Culture

CHAMPAIGN, Ill. -- Artificial sweeteners such as sucralose provide the seductive taste of sweetness without the calories contained in sugar - a seeming win-win for people who need to control their blood sugar and insulin levels or weight.

However, simply tasting or consuming sucralose may affect blood glucose and insulin levels on glucose tolerance tests, scientists at the University of Illinois found in a new study.

The findings suggest that despite having no calories, sucralose may have metabolic effects in some users, said M. Yanina Pepino, a professor of food science and human nutrition at the U. of I., who led the research.

"The most important take-home message is that sweet taste in itself may have an impact on carbohydrate metabolism and glucose control," Pepino said. "Even though the sample population in our study was small, the findings add to a body of evidence that suggests sweetness should be consumed in moderation, regardless of the calories."

The study included 10 people of healthy weight and 11 people with obesity; none of the participants had diabetes or were regular users of artificial sweeteners.

The participants underwent three oral glucose tolerance tests on separate days spaced about a week apart. Prior to one test they consumed distilled water; prior to another, sucralose; and prior to a third test they tasted but did not swallow sucralose.

They performed one of these actions 10 minutes before drinking a solution containing 75 grams of glucose.

The amount of sucralose - 48 milligrams - that the study participants ingested provides a level of sweetness equivalent to that in a typical diet soda, Pepino said.

At each visit, a catheter was inserted into a radial artery to obtain blood samples at regular intervals during the hour before and five hours after the participants drank the glucose. The scientists measured participants' blood concentrations of sucralose, insulin, glucose and other hormones.

Sucralose had differing effects depending on whether participants ingested it or only tasted it and whether they had obesity, the researchers found.

When people of healthy weight swallowed the sucralose, their blood insulin levels decreased modestly during the first hour, and their insulin sensitivity increased by about 50%, said graduate student Clara Salame, who co-wrote the study.

However, when people with obesity swallowed the sucralose, their insulin levels increased significantly more than when they drank water or when they tasted the sucralose but spit it out.

"While insulin responses to either tasting or swallowing the sucralose were similar in those of normal weight, those responses were very different in people with obesity," Pepino said. "Therefore, we hypothesize that some post-ingestive effects of sucralose may occur only in people with obesity.

"However, our study included people who were not habitual consumers of artificial sweeteners, and further studies are needed to explore what happens with this acute effect of sucralose after long-term use."

Pepino cautioned that since the various artificial sweeteners have very different chemical structures and the body may handle them differently - some are broken down in the stomach while others remain unabsorbed in the intestine - the findings on post-ingestive effects may be unique to sucralose.

However, since all artificial sweeteners activate the sweet taste receptors in the mouth, the metabolic effects associated with sweetness may be more generalizable, she said.

Pepino said she had expected that tasting sucralose and spitting it out would have similar effects to consuming water; thus, she was surprised to discover that participants' insulin levels were affected by taste alone.

"Interestingly, we found that in both groups of people - those with obesity and those of normal weight - there was a reduction in insulin response to the glucose tolerance test when they just tasted sweetness before drinking the glucose solution. It was the most surprising finding, and we are following up on that in a new study," Pepino said.

"What our data suggest is that there are mechanisms that we don't understand clearly about how the human body regulates glucose and the potential metabolic effects of tasting something sweet beyond providing a sense of pleasure," Pepino said.

On January 24, 2020, the French Ministry of Health confirmed the first three cases of patients affected by the Wuhan coronavirus. On January 29, 2020, the Institut Pasteur, which is responsible for monitoring respiratory viruses in France, sequenced the whole genome of the coronavirus known as "2019-nCoV", becoming the first institution in Europe to sequence the virus since the start of the outbreak. The virus was sequenced at the Institut Pasteur's Mutualized Platform for Microbiology (P2M), which performs genome sequencing on bacterial, viral, fungal and parasite strains received by National Reference Centers and World Health Organization Collaborating Centers for the purpose of infectious disease surveillance.

In December 2019, an outbreak of apparently viral pneumonia of unknown etiology emerged in the city of Wuhan, in the Chinese province of Hubei.

On January 9, 2020, the Chinese health authorities and the World Health Organization (WHO) announced the discovery of a novel coronavirus, known as 2019-nCoV, which was confirmed as the agent responsible for the pneumonia cases (see the Institut Pasteur's fact sheet on the "Wuhan coronavirus" - page in French).

Over the weekend of January 11-12, the Chinese authorities shared the full sequence of the coronavirus genome, as detected in samples taken from the first patients. "Sequencing the genome of pathogens is crucial for the development of specific diagnostic tests and the identification of potential treatment options," explains Sylvie van der Werf, Director of the National Reference Center (CNR) for Respiratory Viruses at the Institut Pasteur.

Friday January 24, 2020. Detection of the virus confirmed in France

On Friday January 24, late in the morning, the Institut Pasteur received samples of three suspected cases (two patients in Paris and one in Bordeaux). "Using the samples taken from these patients, we detected the novel coronavirus," says Sylvie Behillil, Deputy Director of the CNR at the Institut Pasteur.

From Friday January 24, 2020. Viral genome sequenced at the Institut Pasteur

That same Friday evening, scientists launched the process of sequencing the viral genome based on the samples. The CNR prepared the material for sequencing, ready for P2M to begin work immediately the following Monday. The sequencing run was completed by early evening on the Tuesday, and the scientists used data analysis to obtain the sequence of the whole genome in two of the first three confirmed cases in France. "This proves the efficacy of the CNR's process of analysis based on viral sequencing," continues Vincent Enouf.

Thursday January 30, 2020. The Institut Pasteur obtains and shares the whole sequence of the virus

The P2M platform (see inset below) currently performs at an extremely high level; the average time taken to produce sequences ranges from three days (for emergencies) to a maximum of ten days. In this case, it took just three days for the whole sequence to be determined: "We performed data analysis during the night from Tuesday to Wednesday, then corroborated the results on Wednesday with counter analysis," explains Vincent Enouf. "The whole sequence was confirmed in just three days."

What can we learn from it? "The sequences were identical in all our samples. One member of the couple must have contaminated the other, as the virus is the same." The two full sequences of the virus isolated in two of the first French cases were submitted to the Global Initiative on Sharing All Influenza Data (GISAID) platform,1 which was initially developed to share sequences and monitor the genetic evolution of influenza viruses, a process that is vital to determine the composition of the influenza vaccine. A special "coronavirus" tab has been created so that the scientific community can work together and advance at a quicker pace.

"Around twenty other sequences of the novel coronavirus genome have been obtained worldwide, and if we compare them with ours, we can see that they are all very close; there is not much diversity in the viruses analyzed, which suggests that coronavirus 2019-nCoV did not need to mutate in order to adapt and spread," continues Vincent Enouf.

The National Reference Center (CNR) for Respiratory Viruses at the Institut Pasteur in Paris is one of WHO's reference laboratories for coronavirus 2019-nCoV.

A total of eight people from the CNR and two from the P2M sequencing platform have been working on the virus this week and will continue to monitor the outbreak in France.

P2M, a state-of-the-art mutualized platform for microbiology also open to external CNRs

P2M is also available to external CNRs for sequencing. In 2019 it worked with four CNRs based outside the Institut Pasteur. The platform sequences bacteria, viruses, parasites and fungi. Thanks to experience gained over the past five years (since 2015), P2M today offers a highly efficient service, as shown by a first-pass success rate (i.e. a high-quality sequence providing comprehensive information on the entire genome) of more than 95% in 2019. Sequence production takes between three days (for emergencies) and ten days at most.

In 2019, P2M sequenced around 25,000 pathogens. Genome sequencing increases the sensitivity threshold for outbreak detection. Early identification of outbreaks by the Institut Pasteur's scientists (clustered cases in a short space of time caused by the same pathogen) enables epidemiologists to get to work immediately to determine the origins of the outbreak, and the authorities to coordinate the public health response.

Simple sequence repeats (SSRs) are regions of DNA with high diversity, and they have long been a mainstay for botanists examining the genetic structure of plant populations. However, as the cost of sequencing DNA continues to plummet and genetic technologies advance, newer techniques for mapping genetic diversity such as genotyping-by-sequencing (GBS) or RAD-seq have begun to rival the traditional use of SSRs. In research presented in a recent issue of Applications in Plant Sciences, Dr. Mark Chapman optimized the process of identifying SSRs from genomic and transcriptomic data, helping to assure the continued use and relevance of SSRs in the age of high-throughput sequencing (HTS).

Sequence data generated using HTS can be used to identify candidate SSRs, for which researchers can design primers to examine genetic structure in a species. However, little work has been done to calibrate or optimize this process, both in terms of guidelines for reasonable parameters to specify, or what kind or depth of sequencing may be sufficient and appropriate to identify a workable set of SSRs.

"I've used transcriptome data for over a decade to generate molecular markers and have often wondered whether using genomes or transcriptomes would be preferable," said Dr. Chapman, Associate Professor in Ecology and Evolutionary Biology at the University of Southampton. This study found that each data source had its benefits; genomic data may be preferable in species with low polymorphism, but transcriptomic data usually assembles into longer sequences more amenable to designing primers, and these primers may be more transferable across species.

"In addition, I always generate thousands of markers and only use a dozen or so, so I've always wondered what depth of sequencing would one have to generate to be sure of identifying a small number of markers for a basic population genetic study," said Dr. Chapman.

Researchers on a budget may look to generate the minimum necessary sequence data for SSR identification. Now these researchers have some guidance as to how many reads are sufficient: this study found that small assemblies of two million read pairs could generate about 200-2000 potential markers from the genome assemblies and about 600-3650 from the transcriptome assemblies.

As the cost of sequencing falls below the cost of labor for sample preparation, researchers are increasingly using newer techniques such as GBS and RAD-seq to map genetic diversity in populations. However, Dr. Chapman still sees a place for SSRs in the future of population genetics research. "SSRs have advantages over those other technologies that are unlikely to change even if costs go down, for example, the SSRs can be designed from specific genes of interest," said Dr. Chapman. "Also GBS and RAD-seq aren't really being explored for polyploids, whereas SSR scoring in polyploids can be done, with a bit of background information or careful design of primers. The untailored approach of GBS and RAD-seq is likely to resolve a lot of unscorable alleles in polyploids."

SSRs are a relatively inexpensive and efficient way to map genetic diversity in populations. The deluge of genetic data available from HTS can help to efficiently identify sets of SSRs, but until now there have not been clear guidelines for researchers seeking to do this work. In optimizing protocols and laying out major considerations in generating SSRs from genomic and transcriptomic data, Dr. Chapman has helped to bring SSR studies up to date.

As well as sequencing the whole genome of coronavirus 2019-nCoV, the Institut Pasteur continued to work on the samples taken from the first confirmed cases. The quality of these initial samples enabled rapid cell-culture isolation of the new virus. The Institut Pasteur's scientists now have access to the virus responsible for the infection. The isolation of the virus paves the way for new diagnostic, therapeutic and prophylactic approaches.

With the whole viral genome of coronavirus 2019-nCoV having recently been sequenced at the Institut Pasteur, the isolation of strains of coronavirus 2019-nCoV detected in France has now been successfully finalized, in a very short space of time, using the samples taken from the first confirmed French cases.

Coronavirus 2019-nCoV, responsible for the cases of pneumonia that emerged in China (see the Institut Pasteur's fact sheet on the Wuhan coronavirus - page in French), differs from two other viruses that are well known for causing respiratory outbreaks in recent years: the SARS-CoV virus, responsible for the SARS outbreak in 2003, and MERS-CoV, responsible for an outbreak that has been under way since 2012 in the Middle East.

The Institut Pasteur was actively involved in tackling these previous outbreaks, which yielded valuable lessons for the current situation. "For both SARS-CoV and MERS-CoV, cells known as Vero E6 were identified to culture the two coronaviruses," explains Sylvie van der Werf, Director of the National Reference Center (CNR) for Respiratory Viruses at the Institut Pasteur. "In January 2020, we brought them out of our collection, which is kept under strictly controlled conditions, so that we would be ready as soon as we detected a positive sample for coronavirus 2019-nCoV."

Extremely rapid growth of the virus in culture

The Institut Pasteur was therefore well prepared, and on Friday January 24, 2020, the very day that the first cases were confirmed, it began the process of culturing the samples that had tested positive for the virus on Vero E6 cells. "Using detection methods, we had observed a high viral load in the samples taken from the patients in hospital in Paris. This enabled us to identify which samples should be cultured first," says Sylvie Behillil, Deputy Director of the CNR at the Institut Pasteur.

The viruses continued to be cultured over the weekend of January 25-26, 2020. By the morning of Monday January 27, the culture had already grown! "We didn't think that it would grow so quickly," continues Sylvie Behillil. The rapid growth of the culture may be explained by "the high viral load in the samples," but also by "the quality of the samples," adds Vincent Enouf, Deputy Director of the CNR at the Institut Pasteur.

"We could see the cells becoming damaged and then grouping together, which can indicate that they have been infected. But we did not observe this cytopathic effect for all the inoculated samples; that reassured us that we had managed to isolate the strains, and this was then confirmed by additional analyses."

Virus 2019-nCoV now available for research

Now that the Institut Pasteur's scientists have access to coronavirus 2019-nCoV, they can set out to improve scientific knowledge about the virus.

Research will focus on four main areas.

Serology. Analyzing antigen-antibody reactions based on the antibodies found in patients' blood serum, and developing an effective serology test to screen for the infection among the population.NB: This is not a rapid diagnostic test for hospital use; it is a test to identify seroconversion in the population.

Development of specific treatments. Testing known antiviral molecules that act on the replication cycle of some viruses to assess their therapeutic or even prophylactic potential, and looking for antibodies that may have therapeutic applications.

Vaccination. Based on the virus, developing vaccine approaches that have already been explored for other viruses – Ebola, MERS-CoV and SARS-CoV –, with the aim of proposing a vaccine candidate.

Viral pathogenesis. Understanding how the virus works, how it replicates and interacts with the cell and the host organism, to gain a clearer picture of its pathogenic nature and identify biomarkers for infection or new targets for the development of treatments.

Studies have shown a rapid increase in new cases of type 1 diabetes worldwide. However, scientists and researchers have struggled to identify a direct cause. Many have questioned if changes in the environment or lifestyle have impacted the disease. In a newly released review paper published in The Lancet Diabetes & Endocrinology, faculty from the Colorado School of Public Health at the Anschutz Medical Campus examined whether any environmental exposures can explain why type 1 diabetes is on the rise.

"The incidence of type 1 diabetes has increased 3 percent per year over the past three decades. This increase is too rapid to be due to genetic factors, suggesting that environmental factors may play a role," said Jill Norris, MPH, PhD, professor and chair of epidemiology at the Colorado School of Public Health and lead author of the paper.

Identifying environmental factors associated with type 1 diabetes that influence its incidence can inform future preventive trials and searches for other environmental risk factors. In this paper, researchers reviewed the literature on environmental factors like air pollution, diet, childhood obesity, the duration of breastfeeding, the introduction of cow's milk, infections, and many others that showcase an impact on type 1 diabetes.

The researchers then looked at prevalence of an exposure over time while varying its annual increase under simulated scenarios. Using the simulated data, the research showed that if a single factor were to explain the changes in the incidence of type 1 diabetes over the past few decades, it would have to be very strongly associated with the risk of type 1 diabetes.

The simulated scenarios showed that an environmental factor that increased at a constant rate from nearly absent in the population to nearly ubiquitous would have to confer a relative risk of 5 to explain an approximately 3 percent annual increase in the incidence of type 1 diabetes. However, most of the environmental factors reviewed had a relative risk of less than 2.

"While several factors have been associated with type 1 diabetes, none of the associations are of a magnitude that can explain the rapid increase in incidence alone," Norris said. "Moreover, evidence of the changing prevalence of these same exposures over time is not convincing nor consistent."

The paper explains that more research is required, and it is possible that multiple factors simultaneously may account for the increase in type 1 diabetes cases. Other factors are that the magnitude of observed associations may have been underestimated due to exposure measurement error or mismodeling of complex exposure-time-response relationships.

The study concludes that the identification of environmental factors influencing type 1 diabetes risk and increased understanding of the etiology at the individual level, regardless of the ability to explain the changing incidence at the population level, is important because of the implications for prevention.

Therapeutic horseback riding combined with brain-building exercises can improve the dexterity, coordination and strength of children with neurodevelopmental disorders, shows a study in Frontiers in Veterinary Science.

Neurodevelopmental disorders - such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) - affect as many as one in six American children. Physical activity is known to benefit these patients in a variety of ways, but this is the first study showing the short and long-term effects of a program combining horseback riding and cognitive training.

"We wanted to investigate how a combination of equine-assisted activities and various brain-building tasks, administered by a speech therapist, would affect motor skills in children with disorders including autism spectrum disorder and attention deficit hyperactivity," says Dr. Brandon Rigby, of the Texas Woman's University in the United States.

"Our findings should be helpful to therapists and other healthcare professionals who are tasked with implementing strategies and interventions to improve motor skill proficiency in children and youth with ADHD and ASD, which were the most common diagnoses in our study."

For their study, Rigby and his collaborators recruited 25 children with neurodevelopmental disorders between the ages of 5 and 16. Each child completed one of several different programs ranging in length from eight weeks to one year. The programs included weekly introductory horseback riding, as well as sessions with a speech therapist two to three times per week.

During the horseback riding, the children learned about horse anatomy, riding equipment, and the basics of riding. The brain-building activities focused on exercises that train the brain to process sensory information such as sound, sight, balance and spatial orientation. These sessions included music therapy, eye tracking exercises and hand-eye coordination tasks. The children and their parents were also given daily exercises that they could perform at home.

After eight weeks of the program, the children showed improved motor skills, although there was sometimes a delay before the changes became apparent. For the participants that continued the program for one year, these benefits continued for the duration of the study. These participants also showed improvements in their behavior and academic performance, including social and communication skills. Additionally, anecdotal responses from parents and caregivers suggested that the children were more positive, focused and calm both in and outside of the program.

Given the small size of the study, larger-scale research is still needed to better understand the potential benefits to the range of neurodevelopmental disorders. Some limitations include the varying diagnoses of the participants (as opposed to looking at benefits per ADHD or autism specifically), and the allowance to continue prescribed medications or therapies outside the scope of this program. Despite this, the program's results are promising, and the researchers hope that this will inspire further interest in cross-disciplinary programs.

"These findings may allow for a greater demand for these programs, ultimately making them more accessible and affordable," says Rigby.

Unlike what we commonly refer to as 'genes', these phantom genes or 'Long noncoding RNA' (LncRNAs) do not lead to the production of proteins that our cells, and thus our entire bodies are made of.

Previously, it was believed that LncRNAs served no major purpose in cells, but new research now shows that one of these LncRNAs termed 'LincIRS2' is important for safeguarding our metabolism as LincIRS2 loss favors development of metabolic complications in mice.

In my estimate, only the function of less than 100 of the nearly 60,000 LncRNAs encoded in our genomes has been truly understood says Jan-Wilhelm Kornfeld, Danish Diabetes Academy (DDA) professor for Molecular Biology of Metabolic Diseases at University of Southern Denmark.

In clear comparison, researchers have largely understood the function of the 20,344 genes that encode proteins.

That's why it's so exciting that we were able to identify the key role of this particular LncRNA using mice as a model organism, he says.

In addition, we were able to delineate a new, exciting mechanisms for how LncRNAs themselves are controlled.

Editing mice with CRISPR

Using the 'molecular scissor' CRISPR/Cas9, Jan-Wilhelm Kornfelds research team succeeded in cutting out LincIRS2 from the mouse's genome. Next, the researchers observed that mice lacking LincIRS2 developed metabolic complications like elevated blood sugar levels when the LncRNA had been deactivated. Conversely, when performing treatments that activate LincIRS2, mice maintained healthy blood sugar levels even when becoming obese.

It is difficult to predict exactly how this new knowledge can be used, but it is intriguing to speculate that restoring or inhibiting specific LncRNAs could be used to treat diabetic patients or other metabolic disorders one day, says Jan-Wilhelm Kornfeld.

His research team just published these new findings in the prestigious journal Nature Communications. The lead author of the article is Dr. Marta Pradas-Juni, who is a postdoc in Jan-Wilhelm Kornfelds' research team.

Fact: What is a Long noncoding RNA?

DNA serves as blueprint for producing proteins that constitute the essential building blocks all cells are made of. The molecular intermediary that converts DNA information into proteins is called RNA. Thus, RNA's primary purpose is to translate the 'genes' DNA into protein.

In our bodies, 20,344 different genes are specifically designed to create the many different proteins that our bodies require. The majority of these so-called protein-coding RNAs have been mapped by scientists. That is why, we today largely understand exactly which proteins these RNAs give rise to.

However, nearly 60,000 RNAs called 'Long noncoding RNAs' are written into our genomes that never contribute to the formation of a protein. How they function, and how they are involved in disease development is largely unknown.

PITTSBURGH (Jan. 31, 2020) ... Let's talk about slime.

Mucus is a protective, slimy secretion produced by goblet cells and which lines organs of the respiratory, digestive, and reproductive systems. Slime production is essential to health, and an imbalance can be life-threatening. Patients with diseases such as asthma, chronic obstructive pulmonary disease (COPD), and ulcerative colitis produce too much mucus, often after growing too many goblet cells. Loss of goblet cells can be equally devastating - for instance during cancer, after infection, or injury. The balance of slime creation, amount, and transport is critical, so doctors and medical researchers have long sought the origins of goblet cells and have been eager to control processes that regenerate them and maintain balanced populations.

Recently, a group of bioengineers at the University of Pittsburgh discovered a case of goblet cell regeneration that is both easily accessible and happens incredibly fast on cells isolated from early developing frog embryos. Their findings were published this week in the journal Nature Communications (DOI: 10.1038/s41467-020-14385-y).

Lance Davidson, William Kepler Whiteford Professor of Bioengineering at Pitt, leads the MechMorpho Lab in the Swanson School of Engineering where his researchers study the role of mechanics in human cells as well as the Xenopus embryo - an aquatic frog native to South Africa.

"The Xenopus tadpole, like many frogs, has a respiratory skin that can exchange oxygen and perform tasks similar to a human lung," explained Davidson. "Like the human lung, the surface of the Xenopus respiratory skin is a mucociliated epithelium, which is a tissue formed from goblet cells and ciliated cells that also protects the larva against pathogens. Because of these evolutionary similarities, our group uses frog embryonic organoids to examine how tissue mechanics impact cell growth and tissue formation."

Studying this species is a rapid and cost-effective way to explore the genetic origins of biomechanics and how mechanical cues are sensed, not just in the frog embryo, but universally. When clinicians study cancer in patients, such changes can take weeks, months, or even years, but in a frog embryo, changes happen within hours.

"In this project, we took a group of mesenchymal cells out of the early embryo and formed them into a spherical aggregate, and within five hours, they began to change," Davidson said. "These cells are known to differentiate into a variety of types, but in this scenario, we discovered that they changed very dramatically into a type of cell that they would not have changed into had they been in the embryo."

The lab surprisingly uncovered a case of regeneration that restores a mucociliated epithelium from mesenchymal cells. They performed the experiment multiple times to confirm the unexpected findings and began to look closely at what microenvironmental cues could drive cells into an entirely new type.

"We have tools to modulate the mechanical microenvironment that houses the cells, and to our surprise, we found that if we made the environment stiffer, the aggregates changed into these epithelial cells," explained Davidson. "If we made it softer, we were able to block them from changing. This finding shows that mechanics alone can cause important changes in the cells, and that is a remarkable thing."

Davidson's group is interested in how cells, influenced by mechanics, may affect disease states. The results detailed in this article may drive new questions in cancer biology, prompting researchers to consider whether certain kinds of invasive cancer cells might revert to a resting cell type based on the stiffness or softness of their surroundings.

"When applying these results to cancer biology, one might ask, 'If tumors are surrounded by soft tissues, would they become dormant and basically non-invasive?' Or, 'If you have them in stiff tissues, would they invade and become deadly?'" said Davidson. "These are major questions in the field that biomechanics may be able to help answer. Many researchers focus solely on the chemical pathways, but we are also finding mechanical influencers of disease."

Hye Young Kim, research fellow at the Korea Advanced Institute of Science and Technology (KAIST) and former member of the MechMorpho Lab, will continue this work at the Center for Vascular Research at KAIST's Institute for Basic Science. She will study how cell motility changes during regeneration and how epithelial cells assemble a new epithelium. Davidson and his lab will explore how this novel case of mechanical cues are sensed by mesenchymal cells and how these mechanical induction pathways are integrated with known pathways that control cell fate choices.

"Frog embryos and organoids give us unparalleled access to study these processes, far more access than is possible with human organs," he said. "The old ideas that regeneration is controlled exclusively by diffusing growth factors and hormones is giving way to the recognition that the physical mechanics of the environment - such as how rubbery or fluid the environment - play just as critical a role."

The circadian clock system (from Latin "circa diem", about a day) allows the organisms to anticipate periodical changes of geophysical time, and to adjust to these changes. Nearly all the cells in our body comprise molecular clocks that regulate and synchronize metabolic functions to a 24-hour cycle of day-night changes. Today, increasing evidence show that disturbances in our internal clocks stemming from frequent time zone changes, irregular working schedules or ageing, have a significant impact on the development of metabolic diseases in human beings, including type-2 diabetes. Such disturbances seem to prevent the proper functioning of the cells in the pancreatic islet that secrete insulin and glucagon, the hormones that regulate blood sugar levels. By comparing the pancreatic cells of type 2 diabetic human donors with those of healthy people, researchers at the University of Geneva (UNIGE) and at the University Hospitals of Geneva (HUG), Switzerland, were able to demonstrate, for the first time, that the pancreatic islet cells derived from the Type 2 Diabetic human donors bear compromised circadian oscillators. The disruption of the circadian clocks was concomitant with the perturbation of hormone secretion. Moreover, using clock modulator molecule dubbed Nobiletin, extracted from lemon peel, the researchers succeeded in "repairing" the disrupted cellular clocks and in partial restoring of the islet cell function. These results, published in the Proceedings of the National Academy of Sciences of the United States, provide a first insight into innovative approach for diabetes care.

Two years ago, the team led by Charna Dibner, Principle Investigator in the Departments of Medicine and of Cell Physiology and Metabolism, and Diabetes Centre at UNIGE Faculty of Medicine, and at HUG, has already shown that in rodents the perturbation of pancreatic cellular clocks led to disrupted insulin and glucagon secretion, thus promoting the onset of diabetes. But what is the situation in human beings? "We had also previously observed that if the clocks of human pancreatic cells were artificially disrupted in the cellular culture in vitro, secretion of the key islet hormones - insulin and glucagon - was compromised,» says Volodymyr Petrenko, a researcher in Dr. Dibner's lab and the first author of these publications. Hence our next step, that we report here, was to unravel whether the circadian rhythms were perturbed in human pancreatic islets in type 2 diabetes, and, if so, how would this perturbation affect the islet function."

Using combined bioluminescence-fluorescence time-lapse microscopy, a technology that allows tracking the molecular clock activity in living cells very precisely over time, the scientists compared the behaviour of pancreatic cell of type-2 diabetic donors and those of healthy subjects throughout the day. "The verdict is indisputable", says Charna Dibner. The biological rhythms of the islet cells in type-2 diabetes exhibit both reduced amplitudes of circadian oscillations and poor synchronization capacity. &laquoAs a result, hormone secretion is no longer coordinated. Moreover, the defects in temporal coordination of insulin and glucagon secretion observed in patients with type-2 diabetes were comparable to those measured in healthy islet cells with artificially-disrupted circadian clock."

It's all in the timing!

Circadian clocks represent the daily cycles governing the various cellular functions. There are several interlocking levels of synchronization of these clocks, the main one being light, which in particular regulates the central clock located in the cerebral hypothalamus. Like a conductor in the orchestra, it regulates peripheral clocks present in organs and cells. The latter are therefore partly centrally regulated, but function differently in each organ, and even in each cell, depending on their functions. "Pancreatic cells are also subject to the rhythm of fasting and food intake, and to a tight hormonal regulation", says Charna Dibner. "Coordinating all levels of regulation therefore allows the optimization of metabolic functions. Clocks deregulation in pancreatic islet leads to a compromised function: they are not anymore anticipating food-derived signals. Indeed, if you eat the same food but at night rather than during the day, you may gain weight much faster, due to a suboptimal response of your metabolism."

Setting the right time again

Step two of their research: the Geneva scientists used Nobiletin, a small clock modulator molecule - a natural ingredient of lemon peel whose impact on circadian clocks has been recently discovered - in order to resynchronize the clocks. "By acting on one of the core-clock components, it resets efficiently the amplitude of the oscillations in the human islets" says Volodymyr Petrenko. "And as soon as we got the clocks back in sync, we also observed an improvement in insulin secretion."

"This is the first proof of principle that repairing compromised circadian clocks may help improving the function of the pancreatic islet hormone secretion", says Charna Dibner. "We will continue by exploring this repair mechanism in vivo, first in animal models. Our society experiences epidemic growth in metabolic diseases, concomitant with shifted working and eating schedules, and lack of sleep. By re-synchronizing the perturbed molecular clocks, either by personalized eating and exercise schedules or with the help of clock modulator molecules, we hope to ultimately be able to provide an innovative solution to an epidemical metabolic problem affecting an ever-increasing proportion of the world's population. ."

Physicists believe that in the Universe's first ten microseconds free quarks and gluons filled all of spacetime, forming a new phase of matter named 'quark-gluon plasma' (QGP). Experimental and theoretical work at CERN was instrumental in the discovery of this hot soup of primordial matter, which is recreated today in accelerator-based lab experiments. To discover QGP in such experiments, the observation of exotic 'strange' quarks is very important. If QGP is created, strangeness is readily produced through collisions between gluons. In analysis published in EPJ ST, Dr Johann Rafelski from The University of Arizona, United States, also working at CERN, presents how our understanding of this characteristic strangeness production signature has evolved over the span of his long career.

Using the style of a 'personal diary', Rafelski firstly reviews and summarises decades of work. Describing leading experimental and theoretical contributions, he recounts how and why strange quarks are produced so efficiently in QGP, and how this behaviour has been exploited for QGP discovery. He also explores strangeness as a tool in the search and discovery of this primordial phase of matter; existent at unimaginably high temperatures and pressures. He then follows the line of research through to the ongoing experimental ultra-high-energy experiments involving head-on collisions between both heavy nuclei and lighter protons, carried out at CERN's Large Hadron Collider (LHC).

Secondly, Rafelski follows the narrative with a commented set of his own unpublished work, focusing on pioneering theories and QGP discovery. He also includes a selection from the comments of referees offering both criticism and praise for these studies; along with his own present-day perspectives. This review highlights the numerous successes enjoyed by theorists, through decades of tireless effort to explain and understand the primordial QGP. All the same, it shows that many pressing questions remain to be answered. Rafelski continues to contribute to the field through his rich research experience and will undoubtedly inspire new generations of physicists to continue the study of exotic quarks in the primordial Universe.

Effortless learning during sleep is the dream of many people. The supportive effect of smells on learning success when presented both during learning and sleep was first proven in an extensive sleep laboratory study. Researchers at the University of Freiburg - Medical Center, the Freiburg Institute for Frontier Areas of Psychology and Mental Health (IGPP) and the Faculty of Biology at the University of Freiburg have now shown that this effect can be also achieved very easily outside the lab. For the study, pupils in two school classes learned English vocabulary - with and without scent sticks during the learning period and also at night. The students remembered the vocabulary much better with a scent. The study was published in the Nature Group's Open Access journal Scientific Reports on 27 January 2020.

"We showed that the supportive effect of fragrances works very reliably in everyday life and can be used in a targeted way," said study leader PD Dr. Jürgen Kornmeier, head of the Perception and Cognition Research Group at the Freiburg-based IGPP and scientist at the Department of Psychiatry and Psychotherapy at the University of Freiburg - Medical Center in Germany.

The smell of roses when learning and sleeping

For the study, first author and student teacher Franziska Neumann conducted several experiments with 54 students from two 6th grade classes of a school in southern Germany. The young participants from the test group were asked to place rose-scented incense sticks on their desks at home while learning English vocabulary and on the bedside table next to the bed at night. In another experiment, they also placed the incense sticks on the table next to them during a vocabulary test at school during an English test. The results were compared with test results in which no incense sticks were used during one or more phases.

"The students showed a significant increase in learning success by about 30 percent if the incense sticks were used during both the learning and sleeping phases," says Neumann. The results also suggest that the additional use of the incense sticks during the vocabulary test promotes memory.

Findings are suitable for everyday use

"One particular finding beyond the seminal initial study was, that the fragrance also works when it is present all night," says Kornmeier. "This makes the findings suitable for everyday use." Previous studies had assumed that the fragrance needs to be only present during a particularly sensitive sleeping phase. However, since this sleep phase needs to be determined by an effortful measurement of brain activity by means of an electroencephalogram (EEG) in the sleep laboratory, this finding was not suitable for everyday use. "Our study shows that we can make learning during sleep easier. And who would have thought that our nose could help considerably in this," says Kornmeier.

Rat spermatozoa are two to four times larger than that of other animal species and are easily damaged by changes in pH, osmotic pressure, and temperature. Because these animals are very frequently used in medical research, a cryopreservation method was developed nearly 20 years ago. However, rat spermatozoa motility after thawing is extremely poor, and unless artificial insemination is performed at night (10:00-11:00 pm) no offspring will be produced. Furthermore, the number of offspring produced after successful artificial insemination is often lower than normal so the cryopreservation of rat sperm is not typically considered practical.

To improve cryopreservation methods, Professor Nakagata and Dr. Takeo of the Center for Animal Resources and Development (CARD) at Kumamoto University, Japan have been searching for methods to retain sperm mobility after thawing. They knew that the freezing process significantly reduced sperm motility, so they attempted to chill the sperm first to reduce movement as much as possible before freezing.

They tested their cryopreservation method on a type of genetically modified rat (EGFP rat) sperm that emits green fluorescence and then used it for in vitro fertilization. Surprisingly, the fertilization rate exceeded 80% and the experiment successfully produced over 300 offspring from the sperm of one male rat.

Sperm cryopreservation is easier than the cryopreservation of fertilized eggs, and many cells (50 - 100 million) can be obtained from a single male rat. In recent years, genetically modified rats useful for human disease research have been produced using genome editing technology. This indicates that there is a need for an efficient technique to preserve genetically modified rat strains. The cryopreservation technology developed here can provide an efficient storage method of genetically modified rats and could accelerate the development of treatments for intractable diseases.
"Compared to mice, rats are about ten times the size, require a larger housing space, and simply cost more to keep. There is a need to reduce the amount of space they take up and their cost for research labs," said Professor Nakagata. "Our cryopreservation technique is likely to be very useful in the preservation of genetically modified rat strains. We believe that it could become a new global standard for research resources."

How you interact, how you feel, and how you act: The three basic tenants of social, emotional, and behavioral health are simple concepts, yet they can be some of the strongest predictors of well-being as children grow into adulthood. While a large number of children and adolescents meet the diagnostic criteria for mental health disorders, only a fraction actually receive needed services - and it often takes a crisis situation to initiate access to that help.

Because prevention and early intervention are key, schools are increasingly turned to as the primary identifiers of social, emotional, and behavioral needs, and though numerous screening tools exist, gaps remain between school-based screening initiatives and receipt of services. Through a four-year federally funded project, UConn researchers looked at school districts across the country to better understand how screening tools are being employed, and what factors influence their use.

"I think that there's a shifting perspective that schools can and must be a critical resource in meeting student needs in social, emotional, and behavioral domains," says Sandra Chafouleas, a Board of Trustees Distinguished Professor in the Department of Educational Psychology at UConn's Neag School of Education. Chafouleas is the co-director of the UConn Collaboratory on School and Child Health (CSCH) and served as the project director and co-principal investigator of the National Exploration of Emotional/Behavioral Detection in School Screening, or NEEDS², project.

In addition to Chafouleas, the NEEDS² project team included UConn alumna Amy Briesch, co-principal investigator from Northeastern University; D. Betsy McCoach, co-principal investigator with Neag's Department of Educational Psychology; Jennifer Necci Dineen, from UConn's Department of Public Policy; and project manager Helene Marcy, from the Collaboratory on School and Child Health.

"The majority of kids that receive behavioral health services get their access through schools," Chafouleas says. "So our main task in the project was about getting a national landscape of what's happening - about people's perceptions, their beliefs about behavior as a whole, and then what that means in terms of their approaches to identifying and supporting student needs."

NEEDS² is an exploration project that examined federal, state, and local government administrative data to first identify the extent to which state departments of education have provided specific guidance on social, emotional, and behavioral health screening approaches. The project also conducted extensive nationwide surveys to look at current screening approaches and at how educators and families think about the options available for addressing social, emotional, and behavioral health.

"We hypothesized that if schools used more proactive screening approaches, there would be more comprehensive programming and service delivery to meet those needs, which would lead to better outcomes," Chafouleas says. "What we found was that it's actually a bit flipped, and that school leader knowledge and attitudes may be an important lever. That is, the more that school leaders viewed social, emotional, and behavioral problems as a concern that should be prioritized and addressed, the more likely their districts were to engage in using more proactive programs - like teaching Social and Emotional Learning (SEL) or implementing school-wide Positive Behavioral Interventions and Supports (PBIS) - as well as preventive approaches to risk identification."

As part of its exploration, the NEEDS² research team reviewed states' departments of education websites and coded the level of guidance provided by each state on social, emotional, and behavioral health screening. The team identified 124 unique documents across 50 states and the District of Columbia specifically related to the use of screening practices in K-through-12 settings.

Findings published by the project in 2018 noted that although most state websites included some mention of universal screening, in nearly half the cases, information was limited to a brief definition, or the information provided was not necessarily specific to social, emotional, and behavioral health. Over half the states did not mention universal screening, or only provided vague references to screening. In more than a third of the states, documentation included a reference to universal screening, but the level of guidance was minimal.

The team also created a multi-stakeholder, multi-state survey that reached 1,130 district administrators and looked at the alignment of policy and practice around social, emotional, and behavioral health screening between states and local school districts. Of those 1,130 districts, 911 had policy manuals available, which were then reviewed for references to screening; eighty-seven included references to screening.

A report published this week in the Journal of School Health explored the impact of state-level policies on district-level policies and practices. This review found that only 20 percent of states were identified as containing districts with social, emotional, and behavioral screening policies. While some consistency existed across district policies within the same state, the level of social, emotional, and behavioral screening guidance provided in district policies varied across states.

Inconsistencies were also found between state and district policies; in half the states, district-level policies provided more detailed social, emotional, and behavioral screening guidance than the state-level document.

"[T]here is a need to identify the primary influences on district and building-level social, emotional, and behavioral screening practices," the researchers wrote. "Researchers, policymakers, and educators would then be able to direct attention to these influences in an effort to reduce the gap between the need and receipt of mental and behavioral health services among children and adolescents."

In follow-up interviews to the initial survey, state officials indicated that administrators recognize that universal social, emotional, and behavioral screening is important, but acknowledge that schools have not been proactive in addressing it.

"What we found was that, across all stakeholders, across all the different groups we surveyed, everyone pretty much agreed that schools have an important role in screening for social, emotional, and behavioral needs," says Chafouleas. "But I hope that the findings from this project aren't interpreted to say, well, everybody needs to be doing this screener. This leads to the question of, well, do we need more measures, or do we next need to figure out how we help schools put this in place in an efficient way?"

The group found some limitations in the alignment of federal data, and Chafouleas cautions that their work represents a snapshot of the social, emotional, and behavioral health landscape. With changing trends and renewed focus, the landscape might look significantly different if the work were to be repeated in five or ten years, she says.

But the implications for state and local policymakers and school administrators are important, and implementing workable, usable social, emotional, and behavioral screening policies that then identify appropriate responses and interventions should be a priority.

"We have a lot of work to do in terms of how to we build capacity to be able to think more holistically in a prevention framework about social, emotional, and behavioral spaces for kids," she says. "When we screen we're doing early identification, as opposed to waiting for the student to throw the chair out the window or exhibit impaired coping ability. There will always be kids that need more intensive help, and we need to think strategically about how we partner in school with our community resources as well as what we have within our schools."

PULLMAN, Wash. - When food makes people sick, some blame birds because they hang around farms, and their feces can contain E. coli, Salmonella and Campylobacter, three common pathogens that can cause food-borne illness.

But a recent Washington State University study published in Biological Reviews on Jan. 31 has found scant evidence to support the link between wild birds and human illness involving those three pathogens.

The perceived risk of wild birds can impact their survival, said Olivia Smith, lead author on the study and a recent WSU Ph.D. graduate.

"Farmers are being encouraged to remove wild bird habitat to make their food safer, but it doesn't appear that these actions are based on data," Smith said. "When you restrict birds from agricultural settings, you are doing something that can lead to their decline."

Bird populations have been falling rapidly in recent decades. Scientists estimate that since 1970, North America has lost more than three billion birds. In light of this, the WSU researchers highlighted the need for more definitive research before destroying habitat and banning birds from fields in the name of food safety.

Smith and her colleagues, WSU Associate Professor Jeb Owen and Professor William Snyder, analyzed data for E. coli, Salmonella and Campylobacter in 431 North American breeding bird species and found no relevant studies for 65% of those species, including birds that are commonly found in farm fields such as raptors, great blue herons and black-billed magpies.

In their review, the researchers found only one study definitively linking wild birds to food-borne illness outbreaks: a case where sandhill cranes spread Campylobacter on fresh peas in an outbreak that sickened nearly 100 people in Alaska in 2008.

The most studied birds in relation to these pathogens were ducks, geese as well as two non-native species house sparrows and European starlings that tend to swarm on feed lots and can contaminate the food and water used for cattle. Yet there's a huge gap in knowledge about many other common native species that are often around agricultural crops including American robins.

Only 3% of the studies that the researchers analyzed looked at the entire transmission process from bird to plant to human. The majority simply tested bird feces to see if the bacteria were present or not.

In order for the bacteria to make people sick, the bird needs to get pathogenic strains of E. coli, Salmonella or Campylobacter on a food crop, and that bacteria has to survive long enough until people eat the contaminated food, including through shipment, washing, food processing in plants and food preparation. The data on the pathogen survival is also very limited.

"Birds do carry bacteria that can make people sick, but from our review of the scientific studies, it's unclear how big of a risk they are," Smith said.

Oncotarget Volume 11, Issue 4: The research team's aim was to investigate mAb 6G5j binding characteristics and to validate fluorescence targeting of colorectal tumors and metastases in patient derived orthotopic xenograft models with fluorescently labeled 6G5j.

Nude mice received orthotopic implantation of patient-derived primary colon cancer and patient-derived colon cancer metastases.

Anti-CEACAM antibody 6G5j binds multiple CEACAMs which may lead to improved detection of tumor margins for tumors and metastases that have variable expression of CEA and other CEACAMs.

6G5j mAb may be useful for colon cancer detection for pre-surgical diagnosis and fluorescence-guided surgery.

Dr. Michael Bouvet from the Department of Surgery and the Moores Cancer Center at the University of California in La Jolla California USA as well as the VA San Diego Healthcare System in San Diego, CA, USA said in their Oncotarget article, "Early diagnosis and surgical resection of a wide variety of epithelial malignancies remain a vital challenge due to difficulty of intraoperative recognition of tumor margins and small metastases during minimally invasive procedures."

While immune cells and endothelium solely express CEACAM1, human epithelial cells show a much more complex CEACAM expression pattern.

CEACAM1, CEACAM5 and CEACAM6 are co-expressed in epithelial cells of the gastro-intestinal tract and can also be over-expressed in endometrial, lung, ovarian, cervical, breast and colon cancers.

Prior studies have successfully utilized fluorescently-labeled antibodies in mouse models to specifically visualize pancreatic and colorectal tumors.

While anti-CEA antibodies conjugated to fluorophores have enabled tumor visualization, the simultaneous targeting of multiple antigens may further enhance visualization, provide more distinct tumor margins and improve detection of metastases.

In this Oncotarget study, the authors test a novel anti-CEACAM antibody conjugated to a fluorescent dye for detection of multiple CEACAM antigens to enhance visualization of colorectal PDOX tumors and metastases in murine models.

The Bouvet Research Team concluded that since this mAb binds to multiple antigens that are commonly present in colon tumors, namely CEACAM1, 5 and 6, it may provide improved detection of cancer margins for tumors with variable expression of CEA and other CEACAMs. Further studies are necessary to validate the use of 6G5j-IR800CW in human patients with colorectal cancer.