Culture

New Lancet Series on Gender Equality, Norms, and Health exposes failures by governments and health institutions to make progress towards gender equality, despite compelling evidence on impact of gender - and the spoken and unspoken rules of societies about acceptable gender behaviours - on health

New research published in The Lancet Child and Adolescent Health adds weight to findings of the Lancet Series, providing first known evidence that male and female gender traits expressed during adolescence affect health in adulthood, at times irrespective of biological sex

In an era of #MeToo and #TimesUp, there is renewed opportunity for a global social movement on health and gender equality - to counter conservative backlash and change societal attitudes towards masculinity and femininity for good

The Sustainable Development Goals offer the prospect of ensuring healthy lives for the world's population by 2030. But this ambition will not be realised without eliminating gender inequality and changing society's attitudes to women and men.

Today, The Lancet published a new Series on "Gender Equality, Norms and Health", which finds that governments and health institutions have persistently failed to make progress towards gender equality, despite the impact of gender - and the spoken and unspoken rules of societies about acceptable gender behaviours - on health throughout life. Set to be launched at the annual 'Women Deliver 2019' [1] conference, this Lancet Series is the result of a four-year project developed by over 100 contributors from five continents.

Gary L Darmstadt, Associate Dean of Maternal and Child Health at Stanford University and Chair of the Lancet Series Steering Committee, said: "There are multiple myths about gender and health that must be defeated: for example the myth that gender does not influence health--it does, massively; or views that gender cannot be changed--they can; or that gender is an elusive idea that cannot be measured--it can. With advances in health historically thwarted by the neglect of gender, this Lancet Series aims to provide new understanding of the impact of gender on health, and present the opportunities that exist within health systems, policies, laws, and programmes to transform health for all."

Gender Equality, Norms and Health: the key findings

Around the world, women and men were found to experience different exposures to disease and risk factors that adversely influence their health. These gender driven differences intersect with other related inequalities (age, class, race, ethnicity, religion, ability, sexuality) and amplify negative effects on health and health systems.

Health systems and healthcare delivery were also shown to neglect and reinforce gender inequalities in health, while health research and health data collection are gender biased and incomplete. Corporate interests did not escape scrutiny, with large corporations found to manipulate gender for profit and promote adverse effects on health.

The good news is that laws, policies, and programmes can improve gender equality and health. Equality inspired policies such as free primary education and paid maternity and parental leave, among others, were shown to have a positive impact on a variety of maternal and child health outcomes. But there is not yet wide-spread adoption.

Action on gender and health: is the world ready to act?

Dr. Richard Horton, editor-in-chief of The Lancet, said: "In an era of #MeToo and #TimesUp, the opportunity of connecting global social movements for health and gender equality is real, urgent, necessary, and achievable. However, a conservative backlash, such as the global gag rule and the rollback of sexual and reproductive health and rights, threatens not only the health gains made for women and men, but also the possibility for future gains."

"Political leaders have so far shown wilful indifference towards gender and attitudes to gender and their effects on health. But this Lancet Series offers the evidence and prospects for transformative social and political change."

These prospects come in the form of five evidence-based recommendations:

Reduce gender inequality to advance health outcomes, such as the introduction of free education and paid maternity leave

Reform the workplace and workforce, such as flexible working, parental leave and equal pay

Fill gaps in data on gender and attitudes and behaviours related to gender, to better understand the causes of poor health and to strengthen the foundations for advancing health

Empower and invest in civil society organisations; the political space for civil society to advocate for gender equality is shrinking

Strengthen independent accountability to ensure that promises and commitments are delivered

In particular, the Lancet Series highlights multiple missed opportunities to engage health systems in gender transformative strategies to improve health - and lays out specific recommendations, including: increasing the visibility of women in health leadership and cure roles; recognising and rewarding care roles; addressing sexual harassment and abuse in the workplace; and creating the conditions to enable change in the way women interact with the health system.

The international evidence base for gender and health

Underpinning these findings, the Lancet Series identifies many examples of how gender inequalities - and the unwritten rules that govern the way people understand gender - influence health adversely:

Care seeking for childhood illness (Ethiopia)

Adolescent weight control and mental health (South Africa, Brazil)

School peer influences on adolescent health (USA)

Premarital sex and HIV status (Zambia)
M
Women working outside the home and IPV (Nigeria)

An original article published in The Lancet Child and Adolescent Health today [2] adds further weight to the findings of the Lancet Series, providing the first known evidence that a person's gender expression toward masculinity or femininity can track through time to affect their health in adulthood, including the likelihood of engaging in risky or healthy behaviours and of several health outcomes.

This prospective cohort study explored the impact of gender expression on health in more than 12,000 US residents, from adolescence through to early adult years, and found that adolescent gender expression is correlated with health in adulthood independently of gender expression as an adult. For some outcomes, masculinity or femininity conveyed risks independent of the biological sex of the individual.

Lead author Holly Baker Shakya noted: "While our awareness of "gender" as something which is socially constructed and reinforced is increasing, the degree to which our social expression of gender can impact our well-being throughout our lives is just starting to come into focus."

In an independent commentary, Caroline Moreau from the Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, USA, said: "The results of this study reaffirm the importance of addressing gender inequities in early adolescence before identities solidify, and call for an immediate application of gender transformative interventions that challenge gender ideologies, from which the performance of gender effects the development of unhealthy bodies."

Use of dating apps may be associated with an increased risk of unhealthy weight control behaviors, including vomiting, laxative use, or diet pill use, a study in the open access Journal of Eating Disorders suggests.

A team of researchers at the Harvard T.H. Chan School of Public Health, USA examined data on 1,726 US adults enrolled in the Harvard Chan Physical Activity study who completed an online survey assessing their dating app use within the past 30 days and their engagement in six unhealthy weight control behaviors (UWBCs) within the past 12 months.

Dr Alvin Tran, the lead author of the study said: "To our knowledge, our study is one of the first to explore dating app use in association with unhealthy weight control behaviors. When comparing those who do not use dating apps to those who do, we found that dating app users had significantly elevated odds of engaging in the six unhealthy weight control behaviors we investigated: vomiting for weight control, using laxatives for weight control, fasting for weight control, using diet pills, using muscle-building supplements, and using anabolic steroids."

The authors found that out of the 1,726 adults, 183 women and 209 men used dating apps. Compared to non-users, women who used dating apps had 2.3 to 26.9 times higher odds of engaging in UCWBs, while men who used dating apps had 3.2 to 14.6 times the odds of engaging in UWCBs.

The most common UWCBs were fasting, vomiting and laxative use. Out of those who reported using dating apps, 44.8% (82) of women and 54.1% (113) of men reported fasting, 22.4% (41) of women and 36.4% (76) of men reported vomiting, and 24% (44) of women and 41.1% (86) of men reported using laxatives for weight control. Other prevalent UWCBs included diet pill use, and use of anabolic steroids or muscle building supplements.

Dr Tran said: "Consistent with previous research, we also found elevated rates of UWCBs in racial / ethnic minorities, particularly African Americans. We did not, however, find elevated odds of UWCBs based on sexual orientation."

The authors caution that the cross-sectional nature of the study does not allow for conclusions about cause and effect or the direction of the observed association between dating app use and UWCBs.

Dr Tran said: "While we do not know if the people in our study were already engaging in these weight control behaviors before using dating apps, we worry that the use of these image- and appearance-focused services could exacerbate those behaviors. With the tremendous growth in dating app usage in the U.S., and an increasing number of studies linking their use to body image concerns and UWCBs, there is a need to further understand how dating apps influence health behaviors and outcomes."

Sometimes, the best defense against hostile invaders is a good, long nap. Or at least, that strategy seems to work for bacteria.

In a new study, described in Nature, Rockefeller scientists showed that microbes under viral attack turn their defenses not only on their enemies, but also on themselves. This drastic measure, the researchers found, doesn't kill the bacteria, but rather sends them into a dormant state that prevents the infection from spreading.

Vicious viruses

Among bacteria, viruses called bacteriophages are public enemy number one.

These pathogens propagate by injecting their genome into unsuspecting microbes, eventually causing their host cell to rupture, at which point progeny phage is released to infect other members of a bacterial colony.

To mitigate these attacks, bacteria have evolved immune mechanisms known as CRISPRs, or clustered regularly interspaced short palindromic repeats, which, with the help of associated Cas enzymes, detect and destroy foreign genetic material.

Microbes have at their disposal many different CRISPR systems, one of which caught the attention of Luciano Marraffini due to its unique strategy for fending off intruders. Whereas most Cas enzymes destroy viral DNA, this particular enzyme, Cas13, works by cleaving RNA.

"Since Cas13 targets RNA, it was initially thought to have evolved to impede phages with RNA genomes. The problem is, RNA phages exceedingly rare," he says. "So we wanted to see whether it might have evolved to serve a different function."

Working with Helen Hay Whitney postdoctoral associate Alexander Meeske, Marraffini showed that activation of Cas13 actually protects bacteria from phages with DNA genomes, which are far more common. But how, they wondered, could an RNA-cutting enzyme actually defend microbes from this kind of virus?

Through a series of experiments, the researchers found that Cas13 helps bacteria, ironically, by hindering them. That is, the enzyme cuts up bits of host RNA, sending the bacteria into a dormant state--a kind resting phase in which the microbes remain alive but don't grow. This strategy works, says Meeske, because viruses need host RNA to replicate.

"Phages are parasites: They don't have all the elements needed for their propagation, so they rely on the host," he explains. "And if the host cell isn't making those elements, the phage cannot propagate."

No escape

The researchers also found that Cas13 kills viruses more thoroughly than other Cas enzymes. Standard CRISPR-Cas systems are highly specific, cutting up bits of DNA that match a precise genetic sequence. And while this specificity can be an asset, it also comes with a big drawback: If a virus mutates, CRISPR cannot recognize the invader, and the phage escapes scot-free.

"If a phage has a single point mutation in its target sequence, then usually the virus is invisible to Cas and the infection will succeed," says Marraffini. "But with Cas13 we didn't see any escaper mutants."

The researchers attribute this superb virus-fighting power to the fact that cell dormancy does not target one particular virus, but rather makes it impossible for any phage--including mutants--to propagate. And while an indefinite nap may not seem like much of a life for a microbe, Meeske notes that the real benefit of Cas13 lies not at the level of the individual, but of the bacterial community as a whole.

"The phage has one shot to deliver its genetic payload and replicate," he says. "So if they inject their genome into a host that turns out to be inhospitable, the infection stops there. The phage loses, and the bacterial colony wins."

MIAMI--A team of researchers including scientists at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, published new findings that reveal significant damage to Miami's coral reefs from the 16-month dredging operation at the Port of Miami that began in 2013. The study found that sediment buried between half to 90 percent of nearby reefs, resulting in widespread coral death.

The results, published in the journal Marine Pollution Bulletin, estimate that over half a million corals were killed within 550 yards (500 meters) of the dredged channel, and that dredging impacts may have spread across more than 15 miles (25 kilometers) of Florida's reef tract.

"Coral reefs worldwide are facing severe declines from climate change," said Andrew Baker, associate professor of marine biology and ecology at the UM Rosenstiel School and senior author of the study. "If we want to conserve these ecosystems for the generations that come after us, it's essential that we do all we can to conserve the corals we still have left. These climate survivors may hold the key to understanding how some corals can survive global changes. We have to start locally by doing all we can to protect our remaining corals from impacts, like dredging, that we have the ability to control or prevent."

The researchers reanalyzed data originally collected by consultants as part of the dredge's environmental monitoring program. This program had attributed most of the documented coral losses in the area to a region-wide outbreak of coral disease that occurred at the same time. The new study controlled for these impacts by looking at losses of coral species that were not susceptible to the disease and by testing whether corals closer to the dredge site were more likely to die during the dredge period than those further away. The new analysis revealed that most of the documented coral losses near the Port of Miami were in fact the result of dredging.

"It was important to differentiate these multiple impacts occurring on the reefs to understand the direct effects of dredging specifically," said lead author Ross Cunning, who began the project while a postdoctoral scientist at the UM Rosenstiel School and is now a research biologist at the Shedd Aquarium in Chicago. "We brought together all the available data from satellites, sediment traps, and hundreds of underwater surveys. Together, the multiple, independent datasets clearly show that dredging caused the major damages observed on these reefs."

Florida's reef tract is the only nearshore reef in the continental United States, and coral cover has declined by at least 70 percent since the 1970's. Staghorn corals, which were once common in shallow water, have declined an estimated 98 percent and are now threatened species under the Endangered Species Act. The affected areas adjacent to the dredge site are of high conservation value and have been designated as "critical habitat" for the recovery of these threatened staghorn corals. Nationwide, coral reefs provide over $1.8 billion in flood risk reduction annually.

The researchers also studied whether sediment plumes - milky clouds of suspended dredging sediment visible from space - could predict impacts observed on the reefs below. The authors found that plumes detected using satellites had a remarkably high correlation with impacts documented on the seafloor. This is the first study to show that satellite data can be reliably used to predict dredging impacts on corals and their habitats.

"This connection allowed us to predict impacts beyond where ship-based monitoring was taking place, and showed that dredging likely damaged this reef several kilometers away," said study co-author Brian Barnes of the University of South Florida. "While this same relationship may not apply in all projects, this is a remarkable finding that further establishes Earth-observing satellites as independent monitoring tools to fill in gaps where data are otherwise not available."

"This study provides a clear and scientifically robust estimate of the impact of this dredging project on Miami's coral reef resources. It tells a devastating story of loss that we cannot afford to ignore any longer," said Rachel Silverstein, executive director and waterkeeper of Miami Waterkeeper and a co-author of the study. "We hope that these findings will provide valuable information to guide restoration of the impacted reefs and prevent these kinds of impacts in the future."

The study, titled "Extensive coral mortality and critical habitat loss following dredging and their association with remotely-sensed sediment plumes," was published in the August 2019 online issue of the journal Marine Pollution Bulletin.

Irvine, Calif., May 30, 2019 - Can your liver sense when you're staring at a television screen or cellphone late at night? Apparently so, and when such activity is detected, the organ can throw your circadian rhythms out of whack, leaving you more susceptible to health problems.

That's one of the takeaways from two new studies by University of California, Irvine scientists working in collaboration with the Institute for Research in Biomedicine in Barcelona, Spain.

The studies, published today in the journal Cell, used specially bred mice to analyze the network of internal clocks that regulate metabolism. Although researchers had suspected that the body's various circadian clocks could operate independently from the central clock in the hypothalamus of the brain, there was previously no way to test the theory, said Paolo Sassone-Corsi, director of UCI's Center for Epigenetics and Metabolism and senior author of one of the studies.

To overcome that obstacle, scientists figured out how to disable the entire circadian system of the mice, then jump-start individual clocks. For the experiments reported in the Cell papers, they activated clocks inside the liver or skin.

"The results were quite surprising," said Sassone-Corsi, Donald Bren Professor of Biological Chemistry. "No one realized that the liver or skin could be so directly affected by light."

For example, despite the shutdown of all other body clocks, including the central brain clock, the liver knew what time it was, responded to light changes as day shifted to night and maintained critical functions, such as preparing to digest food at mealtime and converting glucose to energy.

Somehow, the liver's circadian clock was able to detect light, presumably via signals from other organs. Only when the mice were subjected to constant darkness did the liver's clock stop functioning.

In upcoming studies, UCI and Barcelona researchers will phase in other internal clocks to see how different organs communicate with each other, Sassone-Corsi said.

"The future implications of our findings are vast," he noted. "With these mice, we can now begin deciphering the metabolic pathways that control our circadian rhythms, aging processes and general well-being."

In earlier studies, Sassone-Corsi has examined how circadian clocks can be rewired by such factors as sleep deprivation, diet and exercise. Exposure to computer, television or cellphone light just before bed can also scramble internal clocks.

Because of modern lifestyles, it's easy for people's circadian systems to get confused, he said. In turn, that can lead to depression, allergies, premature aging, cancer and other health problems. Further mice experiments could uncover ways to make human internal clocks "less misaligned," Sassone-Corsi added.

WINSTON-SALEM, N.C. - May 30, 2019 - A potential therapeutic strategy to treat viral infection and boost immunity against cancer is reported in the May 30 online issue of the journal Cell.

The work, conducted by scientists at Wake Forest School of Medicine, found that boosting the body's production of type 1 interferon helped clear viral infection and increased immunity against cancer by identifying a sensor involved in suppressing interferon production in an animal model.

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

Interferons also help the immune system fight cancer and may slow the growth of cancer cells.

The principal investigator of the study was Hui-Kuan Lin, Ph.D., professor of cancer biology at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

In the study, Lin's team discovered that RIG-I-like receptors (RLR) mediated interferon (IFN) production, which played a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. They reported that glycolysis, the first step in breaking down glucose to extract energy for cellular metabolism, was inactivated during RLR activity. That inactivation served as the key to turn on type I IFN production.

Using pharmacological and genetic approaches, the scientists showed that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightened type I IFN production to protect from viral infection in mice.

The study established a critical role of glycolysis-derived lactate in limiting RLR signaling and identified MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity, Lin said.

Type I interferons (IFNs), produced by almost all type of cells, played a vital role in host defense against viral infection and cancer immunosurveillance, Lin said.

Lin's team plans to conduct additional studies in other animal models in preparation for potential clinical trials.

New Orleans, LA - Research led by Ashok Aiyar, PhD, Associate Professor of Microbiology, Immunology and Parasitology at LSU Health New Orleans School of Medicine, has identified a target that may lead to the development of new treatments for the most common sexually transmitted infection in the US. The results are published this month online in PNAS, available here.

Chlamydia is caused by infection with Chlamydia trachomatis bacteria. It can affect both the urogenital tract and the eyes. If untreated, the outcome of both ocular and genital infections can be severe. Ocular Chlamydia infections are the leading cause of infectious blindness, and genital infections can lead to infertility. The health of infants born vaginally to infected mothers is also often severely compromised.

Chlamydia trachomatis bacteria need the essential amino acid, tryptophan, to survive. They are dependent upon their host cells, or the microbiome, to provide it. Genital Chlamydia strains have a unique mechanism to avoid tryptophan starvation. By conditionally making an enzyme called tryptophan synthase, they can use a molecule called indole, which is sometimes made by the genital microbiome, to make tryptophan. Ocular strains make an inactive version of tryptophan synthase or have lost the gene for the enzyme entirely. The goal of this research was to discover why ocular Chlamydia no longer make an active tryptophan synthase.

Dr. Aiyar says, "Our studies demonstrate that small molecules, collectively called trp operon de-repressors, which are produced by the gut microbiome and carried by the circulation to other parts of the body, play a key role. These molecules force Chlamydia to make tryptophan synthase. However, activation of tryptophan synthase in the absence of indole generates ammonia, which kills Chlamydia very rapidly. As such, our findings provide new leads for therapeutics against chlamydia infections that leverage products made by the gut microbiome."

Previous studies have shown that trp de-repressors also kill other pathogenic bacteria, such as Legionella pneumophila and Mycobacterium tuberculosis, via unknown mechanisms.

"It is possible that the mechanism we have described for Chlamydia extends to these other bacteria as well," notes Aiyar.

According to the Centers for Disease Control and Prevention (CDC), Louisiana had one of the highest rates of reported cases of Chlamydia trachomatis in the United States in 2017. The CDC reported there were more than 1.7 million cases of chlamydia diagnosed in 2017, representing a 22% increase from 2013 levels. However, the CDC estimates that 2.86 million infections occur annually. A large number of cases are not reported because most people with chlamydia are asymptomatic and do not seek testing.

Next steps include research on the mechanisms to restrict the availability of indole in cells in the genital area, thereby creating conditions under which trp de-repressors will effectively kill genital Chlamydia by forcing the production of ammonia.

Biophysicists from the Moscow Institute of Physics and Technology have joined forces with colleagues from France and Germany to create a new fluorescent protein. Besides glowing when irradiated with ultraviolet and blue light, it is exceedingly small and stable under high temperatures. The authors of the paper, published in the journal Photochemical & Photobiological Sciences, believe the protein holds prospects for fluorescence microscopy. This technique is used in research on cancer, infectious diseases, and organ development, among other things.

Fluorescence microscopy is a method for studying living tissue that relies on induced luminescence. After being exposed to laser radiation at a particular wavelength, some proteins emit light at a different wavelength. This induced "glow" can be analyzed using a special microscope. Researchers append such fluorescent proteins to other proteins via genetic engineering to make the latter ones visible to the microscope and observe their behavior in cells. Fluorescence microscopy proved so scientifically valuable that one Nobel Prize was awarded for its discovery, followed by another one for radically improving the method's accuracy.

Up until now, the fluorescent proteins used for such observations had several flaws. They were vulnerable to heat, fairly bulky, and only glowed in the presence of oxygen.

"For one thing, our protein is more thermostable than its analogues: It only denaturates at 68 degrees Celsius," said the paper's lead author Vera Nazarenko from the MIPT Laboratory of Structural Analysis and Engineering of Membrane Systems. "It is also miniature, while most of the currently used fluorescent proteins are rather bulky. On top of that, it can emit light in the absence of oxygen."

The team originally identified the protein with these remarkable properties in the cells of a the thermophilic bacterium -- that is, one which lives in high-temperature environments, such as hot springs. The researchers then genetically engineered a DNA sequence that reproduced the protein's fluorescent segment but not the other parts, which would make the molecule larger.

By introducing the gene that encodes the protein into the cells of another bacterium, Escherichia coli, the team turned it into a factory mass-producing the fluorescent protein with unique properties.

Researchers studying the processes that occur in living cells have been waiting for a protein combining these crucial features for a long time. By introducing it into cells, they can now obtain essential data on cell life and death. To name a few applications, fluorescence microscopy is seen as one of the best tools for investigating the mechanism behind malignant tumor genesis and development. It is also useful for research on cell signaling and organ development.

The proteins previously used in fluorescence microscopy were bulky and thermally unstable, putting limitations on the method. Thanks to the MIPT team, that obstacle has been eliminated.

JUPITER, Fla.--May 30--Our cells' process for transforming genes into useful proteins works much like an automobile factory's assembly line; there are schematics, parts, workers, motors, quality control systems and even recycling crews. If the cell's recycling process falters, abnormal protein fragments accumulate, potentially causing the cell's death. In nerve cells, the process is linked to a variety of neurodegenerative diseases, including ALS and dementia.

A new study from the lab of Claudio Joazeiro, PhD, published on line in the journal Cell on May 30, uncovers how simpler organisms--bacteria and archaea--manage the recycling of incomplete proteins. The discoveries not only offer new directions for fighting the virulence of some of humanity's most dangerous pathogens, including listeria, staph and streptococcus, they have implications for our understanding of how life itself evolved.

Joazeiro's group found the mechanism isn't so different from one they previously uncovered in plant, animal and fungal cells.

"We know that as cells are making proteins, this process is occasionally halted due to errors," says Joazeiro, who has joint appointments in the Scripps Research Department of Molecular Medicine in Jupiter, Florida, and the Center for Molecular Biology of Heidelberg University, in Germany.

"One of the problems with this is that the accumulation of partially formed proteins may be toxic. So in our lab, we're asking how do cells sense this, and how do they disassemble these proteins and recycle the building blocks?"

Organelles called ribosomes serve as the protein-assembly motors within cells. If they stall during the process of piecing together the parts--amino acids--cells have a variety of systems for responding. In human and other eukaryotic cells, when a ribosome jams, rescue factors split it open. A protein called Rqc2, also known as NEMF, zooms in and recruits another protein--the ubiquitin ligase Ltn1, also called listerin. The Joazeiro lab previously discovered that Ltn1 marks the truncated protein fragment on ribosomes with a destruction tag called ubiquitin. Protease saws then handle the demolition.

Underscoring the importance of this recycling process, Joazeiro discovered in 2009 that mutations in Ltn1 can cause the death of nerve cells in mice, resulting in ALS-like symptoms.
Bacteria have related, but somewhat more direct systems for addressing halted ribosomes and their protein fragments, according to the Cell report. Studying the bacterium B. subtilis, the Joazeiro team found that Rqc2 itself marks the protein fragment with a flag--a polymer made of the amino acid alanine. Thus flagged, proteases come to cut up the bad fragment.

Previous studies had suggested that in some pathogenic bacteria, Rqc2 proteins had a different job, one that functioned outside the cell, helping attach the microbes to hosts.

"We have found this is not the complete story," Joazeiro says. "Rqc2 plays a more fundamental role inside of bacterial cells."

The next step will be to find out whether the defective virulence of strep varieties lacking Rqc2 is primarily a consequence of their failure to recycle protein fragments inside the cell. As increasing varieties of pathogens develop multi-drug resistance to antibiotics, understanding bacterial virulence may prove especially necessary.

Equally important to Joazeiro is the realization that Rqc2 serves as a "living" molecular fossil, illuminating new insights about the ancient ancestral organism that emerged some 4 billion years ago to form the very base of the tree of life that evolved into the planet's biodiversity today.

"Shortly after cells invented how to make proteins, they were also faced with determining how to deal with incompletely made proteins," Joazeiro says. "The analyses suggest that an Rqc2 homolog in the last universal common ancestor already carried out this task."

Bottom Line: This study of nearly 7,700 men and women 50 or older in England looked at how common perceived discrimination was among those with visual impairment and how that was associated with emotional well-being. Of the individuals, 913 reported poor overall eyesight and 658 reported poor eyesight up close. Discrimination was more commonly reported by those adults with poor eyesight than those with good eyesight, with the most common form of discrimination reported being treated with less respect or courtesy. Individuals who reported poor eyesight and discrimination were more likely to report depressive symptoms and loneliness, as well as lower quality of life and life satisfaction than those with poor eyesight but no reported perceived discrimination. A limitation of the study is that poor eyesight was self-reported. Health care practitioners should consider asking patients with visual impairment about their well-being.

Authors: Sarah E. Jackson, Ph.D., University College London, and coauthors

(doi:10.1001/jamaophthalmol.2019.1230)

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

A study from researchers at the Massachusetts General Hospital (MGH) Cancer Center has demonstrated how the response to pancreatic cancer cells of normal tissue - called the stroma - within tumors can influence the ability of individual cancer cells to proliferate and metastasize. Their report, which details how differences in the relative amounts of tumor cells and stromal cells alter patterns of gene expression within individual tumor cells, is being published in Cell and may lead to improved therapies for this difficult-to-treat cancer.

"Our finding that pancreatic cancer cells can behave differently based on the types of cells that are around them may explain why some cells respond to chemotherapy and radiation and some do not," says David Ting, MD, of the Tucker Gosnell Center for Gastrointestinal Malignancies in the MGH Cancer Center, co-senior author of the report. "We also identified a unique cell type that has the ability to replicate and to move at the same time, activates both the MAPK and STAT3 signaling pathways and is killed by combined use of MAPK and STAT3 inhibitors, suggesting a potential therapeutic strategy."

The stroma of pancreatic tumors largely consists of connective tissue cells called cancer-associated fibroblasts (CAFs), along with immune cells and endothelial cells. While some studies have suggested that pancreatic CAFs contribute to the growth and spread of cancer, others have found that reducing CAFs led to more aggressive tumor behavior. These findings, along with the variability of stromal content within pancreatic tumors, suggested that interactions between CAFs and tumor cells are complex.

Recent studies by the MGH team found significant differences in gene expression between pancreatic cancer cells in the primary tumor and those circulating in the bloodstream, with some expressing signatures indicating proliferative features and others more metastatic potential. Subpopulations of cancers cells at the interface between tumor and stroma also expressed these differing genetic signatures, suggesting that they might be influenced by CAFs in the stroma.

The team's current experiments revealed that:

Culturing pancreatic tumor cells (PDACs) with CAFs led to changes in gene expression within cancer cells based on the relative proportions of the two types of cells within the culture. These differences allowed PDACs to be grouped into classes expressing either proliferative or metastatic/invasive signatures, and a subpopulation of "double-positive" cells simultaneously expressing both signatures was primarily seen in cultures with the highest proportion of CAFs.

Tumors with different PDAC:CAF ratios implanted into immunodeficient mice led to changes in tumor growth and the distant spread of tumor cells, implying that stromal differences modulate the gene signatures and the proliferative and metastatic capabilities of pancreatic cancer cells.

CAFs activate the MAPK and STAT3 signaling pathways in double-positive pancreatic cancer cells, and inhibitors of those pathways were more effective in cultures with high proportions of CAFs, with the greatest effects being produced by combining inhibitors of both pathways.

Secretion of TGF-β by CAFs was found to drive the generation of double-positive PDACs, which provides a rationale for therapeutic agents that target TGF-β.

Discrete tumor "glands," comprised of clusters of PDACs, were more useful in predicting treatment outcomes than were individual cells, with glands consisting primarily of double-positive and metastatic/invasive cells associated with treatment resistance and poor patient survival. The prevalence of specific types of PDACs within tumor glands was influenced by the proportions of stromal to tumor cells within glands.

"The assay we developed to identify these different tumor glands provides a strategy to use it as a biomarker to select personalize therapy based on the response of normal cells to the cancer," says Ting, who is an assistant professor of Medicine at Harvard Medical School. "The identification of the roles of both MAPK and STAT3 signaling in generating the different classes of PDACs and the role of CAF-secreted TGF-β in that signaling suggests the importance of investigating how different stromal compositions may determine the optimal drug combinations."

BOSTON - (May 30, 2019) --Research from Joslin Diabetes Center has shown in mice that insulin resistance increases the proportion of aged beta-cells which are dysfunction. Such an increase in aged beta-cells could lead to type 2 diabetes. These researchers confirmed similarly increased proportion of aged beta-cells in islets recovered from humans with type 2 diabetes. The study also showed that beta cell function can be recovered by removing these aged populations either via genetic modification or oral medication.

"Our hypothesis was that there was an important component in the development of diabetes which consisted of accelerated aging of beta-cells and that this population could be targeted therapeutically," says Cristina Aguayo-Mazzucato, MD, PhD, Assistant Investigator in the Section on Islet Cell and Regenerative Biology, first author on the paper, recently published in Cell Metabolism.

This research falls into a broader field of the study of senescence. Senescence is the slow decline of proliferation and function of a specific cell population. These cells accumulate as organisms grow older, but certain circumstances can cause some cells in an organism to age faster than the whole.

The research team, led by Dr. Aguayo-Mazzucato, generated animal models of insulin resistance and tracked the proportion of senescent beta-cells.

"What we found is that indeed, insulin resistance was increasing the amount of senescent or old beta-cells," she says.

Next, they deleted the aged cells through either genetic manipulation or medications that are known to remove senescent cells. The results were striking.

"We were able to recover beta cell function, we were able to restore glucose tolerance," says Dr. Aguayo-Mazzucato

The ability to restore beta cell function with minimal intervention could be a game changer in the care of type 2 diabetes. For many people with the disease, beta cell function declines to the point where they need injectable insulin. Should this research be borne out in clinic trials, the implications for treatment could be huge.

"When you look at the absolute percentage or quantity of the senescent beta-cells, they rarely exceed 20 percent of the whole beta cell population and yet targeting this relatively minor population had a huge effect on function and glucose metabolism and cellular identity," she says.

Medications to delete senescent cells , termed senolytics, are still under investigation. Dr. Aguayo-Mazzucato and her team hope to bring a potential treatment closer to the clinic by partnering with companies that are already working on senolytics, to test if their medications would work for people with diabetes.

"This opens a new target to treat diabetes which is basically to target populations of old or senescent cells that are really contributing to the local disfunction," she says.

Senolysis, or the removal of aged or dysfunctional cells, is a growing field in the treatment of age-related diseases. This new research fits into the larger picture of how senolytics could help combat many different diseases of aging, leading to better quality of life.

"In fact, it's a very exciting and rapidly growing field in medicine, which is called Senolytics or Senolysis," says Dr. Aguayo-Mazzucato. "It has promises, as shown by other laboratories, in osteoarthritis, muscle frailty or degeneration, renal function, some brain function."

While the work was completed in models of type 2 diabetes, the findings could also be relevant in type 1 diabetes.

"What we're seeing is that senescence is, in reality, a response to stress. In the case of type two diabetes, this stress is insulin resistance. In the case of type one diabetes, it is the immune attack on beta-cells," she says. "But in both models, beta-cells are responding to these stresses by becoming senescent. So, we think that the potential of this new vision of preventing diabetes will be valid for both type one and type two."

In July last year, South Africa became the first country to roll out a new anti-tuberculosis drug in its national programme.

This new drug, called bedaquiline, is the first new anti-tuberculosis drug to be developed in four decades. It improves the survival of patients with multidrug resistant TB, potentially offering a shorter treatment time with fewer side effects.

Scientists from Stellenbosch University (SU), in collaboration with a multidisciplinary team of researchers and clinicians, are now trying to conserve this life-saving treatment by studying how Mycobacterium tuberculosis, the bacterium that causes TB, can develop resistance to this drug. Their findings will be used to inform tuberculosis treatment guidelines to ensure that the right combination of anti-tuberculosis drugs are used along with bedaquiline in order to optimise patient treatment outcomes, while minimising the risk of developing resistance to the drug.

"We need to protect bedaquiline from the development of resistance and therefore it is crucial to understand how quickly and through which mechanisms bedaquiline resistance develops," says Dr Margaretha de Vos, one of the lead authors of a scientific commentary article recently published in the New England Journal of Medicine. The article is based on research by De Vos and colleagues at the Division of Molecular Biology and Human Genetics at SU's Faculty of Medicine and Health Sciences (FMHS).

SU researchers studied the development of bedaquiline resistance in TB bacteria in a 65-year-old patient from Cape Town using a combination of novel techniques. These included (1) whole-genome sequencing of the bacteria in patient samples taken throughout various stages of the disease, (2) targeted deep sequencing of Rv0678, a gene of the bacteria that is associated with bedaquiline resistance, and (3) culture-based drug susceptibility testing.

The study showed that resistance to bedaquiline emerged despite the patient adhering to the standard treatment regimen, which requires bedaquiline to be taken along with at least five antibiotic drugs which the bacterium does not resist.

"These results show that it is crucial to increase our efforts to monitor patients receiving bedaquiline and to develop new diagnostic tools to rapidly identify bedaquiline resistance. By rapidly identifying bedaquiline resistance, we will be able change treatment and thereby prevent spread," says Rob Warren, distinguished professor in microbiology and co-author of the article.

Helen Cox, one of the senior co-authors of the study, suggests that "while it is important to monitor the emergence of resistance to new drugs such as bedaquiline, these data should not suggest that we restrict access to bedaquiline for the thousands of patients in South Africa who are in dire need of improved treatment for drug-resistant tuberculosis".

As early responders in the surveillance of malignant cells, natural killer (NK) cells play a significant role in the control of transformed cells at the tumor initiation stage through direct cytolysis. For this reason, NK cell-based immunotherapy is a potential therapeutic strategy for tumor sufferers.

Research groups led by Prof. LI Yan and Prof. Puno Pematenzin from the Kunming Institute of Botany of the Chinese Academy of Sciences found that ent-kaurane diterpenoids, which show a wide range of bioactivity, especially antitumor activity, are good candidates as sensitizer agents for NK cells.

Their work revealed the immunomodulatory role of ent-kaurane diterpenoids toward NK cells for the first time.

The research data not only suggest Prxs-I/II as a promising therapeutic target for cancer immunotherapy, but also provide a compelling rationale for further development of the inhibitor PAA as a sensitizer agent for NK cell-mediated HCC immunotherapy.

The study, entitled "Parvifoline AA Promotes Susceptibility of Hepatocarcinoma to Natural Killer Cell-mediated Cytolysis by Targeting Peroxiredoxin,'' was published online in Cell Chemical Biology.

The results show that the natural ent-kaurane diterpenoid parvifoline AA (PAA) markedly stimulates the expression of NKG2D ligands on hepatocellular carcinoma (HCC) cells, considerably enhancing their recognition and lysis by NK cells.

It involves the covalent binding of PAA to the conserved cysteine site of peroxiredoxins I/II (Prxs-I/II). This binding inhibits the catalytic activity of Prxs-I/II, thus activating the Ros/ERK axis and the immunogenicity of HDD toward NK cells. Robust tumor growth inhibition by PAA dependent on NK cell activation was detected in vivo.

The research data not only suggest Prxs-I/II as a promising therapeutic target for cancer immunotherapy, but also provide a compelling rationale for further development of the inhibitor PAA as a sensitizer agent for NK cell-mediated HCC immunotherapy.

A team of researchers led by Kazuhiro Suzuki from the Immunology Frontier Research Center at Osaka University discovered the COMMD3/8 complex as a molecule involved in immune cell migration, clarifying that the complex plays a critical role in the establishment of immune responses. Their research results were published in The Journal of Experimental Medicine.

Immune cells are constantly moving around in our body. Immune cell migration, which is critically important for efficient immune responses when immune cells detect intrusion of pathogens, is also deeply involved in the development of inflammatory diseases such as autoimmune diseases. The factors in the induction of immune cell migration are chemokines and chemokine receptors. Chemokine receptors, a type of G protein-coupled receptor (GPCR), mediate signal transduction and are involved in various pathologies and conditions. A large fraction of existing drugs target various GPCRs.

While exploring the mechanism of regulating immune cell migration, this team identified a protein complex consisting of copper metabolism MURR1 domain-containing 3 (COMMD3) and COMMD8, or the COMMD3/8 complex, as an adaptor that selectively recruits a specific GPCR kinase (GRK) to chemoattractant receptors.

They found that COMMD3/8 promoted signal transduction of chemokine receptors to facilitate migration of immune cells, including lymphocytes. (Figure 1)

In experiments using COMMD3/8-deficient mice, impaired migration of activated B cells, also known as B lymphocytes, significantly reduced immune responses, causing severe defects in antibody response. In addition, they found that loss of the COMMD3/8 complex reduced lymphocyte migration induced by stimulation of chemokine receptors. They also found that the COMMD3/8 complex functioned as an adaptor that selectively recruits GRK6, a signal transduction molecule, to chemoattractant receptors, inducing activation of signaling of chemokine receptors. (Figure 2)

From these findings, they clarified that the COMMD3/8 complex played an essential role in lymphocyte migration and proper functioning of the immune system. In addition, they revealed that COMMD3 and COMMD8 were degraded by the proteasome in the absence of the other, and deficiency of either protein produced the same phenotypes, which indicates that both COMMD3 and COMMD8 are required for the stability and function of their complex.

The results of their study suggest that inhibiting the function of the COMMD3/8 complex will improve conditions of autoimmune disorders and inflammatory diseases caused by overwhelming immune response. The COMMD3/8 complex will become a drug target for curing these diseases.

"Although it took a long time for us to clarify how the COMMD3/8 complex activated signal transduction of chemokine receptors, our achievement is remarkable in that a signal regulation mechanism common in chemokine receptors and many GPCRs has been clarified," says lead author Akiko Nakai.