HIV is able to hide in reservoirs in the body, infected individuals never fully clear the disease, and ART must be taken every day for the rest of an individual's life to keep the virus inactive. Like other chronic treatments, non-adherence rates for ARTs are estimated at 30%. Non-adherence increases the likelihood that HIV will progress to AIDS, the later stage of the infection, and also increases the risk of treatment resistance.

Waking up sleeping HIV

This research builds upon the scientists' previous discovery that Smac mimetics--which have undergone human safety testing and are currently in clinical trials for certain cancers--can reactivate latent virus in cells from people with HIV undergoing ART. In parallel, scientists are exploring ways to kill the reactivated virus--such as developing broadly neutralizing antibodies or modified T-cells (CAR-T cell therapy) that destroy infected cells--which would complete the "shock and kill" strategy.

In this study, the researchers administered Ciapavir to mice with a human immune system and were infected with HIV. The treatment significantly increased levels of HIV in the blood and bone marrow--indicating that the latent virus was activated. Importantly, immune activation was minimal. Overactivation of the immune system can be deadly and has historically been a problem with the "shock and kill" approach.

"Ciapavir is the first Smac mimetic specifically optimized for an HIV cure, so it is significantly more potent for HIV than other molecules in this class," says Nicholas Cosford, Ph.D., deputy director of the NCI-designated Cancer Center at Sanford Burnham Prebys and co-senior author of the study. "As a result, Ciapavir may be effective when used on its own instead of in combination with a second drug, as our previous research showed, and potentially at lower doses."

The Goldilocks approach

Ciapavir is a small molecule that awakens dormant HIV by activating non-canonical NF-κB signaling in CD4+ T cells, the target of HIV. This lesser-used pathway only activates a subset of the immune system--which is the key to the drug's gentle approach.

"Non-canonical NF-κB signaling is part of the immune system's 'plan B' response to pathogens," explains Lars Pache, Ph.D., research assistant professor in the Chanda lab at Sanford Burnham Prebys and first author of the study. "In this case, we are using this alternate pathway to our advantage. We can wake up the virus without overwhelming the immune system."

Ciapavir will next undergo further evaluation in nonhuman primates, as well as additional toxicology studies to ensure that the drug is ready for testing in humans.

“Early shock and kill attempts to cure HIV used repurposed drugs and did not achieve their goal of reactivating latent HIV to useful levels,” says Rowena Johnston, Ph.D., vice president and director of research at amfAR, The Foundation for AIDS Research. “It’s encouraging to see the HIV cure field move towards purpose-built therapeutics to achieve what has so far been an elusive goal.”

More than 37.9 million people around the world are living with HIV, according to the World Health Organization, including 1.1 million people in the U.S. The virus infects the CD4+ T cells of the immune system. As the infection progresses, the immune system is destroyed, which makes people more vulnerable to other infections and diseases. Without medicine, people with AIDS--or late-stage HIV--typically survive about three years.

The study's DOI is 10.1016/j.xcrm.2020.100037.

Research reported in this press release was supported by the National Institutes of Health (P30AI036214, R01AI124843, R01CA195227, P30CA030199) and the James B. Pendleton Charitable Trust.

The co-senior authors of the study are Cosford, Jerome Zack of UCLA, and Chanda, who is also the corresponding author. Additional study authors include Matthew Marsden of UCLA and Peter Teriete of Sanford Burnham Prebys, who contributed equally to the study; Alex Portillo, Dominik Heimann and Maria Celeridad of Sanford Burnham Prebys; Jocelyn Kim, Mohamed Soliman, Melanie Dimapasoc and Camille Carmona of UCLA; and Adam Spivak and Vicente Planelles of the University of Utah School of Medicine.

Volume 11, Issue 25 of @Oncotarget reported that Administration of landiolol hydrochloride was found to be associated with reduced incidence of atrial fibrillation after esophagectomy for esophageal cancer in our previous randomized controlled trial.

Between March 2014 and January 2016, 100 patients with esophageal cancer were registered in an RCT trial and randomly allocated to receive either administration of landiolol or a placebo.

The authors analyzed data from this RCT to better understand the effect of postoperative AF and severe associated complications on overall survival after esophagectomy for cancer.

In multivariate analysis, high stage alone was an independent prognostic factor for esophageal cancer patients the following esophagectomy.

Dr. Toshiyasu Ojima from The Wakayama Medical University said, "Esophagectomy is considered the optimum treatment against esophageal cancers."

The incidence of major postoperative complications in our previous study increased in patients that developed new-onset AF following subtotal esophagectomy.

The effect of postoperative AF on long-term survival following esophagectomy is therefore controversial.

Severe postoperative complications may make patients with esophageal cancer less likely to survive over the long term.

Patients with esophageal cancer but without severe postoperative complications have been shown to have better long-term survival than patients with complications.

The authors also evaluate the influence of severe postoperative complications on overall survival and whether prophylactic administration of landiolol hydrochloride directly influences prolonged survival in patients with esophageal cancer.

The Ojima Research Team concluded in their Oncotarget Research Paper, "new-onset AF and other severe complications were not associated with poorer long-term survival after esophagectomy. In addition, administration of landiolol hydrochloride after esophagectomy did not contribute to the prolonged OS of patients with esophageal cancer."

"Administration of landiolol hydrochloride after esophagectomy did not contribute to the prolonged OS of patients with esophageal cancer"

Volume 11 Issue 25 of @Oncotarget reported that this study aimed to define the mutation profile of SUM in Caucasians.

Next-generation sequencing-based genomic analysis was used to identify frequently mutated loci in 50 cancer-related genes in 31 SUM primary tumors.

The most abundant mutations in SUM were found in KIT – in 13% of cases and NRAS – also in 13%, while BRAF - only in 3% of cases.

The authors' findings confirmed a high frequency of KIT and NRAS mutations in SUM, as well as a low incidence of BRAF mutations.

They reported novel KRAS, CTNNB1, TP53, ERBB2, and SMAD4 mutations in SUM.

Dr. Aneta Borkowska from The Maria Sklodowska-Curie National Research Institute of Oncology said "Across all human cancers, cutaneous malignant melanoma (MM) genome has one of the highest prevalence of somatic mutations."

"Across all human cancers, cutaneous malignant melanoma (MM) genome has one of the highest prevalence of somatic mutations"

- Dr. Aneta Borkowska, The Maria Sklodowska-Curie National Research Institute of Oncology

At the same time, NRAS mutations are detected in approximately 20% of MM and are more commonly reported in melanomas developing in the skin with chronic sun exposure.

WHO Classification of Skin Tumours recognizes the most common acral melanoma histotype is acral lentiginous melanoma, followed by nodular cutaneous melanoma and superficial spreading melanoma.

Cutaneous MM located on the acral part of extremities - hand and foot melanoma - comprises a rare group within all melanomas in Caucasians.

Whole-genome sequencing study shown that structural changes and mutational signature of acral melanomas were dominated by different than other MMs sites.

SUM seems to be not related to sun exposure, however, in Australian Melanoma Genome Project UVR signatures on acral melanomas occurred most frequently in subungual parts.

The Borkowska Research Team concluded in their Oncotarget Research Paper, "Our study offers new insights into the genetics SUM subtype, for understanding pathogenesis and providing potential biomarkers for future studies. Molecular testing is now widely used in patients with advanced melanoma in the process of therapeutic decisions. Mutations reported in melanoma cells provide starting points for the development of the rational design of novel therapies, including immunotherapy agents. They also may provide to find the molecular pathogenesis and natural history of subtypes of this heterogeneous disease. We confirmed that SUM have different than other cutaneous melanomas genetic profile, which due to its rareness and lack of studies should be subjected to further analyzes in multicenter studies."

Volume 11, Issue 25 of @Oncotarget reported that the present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the INSR gene in breast cancer cells.

The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression.

Wild-type p53 stimulated INSR promoter activity in control cells while disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by p53.

Mutant p53 strongly stimulated INSR promoter.

Furthermore, p53 directly binds to the INSR promoter in cells with a disrupted IGF1R.

Dr. Haim Werner from Tel Aviv University said, "The insulin/insulin-like growth factors (IGFs) create a hormonal network responsible for the regulation of important physiological events throughout life."

"The insulin/insulin-like growth factors (IGFs) create a hormonal network responsible for the regulation of important physiological events throughout life"

- Dr. Haim Werner, Tel Aviv University

The classical view that emerged following the cloning and characterization of the INSR and IGF1R genes in the mid-1980s postulated that activation of INSR by insulin leads, predominantly, to metabolic activities.

One of the cardinal questions still in need of a biologically plausible rationalization is why the INSR and IGF1R, even though they share the majority of their downstream cytoplasmic targets and signaling pathways, are yet responsible for mediating distinct physiological and pathological activities.

Given the emerging evidence of proliferative and potentially anti-apoptotic actions of INSR, the authors investigated in the present paper the regulation of the INSR gene promoter by wild-type and mutant p53 in breast cancer cells.

Using cells with specific disruption of the INSR or IGF1R, the authors also assessed the effect of each one of these signaling pathways on p53 expression and activity.

The data indicate that: activation of p53 is negatively regulated by IGF1R, as indicated by the augmented phosphorylation of p53 in IGF1R-KD cells; p53 directly binds to the INSR promoter region in cells with a disrupted IGF1R; wild-type p53 represses INSR promoter activity in IGF1R-KD and INSR-KD cells while enhancing promoter activity in control cells; mutant p53 stimulates INSR promoter activity in breast cancer cells.

The Werner Research Team concluded in their Oncotarget Research Paper, "we have presented evidence that the INSR gene constitutes a downstream target for p53 action. Whereas wild-type p53 stimulated INSR promoter activity in control MCF7 cells, disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by wild-type p53. Mutant, oncogenic versions of p53, for the most part, strongly stimulated INSR promoter. In addition, p53 exhibits direct binding to the INSR promoter region in cells with a disrupted IGF1R. Taken together, data presented here identifies complex functional and physical interactions between p53 and the INSR pathway. The clinical implications of this interplay in breast cancer needs to be critically assessed."

BEER-SHEVA, Israel...June 23, 2020 - Could furry social robots help bolster moods and reduce pain when human to human contact isn't an option, for example, during a pandemic?

According to a new study by Ben-Gurion University of the Negev (BGU) researchers published in Scientific Reports, a one-time, hour-long session with a plush, seal-like social robot reduced pain and oxytocin levels, and increased happiness. The Japanese social robot, PARO, emits seal-like sounds and moves its head and flippers in response to being spoken to and touched.

Human-to-human contact has been found to bolster mood and reduce pain in previous studies. Dr. Shelly Levy-Tzedek of the BGU Department of Physical Therapy and her team investigated whether a furry social robot could induce similar effects when normal human-to-human contact is not available.

Levy-Tzedek and her team discovered that a single, 60-minute interaction with PARO actually improved mood as well as reduced mild or severe pain. When participants touched PARO, they experienced greater pain reduction than when it was simply present in their room.

Surprisingly, the BGU researchers discovered lower oxytocin levels in those who interacted with PARO than in the control group participants, who did not meet PARO. Typically, oxytocin, sometimes called "the love homone," is elevated among romantic partners or mothers playing with their children, so a lower level of oxytocin wasn't expected. However, more recent studies have shown that outside of close relationships, oxytocin production is a stress indicator and therefore, a reduction could indicate relaxation.

"These findings offer new strategies for pain management and for improving well-being, which are particularly needed at this time, when social distancing is a crucial factor in public health," says Dr. Levy-Tzedek.

The United States is home to more than 21 million military veterans, many of whom have difficulty reintegrating into civilian life. A staggering 20 percent of them suffer from post-traumatic stress disorder (PTSD), one of the most common trauma-induced mental illnesses. Moreover, it is estimated that 20 veterans die of suicide each day, resulting in about 6,000 deaths by suicide each year. With President Trump's announcement last week for a roadmap to increase public awareness and training to curb these deaths in our military veterans, a unique study exploring the human-animal bond could play an important role in helping this initiative.

Human-animal interaction is known to reduce stress. Yet, few studies have examined the health effects of interacting with dogs, specifically in the veteran population. With about 6 to 8 million dogs ending up in shelters in the U.S. each year - half of which won't get adopted - researchers enlisted the help of two no-kill shelters for a study evaluating the effects of walking with a shelter dog on psychological and physiological stress indicators in military veterans.

The randomized study was led by Cheryl Krause-Parello, Ph.D., lead author, a professor and director of Canines Providing Assistance to Wounded Warriors® ( C-P.A.W.W.®), within Florida Atlantic University's Christine E. Lynn College of Nursing, and a faculty fellow of FAU's Institute for Human Health and Disease Intervention (I-HEALTH), who conducted the study while at the University of Colorado, in collaboration with researchers from the University of Maryland's School of Nursing and SUNY Fredonia. The study was funded in part by the ISAZ/Waltham Petcare Science Institute Collaborative Research Award and C-P.A.W.W.®.

Results, published in the journal Anthrozoös, provide evidence that walking with a shelter dog may affect psychological and physiological stress indicators in veterans - with particular potential benefits for veterans with an increase in PTSD symptom severity.

Researchers compared the effects of walking with a shelter dog versus walking with a human on psychological stress indicators, PTSD symptoms, and perceived stress in reintegrating military veterans.

Krause-Parello and collaborators evaluated three physiological stress biomarkers: heart rate variability, salivary cortisol, and the enzyme alpha-amylase over four weeks of walking with a dog and walking with a human. The body's reaction to stress affects these biomarkers. The researchers included the heart rate variability biomarker because of its strong correlations with human physical stress and psychosocial stress.

The clearest indicator for decreases in stress came from the heart rate variability data, which was most apparent for veterans with greater PTSD symptom severity. Heart rate variability was measured before, during and for 30 minutes after walking.

"Based on heart rate variability, our study provides evidence that walking with a shelter dog may benefit veterans with higher symptoms of post-traumatic stress. Severity of symptoms and perceived stress tended to decrease more after walks with a dog than walks with a human," said Krause-Parello.

Responses to walking with a dog and a human from week one to week four were different depending on PTSD symptom severity. Walking with another person did not change stress levels, as measured with cortisol, in those with high PTSD symptom severity. Walking with a dog or another person led to decreases in cortisol among those with low PTSD symptom severity. For individuals with high PTSD symptom severity, walking with a dog did not change stress levels, as indicated by alpha amylase, but walking with a person led to increased stress. For individuals with lower PTSD symptoms, alpha amylase did not change significantly for either type of walk.

"Our findings emphasize the need for more research to determine if this form of human-animal interaction is beneficial to veterans with PTSD and to help us identify the optimal level of interaction that will be most impactful for them," said Krause-Parello.

This unique pairing has the potential to be mutually beneficial for veterans and humankind's "best friend" alike. The researchers emphasize the obvious benefits of human-animal interaction for shelter dogs. They need to be walked and socialized on a consistent basis to develop a positive relationship with humans, maintain a good quality of life, reduce their stress, expand the boundaries of a mundane kennel cage, and improve the likelihood that they will be successfully adopted. The dogs involved in the study resided in the two shelters and were awaiting adoption.

"Considering the large number and availability of shelter dogs in the United States, it really makes sense to consider the potential for these dogs to be involved in a unique intervention that combines the benefits of human-animal interaction with the benefits of altruistic action like volunteerism," said Erika Friedmann, Ph.D., co-author, a professor and associate dean for research at the University of Maryland School of Nursing.

Men and women ages 22 to 69 years old participated in the study. A total of 72 different dogs participated in 124 walks and ranged in size from toy (7.2 pounds) to giant (90 pounds). Each dog walked one to six times. Veterans were asked to draw a name to determine what dog they would be walking with to ensure randomization and to minimize the risk of becoming attached to a shelter dog that might be adopted during the course of the study.

"This innovative research confirms the importance of the human-animal bond. It brings to life an unexpected connection between shelter dogs and veterans, serving to meet a need for both and providing direction for holistic programming that addresses both the health of veterans and that of shelter dogs. It is a win-win," said Patricia Liehr, Ph.D., associate dean of research and scholarship at FAU's Christine E. Lynn College of Nursing.

Study co-authors are former C-P.A.W.W.® research assistants Kelly Blanchard and Megan Payton; and Nancy R. Gee, Ph.D., a professor of psychiatry, Department of Psychiatry, and director of the Center for Human-Animal Interaction, Virginia Commonwealth University School of Medicine, who conducted the research while at SUNY Fredonia.

"At Mars Petcare we believe we have a responsibility to take scientific exploration further when evidence to date shows us that pets can be part of addressing conditions like PTSD," said Kay O'Donnell, vice president, Waltham Petcare Science Institute. "It's important we undertake rigorous studies to understand how companion animals may provide a benefit and we're proud to be part of this study, which takes us another step forward in understanding the human-animal bond."

In their model simulations, climate researchers always have to make compromises. Even with the largest computers available worldwide, they can only reproduce the real world to a limited extent. Depending on the application, simplifications have to be made in the spatial resolution, but also in the physical processes represented by the model. While model experiments over periods of months to a few years can often still be made with high spatial resolution, integrations over centuries to millennia can only be performed at coarser resolution. In the past, models were developed for a specific purpose. Now, GEOMAR Helmholtz Centre for Ocean Research Kiel presented a flexible model kit, called FOCI (Flexible Ocean and Climate Infrastructure). It is based on the Earth system model of the Max Planck Institute for Meteorology in Hamburg and has been modified with the NEMO ocean model, in order to represent small-scale processes in the oceans at higher resolution.

"In FOCI we combine decades of expertise in ocean and climate modelling at GEOMAR. The new system enables the investigation of new questions such as the influence of the stratospheric ozone hole on the circulation in the Southern Ocean or the impact of the Gulf Stream on atmospheric processes", explains Professor Dr. Katja Matthes from the Maritime Meteorology Research Unit at GEOMAR.

"With the new system, we can investigate many different research questions on ar range of time scales", Professor Dr. Arne Biastoch, head of the Ocean Dynamics Research Unit at GEOMAR, points out. "We initially performed a set of standardised basic tests with the FOCI system", the oceanographer continues. "We had to find out whether the model system is capable of reproducing the observed climate and the present ocean circulation. Only if we are confident that the system can successfully simulate the present conditions within limited error bands it can be used to investigate unknown phenomena or for the predictions of future climate conditions". The results, which have been published in the international journal Geoscience Model Development, are very promising. "In particular, our special know-how in operating the ocean model regionally at very high resolution improves the results considerably and reduces, for example, common model errors such as deviations in sea surface temperatures in the Gulf Stream system", says Professor Biastoch. FOCI also enables configurations which were previously impossible at spatial resolutions of up to one kilometre in the ocean.

The basic experiments carried out so far include a control run over 1,500 years with pre-industrial greenhouse gas concentrations and several experiments covering the period from 1850 to the present day, for which observational data are available for verification. "The current results are very encouraging", says Katja Matthes. The system will be further improved and used for various questions to study natural climate fluctuations, but also anthropogenic climate change. "From our point of view, FOCI is the ideal system for GEOMAR to simulate small-scale processes in the ocean, interactions between stratosphere and troposphere as well as biogeochemical processes in the ocean. It also allows us to carry out complex projects such as a large number of model simulations over several decades with a reasonable amount of computing time", Professor Matthes concludes.