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January 3, 2020 -- In an invited Commentary just published in JAMA Internal Medicine, Columbia Mailman School of Public Health professors Drs. Steven Stellman and Jeanne Mager Stellman offer their perspective on results from a recent study on Pyrethroid, among the most widely used insecticides in the world for public health control of vector-borne illnesses, including West Nile virus. While the insecticides are generally regarded as posing low health risks to humans in ordinary exposure situations, a recent study reported a 50 percent increase in total mortality and three-fold increase in heart disease deaths in persons with high urinary levels of 3-PBA, a metabolic product of pyrethroids indicative of human exposure.

Pyrethroid pesticides are a large family of synthetic analogues of naturally occurring pyrethrins that are also widely used in numerous consumer products. Collectively, they are the second most-used insecticides in the world, totaling thousands of kilograms and billions of dollars in U.S. sales.

According to Steven Stellman, PhD, Columbia professor pf Epidemiology, and Jeanne Stellman, PhD, professor of Health Policy and Management, this unexpected finding of increased risk of death from exposure to such a commonly used agent merits urgent follow-up.

Unlike pesticides, such as DDT and dieldrin, which can persist in adipose tissue for decades, the biomarker 3-PBA has a very short half-life, as low as 5.7 hours. The prevalence of detectable levels of a rapidly eliminated pyrethroid metabolite in a large, geographically diverse population is suggestive of chronic exposure, which also makes it important to identify specific environmental sources, note the Stellmans.

However, caution is needed in interpreting the original study published by the University of Iowa School of Public Health. First, data were available only on adults aged 20-59 years at baseline, so that the average age at the end of follow-up was approximately 57 years, which is young for assessing cardiovascular mortality effects. Other than cigarette smoking, few, if any, chemical exposures are known to trigger a 3-fold increase in the risk of death from heart disease, especially in persons younger than 60 years, suggesting that other, as yet unknown, factors may be associated with these increased risks.

Further detailed studies based on validated exposure assessment methods, including both questionnaires and biomarkers, are needed to assess these toxicological parameters. Pyrethroid pesticides are ubiquitous, and exposure is unavoidable; in New York City and elsewhere, aerial spraying for mosquito control to prevent West Nile virus and other vector-borne illnesses is largely based on pyrethroids. This study challenges the assumption that such exposures are safe.

ROCHESTER, Minn. -- Cardiorespiratory exercise -- walking briskly, running, biking and just about any other exercise that gets your heart pumping -- is good for your body, but can it also slow cognitive changes in your brain?

A study in Mayo Clinic Proceedings from the German Center for Neurodegenerative Diseases provides new evidence of an association between cardiorespiratory fitness and brain health, particularly in gray matter and total brain volume -- regions of the brain involved with cognitive decline and aging.

Brain tissue is made up of gray matter, or cell bodies, and filaments, called white matter, that extend from the cells. The volume of gray matter appears to correlate with various skills and cognitive abilities. The researchers found that increases in peak oxygen uptake were strongly associated with increased gray matter volume.

The study involved 2,013 adults from two independent cohorts in northeastern Germany. Participants were examined in phases from 1997 through 2012. Cardiorespiratory fitness was measured using peak oxygen uptake and other standards while participants used an exercise bike. MRI brain data also were analyzed.

The results suggest cardiorespiratory exercise may contribute to improved brain health and decelerate a decline in gray matter. An editorial by three Mayo Clinic experts that accompanies the Mayo Clinic Proceedings study says the results are "encouraging, intriguing and contribute to the growing literature relating to exercise and brain health."

Ronald Petersen, M.D., Ph.D., a Mayo Clinic neurologist and first author of the editorial, says the most striking feature of the study is the measured effect of exercise on brain structures involved in cognition, rather than motor function. "This provides indirect evidence that aerobic exercise can have a positive impact on cognitive function in addition to physical conditioning," he says. "Another important feature of the study is that these results may apply to older adults, as well. There is good evidence for the value of exercise in midlife, but it is encouraging that there can be positive effects on the brain in later life as well."

Dr. Petersen is the Cora Kanow Professor of Alzheimer's Disease Research and the Chester and Debbie Cadieux Director of the Mayo Clinic Alzheimer's Disease Research Center.

The study's finding of higher gray matter volume associated with cardiorespiratory exercise are in brain regions clinically relevant for cognitive changes in aging, including some involved in Alzheimer's disease. The editorial calls those associations interesting but cautions against concluding that cardiorespiratory fitness correlations would affect Alzheimer's disease.

"This is another piece of the puzzle showing physical activity and physical fitness is protective against aging-related cognitive decline," says Michael Joyner, M.D., a Mayo Clinic anesthesiologist and physiologist, and editorial co-author. "There's already good epidemiological evidence for this, as well as emerging data showing that physical activity and fitness are associated with improved brain blood vessel function. This paper is important because of the volumetric data showing an effect on brain structure."

Dr. Joyner is the Frank R. and Shari Caywood Professor at Mayo Clinic.

Long-term studies on the relationship between exercise and brain health are needed, which will be costly and logistically challenging to produce. "Nevertheless, these data are encouraging," says Clifford Jack Jr., M.D., a Mayo Clinic neuroradiologist and co-author of the editorial. "The findings regarding cardiorespiratory fitness and certain brain structures are unique."

Dr. Jack is the Alexander Family Professor of Alzheimer's Disease Research.

According to Mayo Clinic experts, moderate and regular exercise -- about 150 minutes per week -- is recommended. Good cardiorespiratory fitness also involves:

Not smoking

Following healthy eating habits

Losing weight or maintaining a healthy weight level

Managing blood pressure and avoiding hypertension

Controlling cholesterol levels

Reducing blood sugar, which over time can damage your heart and other organs

University Medicine Greifswald, Germany, also was part of the research project. Katharina Wittfeld, Ph.D., a researcher at the German Center for Neurodegenerative Disease, is first author.

Testicular cancer can be prevented from coming back using half the amount of chemotherapy that is currently used, a new clinical trial has shown.

In many men who have had surgery for an aggressive form of testicular cancer, the disease can come back elsewhere in their bodies and need intensive treatment, often within two years after initial diagnosis.

The new trial showed that giving men one cycle of chemotherapy was as effective at preventing men's testicular cancer from coming back as the two cycles used as standard.

Crucially, lowering the overall exposure to chemotherapy reduced the debilitating side effects which can have a lifelong impact on patients' health.

The 111 trial has already begun to change clinical practice, reducing the number of hospital admissions, and lowering the costs of treatment.

The trial, led by The Institute of Cancer Research, London, and University Hospitals Birmingham NHS Foundation Trust, involved nearly 250 men with early-stage testicular cancer at high risk of their cancer returning after surgery.

The research was published in the journal European Urology today (Thursday), and was funded by Cancer Research UK and the Queen Elizabeth Hospital Birmingham Charity.

Testicular cancer is the most common cancer affecting young men, with many patients being diagnosed in their twenties or thirties.

After surgery, patients are currently offered two cycles of chemotherapy to destroy any cancer cells that may have already spread, or a watch-and-wait approach - where they receive no treatment unless their cancer comes back, at which point they are given three cycles of chemo.

Survival rates are very high, but as men are diagnosed young, if they choose to have chemotherapy they may have to live with long-term side effects for many decades.

In the new study, patients were given one three-week cycle of a chemotherapy known as BEP - a combination of the drugs bleomycin, etoposide and the platinum agent cisplatin.

The researchers looked at the percentage of men whose testicular cancer returned within two years of being treated with one cycle of chemotherapy, and compared these relapse rates with established data from previous studies in patients who were given two cycles.

The researchers found that only three men - 1.3 per cent - saw their testicular cancer return after finishing treatment - a nearly identical rate to previous studies using two cycles of BEP chemotherapy.

In the new study, 41 per cent of men receiving one cycle of chemotherapy experienced one or more serious side effects while receiving treatment, such as an increased risk of infection, sepsis or vomiting. But only a small number - six patients, or 2.6 per cent - experienced long-term side effects such as damage to their hearing.

It is well established that lower chemotherapy doses are related to reduced rates of side effects, and the researchers are confident that the rates found in this study are substantially lower than those currently seen in the clinic.

Professor Robert Huddart, Professor of Urological Cancer at The Institute of Cancer Research, London, and Consultant in Urological Oncology at The Royal Marsden NHS Foundation Trust, said:

"Men with testicular cancer who are at high risk of recurrence have generally been treated with two cycles of chemotherapy - but our new study found that one cycle was enough to stop their tumour from coming back.

"Reducing the overall dose of chemotherapy could spare young men who have their whole lives ahead of them from long-term side effects, and also means they will need fewer hospital visits for their treatment.

"This new trial is already changing clinical practice on a global scale, and is set to improve patients' quality of life as well as reducing the cost of testicular cancer treatment.

"Reducing the number of cycles and the dosage of chemotherapy for testicular cancer could save the NHS money, and free up valuable hospital time and resources."

Kris Taylor, 35, from the West-Midlands, was treated as part of the 111 trial at the Queen Elizabeth Hospital Birmingham after having surgery for his testicular cancer. He said:

"I was playing football semi-professionally at the time I was diagnosed. Even though my prognosis was good, knowing that you have cancer is really scary, and the key thing for me was to get back to normality as soon as possible. I'd already had to have time off for surgery, so, when I was offered the chance to have less chemo but with no greater risk the cancer would return, I jumped at it.

"The side effects of the treatment were really difficult, but I was straight back on the pitch as soon as it finished - five years on, and I'm still fighting fit. It's great to know that others may now be able to benefit from the trial's findings. Being able to reduce the amount of chemotherapy a person receives can make such a big difference to their quality of life in both the short-term and the long-term."

Professor Emma Hall, Deputy Director of the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, said:

"We tend to be focused on whether we can cure a cancer or not, but for a disease like testicular cancer which affects young people, it is also crucial to ensure treatment does not leave patients with a lifetime of adverse effects.

"There is an important balance to be struck in giving men enough chemotherapy to stop their testicular cancer from coming back, without giving them so much that they suffer unnecessary side effects.

"Our study has found strong evidence to suggest that testicular cancer chemotherapy can be safely reduced from two cycles to just one - making their treatment shorter, kinder and cheaper."

Martin Ledwick, Cancer Research UK's head information nurse, said:

"Thanks to advances in treatments, survival for testicular cancer is very high, but the chemotherapy can cause unpleasant, sometimes lasting side effects. That's why it's such good news to see that we can cut down the amount of treatment we give.

"Providing men with a kinder treatment option linked to fewer side effects could make a huge difference to their quality of life. As more and more people survive cancer, it's essential to carry out studies like this, which look at how to improve things for people living with and after the disease."

(Boston)--While the average American woman's waist circumference and dress size has increased over the past 20 years, Victoria's Secret fashion models have become more slender, with a decrease in bust, waist, hips and dress size, though their waist to hip ratio (WHR) has remained constant.

These findings represent an ideal of beauty that continuously moves further away from the characteristics of the average American woman.

Quantifying female body attractiveness is complex. Perceived attractiveness is influenced by physical and nonphysical traits and is further guided by media exposure and sociocultural standards of the time. One of the more established parameters to evaluate female body attractiveness is the WHR, which measures body fat distribution. Interestingly, WHR has continued to be an ideal beauty trait that has stayed constant over time and cross-culterally.

In order to evaluate trends of physical body attributes, researchers from Boston University School of Medicine (BUSM) measured and compared Victoria's Secret models from 1995 to 2018. The first Victoria's Secret runway show debuted 23 years ago and since then has been viewed by millions annually, making it the most watched fashion show worldwide.

The data showed that over time, Victoria's Secret fashion models have become thinner, with smaller busts, waist, hips and dress size, whereas their WHR remained constant. "Conversely, the average American woman's waist circumference and dress size has increased and varies between a misses size 16 and 18," explained corresponding author Neelam Vashi, MD, assistant professor of dermatology at BUSM.

According to the researchers, in parallel with this trend, the percentage of women seeking cosmetic surgical procedures has dramatically increased and may be due to the desire to achieve the ideal WHR, which is a narrow waist set against fuller hips. Buttock and lower body lift has increased by 4,295 percent and 256 percent, respectively since 2000.

"Our results represent a potentially changing weight ideal of beauty that is moving farther away from the characteristics of the average American woman; however, a constant idealized WHR remains intact," added Vashi, who also is director of the Boston University Cosmetic and Laser Center at Boston Medical Center.

Supplementing the body's short chain fatty acids can improve stroke recovery, according to research in mice recently published in JNeurosci. Short chain fatty acid supplementation may be a non-invasive addition to stroke rehabilitation therapies.

The gut microbiome influences brain health, including how the brain recovers from stroke. Short chain fatty acids, a fermentation product from the bacteria in our guts, are a key component of gut health but their role in stroke recovery has not been explored.

Sadler et al. added short chain fatty acids to the drinking water of mice for four weeks before inducing a stroke. The mice that drank the fatty acid water experienced a better stroke recovery compared to the control mice, including reduced motor impairment and increased spine growth on dendrites - a crucial memory structure. Additionally, the fatty acid-supplemented mice expressed more genes related to microglia, the brain's immune cells. Microglia activity could be responsible for increasing dendritic spines and improving stroke outcome. This relationship indicates short chain fatty acids may serve as messengers in the gut-brain connection by influencing how the brain responds to injury.

Bariatric surgery is associated with a distinct reduction in skin-cancer risk, a study shows. This finding can be described as a key piece of evidence that substantiates the connection between weight loss and malignant skin cancer.

"This provides further evidence for a connection between obesity and malignant skin cancer, and for the view that we should regard obesity as a risk factor for these forms of cancer," says Magdalena Taube, the first author behind the study and a researcher in molecular and clinical medicine at Sahlgrenska Academy, University of Gothenburg, Sweden.

That obesity is a risk factor for several types of cancer is well known. The same applies to the fact that people's risk level can be lowered by means of an intentional weight reduction. However, the evidence for a connection between obesity and weight loss on the one hand and, in particular, malignant skin cancer on the other has been limited to date.

The current study, published in JAMA Dermatology, used data from what is known as the SOS (Swedish Obese Subjects) study, which is led and coordinated from the University of Gothenburg. Other data sources included the Swedish Cancer Register kept by the Swedish National Board of Health and Welfare.

The researchers studied a group of 2,007 people who underwent bariatric surgery, and compared them with a control group of 2,040 individuals. The latter also had severe obesity but were not given bariatric surgery. Otherwise, in terms of gender, age, body composition, risk factors for cardiovascular disease, and psychosocial variables, the groups were comparable.

The surgery group included 23 individuals who developed malignant skin cancer, i.e. squamous cell carcinoma or malignant melanoma, in parallel with marked weight loss. The corresponding figure for such cancer cases in the control group was 45, while this group remained at the severe obesity level. The median follow-up period was just over 18 years.

The largest difference related to malignant melanoma: 12 people in the surgery group were affected, against 29 in the control group. The results thus show a 57 percent fall in risk for malignant melanoma in the group who lost weight after bariatric surgery. The corresponding risk decrease for both cancer forms combined was 42 percent.

"In these contexts, it's a clear and striking change. And that's why it's so interesting," Taube says.

The findings support the idea that obesity is a risk factor for malignant skin cancer, including melanoma, and indicate that weight loss in individuals with obesity may reduce their risk for this severe form of cancer.

"We can say this with certainty now, thanks to our having an extremely well documented and described population that we've been able to monitor for a long time, and in which we can see very clearly what happens when a major, lasting weight loss takes place," Magdalena Taube concludes.

On a hillside above Stanford University, the SLAC National Accelerator Laboratory operates a scientific instrument nearly 2 miles long. In this giant accelerator, a stream of electrons flows through a vacuum pipe, as bursts of microwave radiation nudge the particles ever-faster forward until their velocity approaches the speed of light, creating a powerful beam that scientists from around the world use to probe the atomic and molecular structures of inorganic and biological materials.

Now, for the first time, scientists at Stanford and SLAC have created a silicon chip that can accelerate electrons - albeit at a fraction of the velocity of that massive instrument - using an infrared laser to deliver, in less than a hair's width, the sort of energy boost that takes microwaves many feet.

Writing in the Jan. 3 issue of Science, a team led by electrical engineer Jelena Vuckovic explained how they carved a nanoscale channel out of silicon, sealed it in a vacuum and sent electrons through this cavity while pulses of infrared light - to which silicon is as transparent as glass is to visible light - were transmitted by the channel walls to speed the electrons along.

The accelerator-on-a-chip demonstrated in Science is just a prototype, but Vuckovic said its design and fabrication techniques can be scaled up to deliver particle beams accelerated enough to perform cutting-edge experiments in chemistry, materials science and biological discovery that don't require the power of a massive accelerator.

"The largest accelerators are like powerful telescopes. There are only a few in the world and scientists must come to places like SLAC to use them," Vuckovic said. "We want to miniaturize accelerator technology in a way that makes it a more accessible research tool."

Team members liken their approach to the way that computing evolved from the mainframe to the smaller but still useful PC. Accelerator-on-a-chip technology could also lead to new cancer radiation therapies, said physicist Robert Byer, a co-author of the Science paper. Again, it's a matter of size. Today, medical X-ray machines fill a room and deliver a beam of radiation that's tough to focus on tumors, requiring patients to wear lead shields to minimize collateral damage.

"In this paper we begin to show how it might be possible to deliver electron beam radiation directly to a tumor, leaving healthy tissue unaffected," said Byer, who leads the Accelerator on a Chip International Program, or ACHIP, a broader effort of which this current research is a part.

Inverse design

In their paper, Vuckovic and graduate student Neil Sapra, the first author, explain how the team built a chip that fires pulses of infrared light through silicon to hit electrons at just the right moment, and just the right angle, to move them forward just a bit faster than before.

To accomplish this, they turned the design process upside down. In a traditional accelerator, like the one at SLAC, engineers generally draft a basic design, then run simulations to physically arrange the microwave bursts to deliver the greatest possible acceleration. But microwaves measure 4 inches from peak to trough, while infrared light has a wavelength one-tenth the width of a human hair. That difference explains why infrared light can accelerate electrons in such short distances compared to microwaves. But this also means that the chip's physical features must be 100,000 times smaller than the copper structures in a traditional accelerator. This demands a new approach to engineering based on silicon integrated photonics and lithography.

Vuckovic's team solved the problem using inverse design algorithms that her lab has developed. These algorithms allowed the researchers to work backward, by specifying how much light energy they wanted the chip to deliver, and tasking the software with suggesting how to build the right nanoscale structures required to bring the photons into proper contact with the flow of electrons.

"Sometimes, inverse designs can produce solutions that a human engineer might not have thought of," said R. Joel England, a SLAC staff scientist and co-author on the Science paper.

The design algorithm came up with a chip layout that seems almost otherworldly. Imagine nanoscale mesas, separated by a channel, etched out of silicon. Electrons flowing through the channel run a gantlet of silicon wires, poking through the canyon wall at strategic locations. Each time the laser pulses - which it does 100,000 times a second - a burst of photons hits a bunch of electrons, accelerating them forward. All of this occurs in less than a hair's width, on the surface of a vacuum-sealed silicon chip, made by team members at Stanford.

The researchers want to accelerate electrons to 94 percent of the speed of light, or 1 million electron volts (1MeV), to create a particle flow powerful enough for research or medical purposes. This prototype chip provides only a single stage of acceleration, and the electron flow would have to pass through around 1,000 of these stages to achieve 1MeV. But that's not as daunting at it may seem, said Vuckovic, because this prototype accelerator-on-a-chip is a fully integrated circuit. That means all of the critical functions needed to create acceleration are built right into the chip, and increasing its capabilities should be reasonably straightforward.

The researchers plan to pack a thousand stages of acceleration into roughly an inch of chip space by the end of 2020 to reach their 1MeV target. Although that would be an important milestone, such a device would still pale in power alongside the capabilities of the SLAC research accelerator, which can generate energy levels 30,000 times greater than 1MeV. But Byer believes that, just as transistors eventually replaced vacuum tubes in electronics, light-based devices will one day challenge the capabilities of microwave-driven accelerators.

Meanwhile, in anticipation of developing a 1MeV accelerator on a chip, electrical engineer Olav Solgaard, a co-author on the paper, has already begun work on a possible cancer-fighting application. Today, highly energized electrons aren't used for radiation therapy because they would burn the skin. Solgaard is working on a way to channel high-energy electrons from a chip-sized accelerator through a catheter-like vacuum tube that could be inserted below the skin, right alongside a tumor, using the particle beam to administer radiation therapy surgically.

"We can derive medical benefits from the miniaturization of accelerator technology in addition to the research applications," Solgaard said.

A study out of the University of Hyogo in Awaji, Japan, details the stress-reducing benefits to office workers that even a small plant situated within easy viewing can impart.

Masahiro Toyoda, Yuko Yokota, Marni Barnes, and Midori Kaneko explored the practical use of indoor plants to boost mental health among employees typically removed from exposure to healthy green environments.

Their findings are illustrated in their article "Potential of a Small Indoor Plant on the Desk for Reducing Office Workers' Stress" published in the open access journal HortTechnology, by the American Society for Horticultural Science.

In modern society, stress reduction in the workplace is a pressing issue. While it has been commonly assumed that plant life is soothing to those required to regularly face stressful or mundane situations, this study scientifically verifies the degree of psychological and physiological impact induced by indoor plants. Rather than conducting experiments in a laboratory setting, the researchers calculated stress reduction on employees in real office settings.

Toyoda adds, "At present, not so many people fully understand and utilize the benefit of stress recovery brought by plants in the workplace. To ameliorate such situations, we decided it essential to verify and provide scientific evidence for the stress restorative effect by nearby plants in a real office setting."

Toyoda and his team investigated changes in psychological and physiological stress before and after placing a plant on the workers' desks. Sixty-three office workers in Japan were the participants of this study. The participants were directed to take a 3-minute rest while sitting at their desks when they felt fatigue.

There were two phases of the study: a control period without plants and an intervention period when the participants were able to see and care for a small plant. The researchers measured psychological stress in the participants using the State-Trait Anxiety Inventory. The ratio of the participants whose pulse rate lowered significantly after a 3-minute rest with interaction with their desk plant proved definitive.

The objective of this study was to verify the stress-reducing effect of gazing intentionally at a plant in a real office setting when a worker felt fatigue during office hours. Each plant used in the study was chosen and cared for by the worker. Both passive and active involvement with plants in the workplace were considered for their contribution to mitigation of stress and fatigue.

Participants were provided routine visual access to plants by having their choice of plant situated conveniently on their desks (a passive involvement with plants). They also had the opportunity to care for their plant (an active involvement with plants). Furthermore, the researchers considered that intentionally gazing at the plant was, though not involving physical movement, an active interaction with plants that office workers could do quickly and easily at their desks.

Participants were offered a choice of six different types of plants to keep on their desks: air plants, bonsai plants, san pedro cactus, foliage plants, kokedama, or echeveria. Each participant chose one of the six types of small indoor plants and placed it near the PC monitor on their desk.

The calming effects calculated during the study showed that anxiety decreased significantly from pre- to post-intervention. The results did not skew when looking at the data within the various age groups of the workers or with different plant selections. The researchers suggest that placing small plants within close sight contributed to psychological stress reduction across the board.

Toyoda and his team suggest for business owners that small indoor plants could be economical and helpful in efforts improve office conditions for employees. In addition, for growers of indoor plants and business owners of retail plant companies, the field of mental health for office workers could open up a new avenue of a promising market.

Clostridium Difficile (C. diff) is a virulent health care-associated infection responsible for nearly 13,000 deaths and over $5 billion in health care related costs annually in the U.S.

Overuse of antibiotics has helped spread C. diff, one of the most difficult to treat bacterial infections.

Researchers from the Advanced Science Research Center at The Graduate Center, CUNY; Maryland School of Medicine; Institute for Bioscience and Botechnology Research; and Merck have characterized the molecular structure of the binary toxin driving some drug-resistant strains of C. diff.

The work provides a new target for effective treatment of the most dangerous strains of this life-threatening bacteria.

NEW YORK, January 2, 2020 -- A newly published paper in PNAS details a research breakthrough that provides a promising starting point for scientists to create drugs that can cure C. diff -- a virulent health care-associated infection that causes severe diarrhea, nausea, internal bleeding, and potentially death. The bacteria affects roughly half-a-million Americans and causes nearly 15,000 deaths in the U.S. annually.

Overuse of antibiotics has increasingly put patients in heath care facilities at risk for acquiring C. diff and made some strains of the bacteria particularly hard to treat. But newly discovered information about a type of toxin released by the most dangerous strains of C. diff is providing researchers with a map for developing drugs that can block the toxin and prevent the bacteria from entering human cells.

"The most dangerous strains of C. diff release a binary toxin that first binds to cells and then creates a pore-forming channel that allows the toxin to get inside and do harm," said Amedee de Georges, the study's principal investigator and a professor with the Advanced Science Research Center at The Graduate Center, CUNY's Structural Biology Iniative. "We were able to combine several increasingly popular biophysical imaging techniques to visualize and characterize every atom of this binary toxin and show us where they are positioned. These details provide a critical and extremely useful starting point for designing drugs that can prevent C. diff infection."

Researchers used a combination of tools -- cryogenic electron microscopy, X-ray crystallography, nuclear magnetic resonance, and small angle X-ray scattering -- to observe and identify the C. diff toxin's structure and mode of action. Researchers believed that it is a binary toxin (meaning it needs two components to function) that might employ a similar method to anthrax toxin to enter cells. Using that as their starting point, they sought to characterize how C. diff toxin is different than anthrax.

"We observed two similar but distinct forms of the C. diff toxin -- one where we see the pore-forming channel and one where it is invisible," said the first author, Xingjian Xu, a Graduate Center, CUNY Ph.D. student and a researcher in de Georges' lab. "This gives us clues as to how to prevent the formation of the channel and stop the bacteria from entering the cell."

Researchers also identified a novel calcium binding site on one of the C. diff toxin's domains. This type of binding structure hasn't been identified on any other similar toxins, suggesting that calcium plays a critical role in regulating the formation and transition C. diff into cells.

The study's findings will guide the design of drugs targeting C. diff infections, and specifically, the more severe C. diff bacteria strains.

The reconstitution of the blood system in humans holds great therapeutic potential to treat many disorders, like blood cancers, sickle-cell anemia and others. Successful reconstitution requires the transplantation and engraftment of hematopoietic (or blood) stem cells (HSCs), which after reaching their niche, start producing all types of blood cells, including platelets, white and red blood cells.

In current clinical practice, this is carried out by infusing HSCs obtained from a matched donor who is immunologically compatible with the patient in need (allogeneic transplantation), or by the expansion of the patient's own HSCs in the lab, and then re-infusing them back into the patient (ex-vivo, autologous transplantation). However, the utility of both routes is currently limited by a number of factors. First, in the case of allogeneic transplantation, the scarcity of matched donors significantly increases the waiting time, which could be detrimental to the patient. Second, the ex vivo expansion of HSCs, whether allogeneic or autologous, has been a challenging task, due to the limited proliferative potential these cells exhibit in culture. These limitations have raised the need for other sources of HSCs that would alleviate the need for matched donors and yield functional HSCs in large quantities.

In 2007, Professor Shinya Yamanaka and colleagues demonstrated that somatic cells, like skin fibroblasts, could be reprogrammed back to a cellular state that resembled human embryonic stem cells (hESCs), which are a group of cells found in the blastocyst-stage human embryo and contribute solely to the development of the human fetus during pregnancy. The reprogrammed cells were termed, Induced Pluripotent Stem Cells (iPSCs). In addition to their developmental potential, human ESCs and iPS cells display unlimited proliferative potential in culture, which makes them an ideal source of cells for regenerative medicine in general and for hematopoietic differentiation to obtain possibly unlimited quantities of HSCs. Therefore, there has been a growing interest to harness the potential of these cells for treating blood disorders.

However, advancement in deriving functional HSCs from human pluripotent stem cells has been slow. This has been attributed to incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, the authors discuss the latest efforts to generate HSCs capable of long-term engraftment and reconstitution of the blood system from human pluripotent stem cells. Stem cell research has witnessed milestone achievements in this area in the last couple of years, the significance of which are discussed and analyzed in detail.

The authors additionally discuss two highly important families of transcription factors in the context of hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA proteins. These are thought of as master regulators, in the sense of having numerous transcriptional targets, which upon activation, could elicit significant changes in cell identity. The authors hypothesize that precise temporal control of the levels of certain members of these families during hematopoietic differentiation could yield functional HSCs capable of long-term engraftment.

The authors conclude the review with a summary of future perspectives, in which they discuss how newly developed techniques, like the deactivated-Cas9 (dCas9) gene-expression control system, can be utilized during the course of hematopoietic differentiation of pluripotent stem cells for precise temporal control of the aforementioned master regulators to achieve functional HSCs.

WOODS HOLE, Mass. - A longstanding goal in neuroscience is to classify the brain's many cells into discrete categories according to their function. Such categories can help researchers understand the complex neural circuits that ultimately give rise to behavior and disease. However, there's little consensus about what metrics should define a cell's identity.

In a new study, a collaboration born in part from the Neural Systems & Behavior (NS&B) course at the Marine Biological Laboratory tests the notion that a cell's identity can be described solely by the genes it expresses. The study, published in Proceedings of the National Academy of Sciences, advocates a more "multimodal" approach to defining cell identity.

By using popular and powerful RNA sequencing techniques, researchers can take a snapshot of all the genes that are currently turned on inside a cell. But it's becoming increasingly clear that such strategies may be limited in their ability to give a complete picture of cell identity, or represent changes over time.

Along with their collaborators, NS&B instructors Hans Hofmann, David Schulz, and Eve Marder put two popular RNA-based methods to the test: single-cell RNA sequencing and quantitative RT-PCR. They applied these techniques to two well-studied nerve clusters in the crab Cancer borealis -- the stomatogastric and cardiac ganglia --which allowed them to compare the results from the RNA-based approaches to other known metrics of cell identity.

They found that the cell identities generated by the complete RNA profiles, or "transcriptomes," did not match the existing cell identities they had compiled over years of observation. In fact, categorizing cells based on their entire transcriptome ultimately yielded "scrambled" identities.

However, as the researchers further refined their selection of key genes to input into their analysis, the RNA profiles began to more closely resemble the identities gleaned from other attributes, such as innervation patterns, morphology, and physiology. Thus, this multimodal approach has the potential to reveal a more accurate portrayal of cell identity than RNA sequencing alone.

According to Hofmann, most studies don't bother to validate transcriptomic data with other metrics of cell identity like morphology and physiology. "Classification and characterization of cell types is often performed within the context of specific studies, and not based on a systematic approach," he says. "We really have to collect a lot of additional data, even across species, to come up with a robust taxonomy of cell types."

"RNA sequencing is tremendously promising and powerful, but this study provides a valuable and necessary check," Schulz adds. "Rather than relying entirely on analytics applied blindly to cell type, whenever possible it's important to consider multiple modalities of information as well."

The trick, Hofmann and Schulz agree, is knowing which data are indicative of cell identity, and which are simply noise that will interfere with accurate classification.

Researchers must also eventually agree on a definition of "cell identity." Drawing firm boundaries between cell types is useful in many ways, but may ultimately be problematic.

"Soon," Schulz says, "we'll start to see the limitations of trying to impose very discrete categories on the spectrum of cell types within and across individuals."

Parasites in the genus Plasmodium, which cause malaria, are transmitted to humans through bites from infected mosquitoes. The parasites manage to acclimatize to these two completely different hosts because the plasticity of their genome enables them to adapt as necessary. Scientists at the Institut Pasteur and the CNRS decided to investigate the epigenetic mechanisms behind this plasticity, in particular DNA methylation. They identified molecules capable of inhibiting DNA methylation and effectively killing even the most resistant Plasmodium falciparum parasites. The results of their research were published on November 27, 2019 in the journal ACS Central Science.

Malaria affects more than 200 million people worldwide every year, and resistance to antimalarial treatments is constantly increasing. This infectious disease is caused by Plasmodium parasites that are capable of adapting to varied environments. During the parasite's life cycle, it lives in the salivary glands of the mosquito vector before infecting the liver and then the blood of the human host. "At each stage in the cycle, epigenetic mechanisms such as histone or DNA modifications regulate the expression of the parasite's genes, enabling the specific expression of some genes in the cell at a given time so that the parasite can adapt to its environment," explains Flore Nardella, a contract researcher in the Biology of Host-Parasite Interactions laboratory (Institut Pasteur/CNRS/Inserm).

In 2019, her laboratory, led by CNRS scientist Artur Scherf, demonstrated the importance of epigenetic DNA modifications for the parasite's life cycle. The Institut Pasteur's Epigenetic Chemical Biology laboratory has unparalleled expertise in the field of DNA methyltransferase inhibitors. So it was logical for the two teams to work together to identify molecules capable of inhibiting DNA methylation and killing parasites. "Artur's team had a thorough knowledge of the epigenetic mechanisms in malaria, and we had an original chemical library with inhibitors that had already been optimized for these modifications," explains Paola B. Arimondo, a chemist, CNRS Director of Research and Head of the Epigenetic Chemical Biology Unit (Institut Pasteur/CNRS).

So the scientists decided to work on the Plasmodium falciparum parasite, especially strains of artemisinin -resistant parasites provided by the Institut Pasteur du Cambodge. In a first series of in vitro experiments, the Plasmodium falciparum parasites were allowed to interact with human red blood cells so that they could infect and develop in them. More than 70 methylation-inhibiting molecules were then tested to assess their efficacy and their specificity in relation with the parasites. "As soon as we tested the first molecules, we saw significant activity, comparable with drugs such as chloroquine," recalls Flore Nardella. "That's very rare when testing a new library of molecules." "The inhibitor molecules were very effective, and some of them killed the Plasmodium falciparum parasites in the blood in just 6 hours," adds Paola B. Arimondo.

The scientists then continued their research. In a second series of experiments, the most effective molecules were tested on resistant isolates and, once again, the results were conclusive: the molecules effectively killed the blood parasites. "This study shows, for the first time, that parasites in the blood, including artemisinin-resistant strains, can be killed rapidly by targeting DNA methylation," concludes Paola B. Arimondo. "Given the treatment failure observed in South-East Asia in particular, it is important to find new therapeutic targets. Methylation could pave the way for new drugs that, combined with artemisinin, could eliminate resistant parasites," adds Flore Nardella.

For the third stage of their work, the scientific team tested the inhibitors in vivo in mice infected with the parasite Plasmodium berghei. Once again, the approach proved successful: the treatment killed the blood parasites and the mice survived the cerebral malaria infection. The next steps for the two research teams are to continue optimizing the selectivity and efficacy of the most promising molecules (this is crucial if the molecules are to be used in humans) and to identify molecules that may act on other development stages of the parasites responsible for transmission.

Visible imagery from NASA's Aqua satellite on Dec. 31 revealed that Tropical Cyclone Calvinia had moved south of the island of Mauritius in the Southern Indian Ocean.

A tropical cyclone warning class III was still in effect in Mauritius.

On Dec. 31 at 0300 UTC (Dec. 30 at 10 p.m. EST) the Joint Typhoon Warning Center noted that Tropical Cyclone Calvinia was located near latitude 21.1 degrees south and longitude 58.0 degrees east, about 72 nautical miles south-southeast of Port Louis, Mauritius. Maximum sustained winds had increased to 60 knots (69 mph/112 kph).

Later on Dec. 31 the Moderate Resolution Imaging Spectroradiometer or MODIS instrument that flies aboard NASA's Aqua satellite provided a visible image of Calvinia that showed the storm had a well-rounded shape. The MODIS image revealed bands of thunderstorms spiraling into the tight low-level center of circulation.

Calvinia is forecast to turn to the southeast and strengthen to 65 knots.  After Jan. 1, the storm will start to become extra-tropical.

NASA-NOAA's Suomi NPP satellite provided forecasters with an image of Tropical Cyclone Sarai and it showed a much weaker storm near Tonga in the South Pacific Ocean.

Visible imagery from NASA satellites help forecasters understand if a storm is organizing or weakening. The Visible Infrared Imaging Radiometer Suite (VIIRS) instrument aboard Suomi NPP provided a visible image of Sarai on Dec. 31.

The shape of a tropical cyclone provides forecasters with an idea of its organization and strength, and NASA-NOAA's Suomi NPP satellite provided a visible image of Sarai that showed the center of circulation was surrounded by wispy clouds, while the bulk of clouds and showers were pushed to the southeast of the center from outside winds or vertical wind shear. Because the center of circulation was near Tonga, Regional warnings were still in effect for Tonga. A gale warning is in force for Vava'u, Ha'apai, Tongatapu and 'Eua land areas.

At 4 a.m. EST (0900 UTC), the Joint Typhoon Warning Center issued the final advisory on  Tropical cyclone Sarai as it weakened to a depression. Sarai was centered near latitude 20.3 degrees south and longitude 174.3 degrees west, about 259 miles west-southwest of Niue. The storm is moving to the east-northeast with maximum sustained winds 30 knots  (34.5 mph/55.5 kph).

Sarai is rapidly weakening and is dissipating under adverse atmospheric conditions.

The American coot is a somewhat drab water bird with gray and black feathers and a white beak, common in wetlands throughout North America. Coot chicks, however, sport outrageously bright orange and red feathers, skin, and beaks. A new study explains how the bright coloring of coot chicks fits in with the reproductive strategy of their less colorful parents.

Previous research had shown that coot parents preferentially feed the brightly ornamented chicks over those whose plumage has been manipulated to be less colorful, giving the ornamented chicks a survival advantage. This parental preference within families can drive the evolution of ornamentation in the offspring, just as female mate choice can result in ornamented males in the context of sexual selection (peacocks being the classic example of that).

Left unresolved by the earlier research, however, was why coot parents would have a preference for ornamented chicks in the first place, and whose fitness interests are served by the ornamentation, said Bruce Lyon, professor of ecology and evolutionary biology at UC Santa Cruz and first author of the new study, published December 30 in Proceedings of the National Academy of Sciences.

"It's an interesting question, because there are theories about conflicts of interest between parents and offspring suggesting that it could be the chick manipulating the parents to get more food," Lyon said. "Having shown that the parents really care about the ornamentation, we focused in this study on the natural variation in chick coloring."

At their field sites in British Columbia, Lyon and coauthor Daizaburo Shizuka from the University of Nebraska-Lincoln were already conducting studies that involved collecting eggs from coot nests and hatching them indoors. Using a photospectrometer, they were able to get precise color measurements of almost 1,500 coot chicks. For every chick, they knew the family it came from, the egg laying and hatching order, and in many cases whether or not it was a parasitic egg.

Lyon has spent years studying birds that lay eggs in the nests of other birds. Called brood parasitism, this practice is rampant among coots, with most females laying some eggs in the nests of other coots in addition to laying a clutch in their own nest.

"We thought the parasitic chicks might be more colorful to gain an advantage," Lyon said. "Instead, we found that the parasites are actually less colorful. That was a bit of a shock."

A key finding came from looking at the chicks' coloring in relation to the order in which they hatched. Coots lay about ten eggs, one per day, and the eggs hatch in the order in which they were laid. It turns out that the later a chick hatches the more colorful it is.

"That tells us the chicks can't be controlling their coloration, because they don't know where they are in the laying order. This is a maternal effect, presumably due to the mom putting more carotenoid pigments in the later eggs," Lyon said.

So why would coot mothers want to mark their chicks in this way? The answer has to do with the American coot's brutally harsh reproductive strategy. Coots lay a lot of relatively small eggs, producing more chicks than the food supply can support in most years. As a result, chick mortality is extremely high, with about half of each brood dying of starvation.

"It's very efficient for coots, because their eggs are not very costly to produce. By laying an optimistic clutch size and then culling the brood to bring it in line with the food supply, they're always raising as many chicks as they can," Lyon said.

The culling takes place mostly during the first ten days after the eggs hatch, when the parents do not show any feeding preferences and feed whichever chick reaches them first when they have food. The first chicks to hatch get a head start on growth, so most of the mortality is among the later hatched chicks.

Everything changes, though, at about ten days after the last chick hatches. At that point, the parents start controlling food allocation to make sure the remaining runts in the brood get enough food to survive. Each parent chooses a favorite who gets preferential feeding, and these favored chicks are the most colorful, later-hatched chicks. Their larger, early-hatched siblings, meanwhile, endure a form of parental aggression called tousling (shaking them by the back of the neck) to keep them from hogging too much food. The favored chicks are initially much smaller than their siblings, but the extra feeding allows them to catch up and sometimes exceed the others in body mass.

"The male and female divide up the brood, with each parent exclusively feeding their half of the brood, and each parent also picks a favorite. Color predicts which one they choose, so the ornamentation may serve as a signal to tell them which chick needs the most help," Lyon explained. "They start by creating an uneven playing field, which allows them to cull the brood, and then they intervene to level the field. The orange plumage seems to be a feature that helps them do that."

The effect of laying order on coloring also explains why the parasitic eggs are less colorful. The eggs a female lays in a stranger's nest are the first ones in her laying sequence, so they get the least pigment. The parasitic egg-laying behavior is opportunistic, so the female may not know when she's forming an egg whether she will be laying it in her own nest or someone else's.

"They're complicated birds. For over 20 years, we've been chipping away at understanding their reproductive behavior, and this is another interesting aspect of that," Lyon said. Lyon described parental preferences for ornamented chicks in a 1994 Nature paper, and he and Shizuka described coot parents' food allocation strategies in a 2013 Ecology Letters paper.