Culture

As obesity increases in aging Western populations, frailty--which is exacerbated by obesity--is becoming a greater health concern and a major healthcare cost. Now, researchers report July 3 in the journal Cell Metabolism that combining aerobic exercise and resistance training helps elderly obese individuals preserve muscle mass and reverse frailty as they work to lose weight. Based on a small clinical trial, the study showed that patients who completed these exercises had increased muscle protein synthesis and preserved muscle quality compared to control groups.

In a previous study, Dennis T. Villareal, professor and geriatric endocrinologist at Baylor College of Medicine, hypothesized that resistance training would best complement weight loss for improving physical function in older obese adults. Study participants took part in a weight-management program and were randomly assigned aerobic workouts, resistance training or a combination of both.

Villareal and colleagues were surprised to find that combined aerobic and resistance training improved cardiovascular fitness to the same extent as aerobic training alone and improved muscle strength to the same extent as resistance training alone. They reported in the New England Journal of Medicine in May 2017 (doi: 10.1056/NEJMoa1616338) that combined aerobic and resistance training resulted in the greatest improvement in physical function and reducing frailty in older obese.

However, it was unclear how obese older adults in particular benefitted from aerobic workouts geared toward cardiovascular fitness combined resistance training. In the Cell Metabolism study, the researchers used molecular and cellular techniques to assess changes in their muscle protein synthesis and myocellular quality to examine the mechanisms underlying the obese older adults' improvement in physical function and preservation of lean body mass.

A subset of participants--47 of the original 160--agreed to undergo muscle biopsies before and after six months of lifestyle interventions to see how their muscle tissue was affected. The participants were men and women that averaged between 69 and 72 years of age and more than half were Hispanic/Latinx. Aerobic activities included treadmill walking, stationary cycling, and stair climbing, with participants exercising at approximately 65% of their peak heart rate; resistance training consisted of 1 to 3 sets of 8 to 12 reps on nine upper-body and lower-body weight-lifting machines.

"Our findings indicated that despite negative energy balance from diet-induced weight loss, exercise training in older adults with obesity helps to preserve muscle mass, improve physical function and reduce frailty," Villareal says.

The study found that the participants' muscle protein synthesis rate increased more with resistance training and combined aerobic-resistance exercise than in the control group. The combined aerobic-resistance exercise was also associated with lower expression of genes associated with muscle atrophy and the best preservation of muscle growth regulators, which the researchers hypothesized could also play a role in promoting muscle mass preservation and improvement in physical function in that group.

In the elderly obese, combined aerobic and resistance exercise is superior to either mode independently for maintaining muscle mass during weight-loss therapy, he says. Aerobic and resistance training is the most effective strategy and therefore, Villareal notes, "the best approach."

Cancer took more than 8.7 million years of life and $94.4 billion in lost earnings among people ages 16 to 84 in the United States in 2015. The calculation comes from a new report by American Cancer Society researchers that appears early online in JAMA Oncology.

Cancer is the second-leading cause of death in the U.S., expected to cause more than 606,880 deaths in 2019. Cancer deaths impose significant economic burden in the United States because of productivity losses due to premature death. Accurate information on the economic burden of cancer mortality can help in setting policies and prioritizing resources for cancer prevention and control. However, contemporary data are lacking for the United States nationally and by state.

To update estimated lost earnings due to death from cancer, investigators led by Farhad Islami, M.D., Ph.D., calculated person-years of life lost using numbers of cancer deaths and life expectancy data in individuals aged 16 to 84 years who died from cancer in the United States in 2015. They created estimates for cancer deaths overall and for the major cancers in the United States nationally and by state. The estimates are for lost earnings alone, and do not include other costs associated with cancer, including costs of treatment and caregiving.

A total of 492,146 cancer deaths occurred in people ages 16 to 84 in the U.S. in 2015, translating to a total of 8,739,939 life years lost. Overall lost earnings were $94.4 billion, and $191,900 per cancer death. Lost earnings were $29.0 million per 100,000 population overall.

Lung cancer cost the most in lost earnings ($21.3 billion; 22.5% of total), followed by colorectal ($9.4 billion; 10.0%), female breast ($6.2 billion; 6.5%), and pancreatic ($6.1 billion; 6.5%) cancers. By age, lost earnings were highest for leukemia in ages 16 to 39 while lung cancer was highest in ages 40 and over.

Lost earnings per 100,000 population varied considerably by state, ranging from $19.6 million per 100,000 in Utah to $35.3 million per 100,000 in Kentucky. States with the highest age-standardized lost earning rates were in the South, followed by states in the Midwest. States with the lowest age-standardized lost earning rates were in the West, Northeast, and Hawaii.

If all states had Utah's lost earnings rate in 2015, lost earnings in the U.S. would have been reduced by 29.3%, or $27.7 billion, and life years lost nationwide in 2015 would be reduced by 2.4 million.

"Years of life lost and lost earnings were high for many cancers for which there are modifiable risk factors and effective screening and treatment, which suggests that a substantial proportion of our current national mortality burden is potentially avoidable," said Dr. Islami. "Applying comprehensive cancer prevention interventions and ensuring equitable access to high-quality care across all states could reduce the burden of cancer and associated geographic and other differences in the country. Health care professionals can contribute to achieving this goal because they play a central role in the delivery of cancer prevention, screening, and treatment."

As antibiotic resistance is growing and posing a threat on public health, developing new antibiotics has become more urgent than ever. Researchers at City University of Hong Kong (CityU) have recently revealed the virulence regulatory mechanism in Pseudomonas aeruginosa, a superbug which is common in patients with a weak immune system and is resistant to many antibiotics. The findings pave ways for identifying good antibiotic targets for new drug development.

Superbug Pseudomonas aeruginosa is a common pathogen of nosocomial infections, causing high morbidity and mortality in immunocompromised patients. It is also naturally tolerant to many clinically important antibiotics such as ampicillin, amoxicillin, and vancomycin. In 2017, the World Health Organization (WHO) classified this notorious bacterium as one of the three "critical priority pathogens" that new drugs are urgently needed.

A joint research led by Dr Deng Xin (Assistant Professor), a microbiologist, and Dr Wang Xin (Associate Professor), a computational biologist from Department of Biomedical Sciences (BMS) at CityU, have recently revealed the genomic regulatory network in Pseudomonas aeruginosa and identified the master regulators on key pathogenic pathways. The development of inhibitors against these newly identified master regulators can potentially lead to the discovery of novel drugs that target Pseudomonas aeruginosa.

The findings were published in the latest issue of Nature Communications, titled "An integrated genomic regulatory network of virulence-related transcriptional factors in Pseudomonas aeruginosa".

Finding good antibiotic targets: master regulators

Bacterial pathogenicity is mediated via regulatory networks that include virulence-related transcriptional factors. Transcriptional factors (TFs) are proteins which can turn the specific genes (their functional target genes) "on" and "off", generally a key determinant in whether the gene functions at a given time. And master regulators are the transcriptional factors that appear to control most of the regulatory activities of other transcriptional factors and the associated genes. Therefore, the master regulators are often good antibiotic targets that can be used for future drug development.

In Pseudomonas aeruginosa, numerous TFs regulate virulence by tuning quorum sensing (QS), the type III secretion (T3SS) and type VI secretion system (T6SS). In the past seven years, in collaboration with Professor Liang Haihua from Northwest University (China), Dr Deng has been working to reveal the pathogenesis of Pseudomonas aeruginosa, and to discover and clarify the regulation mechanism of multiple virulence-related TFs (Shao et al, J Bacteriol, 2018; Zhao et al, PLOS Biol, 2016; Kong et al, Nucleic Acids Res, 2015; Liang et al, Nucleic Acids Res, 2014; Liang et al, J Bacteriol, 2012).

To further conduct a global analysis of the pathogenicity and discover new potential drug targets of Pseudomonas aeruginosa, Dr Deng's team and Dr Wang's team collaborated on the analysis and discovery of the crosstalk - signal pathway affecting another - in the known 20 virulence-related TFs. Subsequently, they mapped the Pseudomonas aeruginosa Genomic regulatory network (PAGnet) to encode the regulatory relationships of these 20 TFs with their functional target genes (Figure 1).

This PAGnet revealed the intricate mechanism of virulence regulation mediated by these TFs and the related crosstalk, and hence led to the identification of nine master regulators, in QS and T3SS.

An online platform for potential wider pathological use

As a contribution to the research community, they have also developed an online platform and R package based on PAGnet to ensure an up-to-date regulatory network and facilitate user-customized analyses (Figure 2). This platform and R package provide network visualization, subnetwork filtering and downloading services to the user, to facilitate the visualization and exploration of the virulence regulatory network, as well as master regulator analysis for the identification of key TFs that mediate a biological process or pathway in Pseudomonas aeruginosa.

"The master regulators we identified are potential antibiotic targets, which has important clinical significance for the development of new antibiotics for Pseudomonas aeruginosa in the future. More importantly, the network we build is not just for Pseudomonas aeruginosa, the methodology and conclusions of this work may be applicable to other bacterial pathogens in the future," commented Dr Deng.

Dr Deng and Dr Wang are the correspondence authors of the paper. The first co-authors are PhD student Huang Hao, Xie Yingpeng and research assistant Dr Shao Xiaolong at CityU's BMS Department. Other authors include PhD student Wang Tingting and research assistant Zhang Yingchao from the Department.

DALLAS (SMU) - Researchers from Southern Methodist University (SMU) could help determine if Saturn's icy moon - Titan - has ever been home to life long before NASA completes an exploratory visit to its surface by a drone helicopter.

NASA announced in late June that its "Dragonfly" mission would launch toward Saturn's largest moon in 2026, expecting to arrive in 2034. The goal of the mission is to use a rotorcraft to visit dozens of promising locations on Titan to investigate the chemistry, atmospheric and surface properties that could lead to life.

SMU was awarded a $195,000 grant, also in June, to reproduce what is happening on Titan in a laboratory setting. The project, funded by the Houston-based Welch Foundation, will be led by Tom Runčevski, an assistant professor of chemistry in SMU's Dedman College of Humanities and Sciences. SMU graduate student Christina McConville was also awarded a fellowship by the Texas Space Grant Consortium to help with the project.

Before the rotorcraft lands on Titan, chemists from SMU will be recreating the conditions on Titan in multiple glass cylinders -- each the size of a needle top -- so they can learn about what kind of chemical structures could form on the Titan's surface. The knowledge on these structures can ultimately help assess the possibility of life on Titan -- whether in the past, present or future.

Scientists have long considered Titan to be very similar to pre-biotic Earth, even though it is a frigid world much farther from the sun than our planet. Titan is the only moon in the solar system to have a dense atmosphere like Earth, and is also the only world other than Earth to have standing bodies of liquids, including lakes, rivers and seas, on its surface. In addition, NASA scientists believe Titan may have a subsurface ocean of water.

"Titan is a hostile place, with lakes and seas of liquid methane, and rains and storms of methane. The storms carry organic molecules produced in the atmosphere to the surface, and at the surface conditions, only methane, ethane and propane are liquids. All other organic molecules are in their solid form - or, as we would call them on Earth, minerals," Runčevski explained.

"We are interested in the chemical composition and crystal structure of these organic minerals, because it is believed that minerals played a key role in the origins of life on Earth," he said. "Hence, our research may help assess these possibilities for strange "methanogenic" Titanean life."

Runčevski added that any information that they get about the structure of Titan's upper layer crust, which is made of organic minerals, could prove very useful to NASA's Dragonfly mission.

In order to create these "Titans in a jar" at SMU, Runčevski said they will use information about the conditions on Titan that were obtained during the mission Cassini-Huygens, which ended two years ago.

"We can recreate this world step by step in a cylinder made of glass," he said. "First, we will introduce water, which freezes into ice. Second, we will top that layer of ice with ethane that liquidizes as a 'lake.' Then we will fill the remaining cylinder with nitrogen."

After that, they can introduce different molecules into the system, mimicking the rainfall. Lastly, they will "dry" the lakes by slightly raising the temperature and produce the surface of the moon. The cylinder that this moon will be created inside is specifically designed, so that multiple state-of-the-art experiments can be done and they can learn from the structure of the real Titan. Large parts of these experiments will be performed at research facilities that provide modern synchrotron and neutron radiation, such as Argonne National Laboratory in Illinois and the National Institute and Technology in Maryland.

For the first time, a team of neuroscientists from Columbia University have controlled a visual behavior of a mouse by activating a few neurons in its visual cortex.

In their study, published in Cell, the researchers demonstrated that specific groups of neurons, known as neuronal ensembles, have a causal role in behavior. The researchers used new optical and analytical tools to identify cortical ensembles in mice while they performed a visual task. They also used high-resolution optogenetics to simultaneously target selected neurons with single-cell precision, taking control of the mice's behavior. While the precise activation of neurons related to the task improved the performance of the animal, the activation of other neurons, not related to the task, degraded the behavior.

"This is the most exciting work to come out of my laboratory in decades since we are proving that cortical ensembles are key for behavior and that we can play the piano with them and alter at will the behavioral performance of animals," said Rafael Yuste, the senior author of the study and professor of Biological Sciences at Columbia. "The data indicates, moreover, that neuronal ensembles are internal representations of a visual stimulus," added Yuste, who is also a member of the Data Science Institute at Columbia.

The research may have significant applications in medicine. Identifying physiologically relevant neuronal ensembles with single-cell precision could be used to reorganize the patterns of activity between targeted neurons and to reprogram faulty neural circuits. And reorganizing those neuronal patterns has the potential to treat pathological conditions caused by abnormal activity patterns in mental and neurological diseases such as Alzheimer's, Parkinson's disease or schizophrenia, said Luis Carrillo-Reid, a former researcher in the Yuste Lab and lead author of the paper, "Controlling Visually Guided Behavior by Holographic Recalling of Cortical Ensembles."

"We are still far from using these methods as treatments for patients," said Carrillo-Reid, "but this study could represent a road map toward precisely reprogramming the brain, bringing neuroscience a step closer to the clinic."

Working in the Yuste Lab, the researchers used two-photon calcium imaging of neural circuits and two-photon optogenetics, methods originally developed by the Yuste group to optically read and write neuronal activity. With calcium imaging, one can track which neurons are firing in a neural circuit, whereas with optogenetics, one can activate neurons at will. Using two-photon lasers, moreover, enabled the team to perform calcium imaging and optogenetics with single-cell precision in the brains of animals as they run on treadmills.

The researchers injected mice with viruses, which allowed them to observe the neuronal activity patterns in their brains. They were also able to precisely manipulate the activity of their neurons with light. Next, they attached the mice to a two-photon microscope and observed them while they ran on small treadmills. For two weeks, the researchers trained the mice to associate a visual stimulus - drifting vertical bars presented to them on a video screen - with water so that whenever the vertical bars appeared they would lick at a water spout. After the mice learned to associate the visual stimulus with licking, the researchers identified the group of neurons in the mice that responded to the vertical bars, and reactivated those neurons using a two-photon laser. This reactivation helped the mice to lick correctly more times than expected and even evoked licking in the absence of any visual stimuli, as if the mice were seeing the vertical bars as a hallucination. The researchers even triggered the licking behavior by stimulation only two neurons, as long as they were the specific group of neurons associated with the behavior.

Electrical stimulation of different areas of the brain has been used for decades to ameliorate symptoms of movement disorders such as Parkinson's, and more recently, to treat neuropsychiatric disorders as depression. This technique, known as Deep Brain Stimulation, is used to help tens of thousands of patients every year. The technique, however, involves the manipulation of a large volume of neurons whose spatial location and identity are unknown. In this study, the researchers showed the proof of principle that identifying and targeting very specific neurons can change a behavior, opening a pathway to using this technique to help correct the problems of brain diseases," said Carrillo-Reid, who now directs a laboratory at the National Autonomous University of Mexico.

"In addition, the fact that one can supplant a sensory stimulus by activating a few neurons indicates that we may be starting to get closer to understanding what a perception is, or what is a thought," said Yuste. "And that could be an important step forward in understanding how our mind works."

Scientists at Harvard Medical School and Boston Children's Hospital have used a novel gene-editing approach to salvage the hearing of mice with genetic hearing loss and succeeded in doing so without any apparent off-target effects as a result of the treatment.

The animals--known as Beethoven mice--were treated for the same genetic mutation that causes progressive hearing loss in humans, culminating in profound deafness by their mid-20s.

The new approach, described online July 3 in Nature Medicine , involves an optimized, more precise version of the classic CRISPR-Cas9 gene-editing system that is better at recognizing the disease-causing mutation seen in Beethoven mice. The refined tool allowed scientists to selectively disable the defective copy of a hearing gene called Tmc1, while sparing the healthy copy.

Notably, the researchers report, their system managed to recognize a single incorrect DNA letter in the defective copy among 3 billion letters in the mouse genome.

Much more work remains to be done before even a highly precise gene-editing therapy like this one could be used in humans, the researchers cautioned. However, they said, the work represents a milestone because it greatly improves the efficacy and safety of standard gene-editing techniques.

"Our results demonstrate that this more refined, better targeted version of the now-classic CRISPR/Cas9 editing tool achieves an unprecedented level of identification and accuracy," said study co-senior investigator David Corey, the Bertarelli Professor of Translational Medical Science in the Blavatnik Institute at Harvard Medical School.

Furthermore, the team said, the results set the stage for using the same precision approach to treat other dominantly inherited genetic diseases that arise from a single defective copy of a gene.

Everyone inherits two copies of the same gene--one from each parent. In many cases, one normal gene is sufficient to ensure normal function that spares the individual from disease. By contrast, in so-called dominantly inherited genetic disorders, a single defective copy can cause illness.

"We believe our work opens the door toward a hyper-targeted way to treat an array of genetic disorders that arise from one defective copy of a gene," said study co-senior investigator Jeffrey Holt, Harvard Medical School professor of otolaryngology and neurology at Boston Children's Hospital, who is also affiliated with the F.M. Kirby Neurobiology Center at Boston Children's. "This truly is precision medicine."

The mice carrying the faulty Tmc1 gene are known as Beethoven mice because the course of their disease mimics the progressive hearing loss experienced by the famed composer. The cause of Ludwig van Beethoven's deafness, however, remains a matter of speculation.

In mice, the Beethoven defect is marked by one incorrect letter in the DNA sequence of the Tmc1 gene--an A instead of a T--a single error that spells the difference between normal hearing and deafness.

Disabling, or silencing, the mutant copy of the Tmc1 gene would be sufficient to preserve the animal's hearing, but how could it be done without inadvertently disabling the healthy gene as well?

Two keys are better than one

Classic CRISPR-Cas9 gene editing systems work by using a guiding molecule--gRNA--to identify the target mutant DNA sequence. Once the target DNA is pinpointed, the cutting enzyme--Cas9--snips it.

So far, these gene editors have shown less-than-perfect accuracy. This is because the guide RNA that leads the Cas9 enzyme to the target site and the Cas9 enzyme that cuts the target DNA are not entirely precise and could end up cutting the wrong DNA.

To circumvent these challenges, researchers adapted a tool originally developed by Keith Joung, HMS professor of pathology, and Ben Kleinstiver, HMS assistant professor of pathology, at Massachusetts General Hospital, which uses a modified Cas9 enzyme derived from Staphylococcus aureus instead of the standard Cas9 that is derived from the bacterium Streptococcus pyogenes.

To achieve enhanced accuracy of the detection and disruption, the new, optimized system combines two levels of recognition--gRNA to locate the target gene and a modified form of Cas9 that can pinpoint the specific DNA mutation in Beethoven mice. The use of two forms of identification ensures the precise and selective cutting of the aberrant copy--and only the aberrant copy--of that gene.

"We took advantage of the fact that this system recognizes mutant DNA but not normal DNA and uses a dual recognition system for enhanced precision," said study first author Bence Gyorgy, who conducted the work while at Harvard Medical School and is now at the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland. "This approach resulted in an unprecedented level of specificity in targeting the mutant gene."

In an initial set of experiments in cells with and without the Beethoven mutation, the tool accurately distinguished between mutant DNA and normal DNA in copies of the Tmc1 gene. Further analysis revealed that in Beethoven cells, which contained one defective and one normal copy of the gene, at least 99 percent of the molecular "cuts" occurred exclusively in the defective copy of the gene.

Next, researchers injected the gene-editing treatment into the inner ears of mice with and without the Beethoven mutation. DNA analysis showed that editing activity occurred only in the inner ear cells of mice with the Beethoven defect. No editing changes were detected in cells from the inner ears of treated mice that didn't have the mutation--a finding that confirmed the tool's precision.

To determine whether the gene-editing therapy interfered with normal gene function, the scientists stimulated hearing cells--called hair cells--from the inner ears of treated mice that didn't carry the Beethoven defect. The cells showed unchanged, normal hearing responses, affirming that the gene-editing therapy had no effect on normal gene function.

Silencing Beethoven

To measure whether the therapy worked in animals rather than just in cells, researchers performed the gold-standard test for hearing. They measured the animals' auditory brainstem responses, which capture how much sound is detected by hair cells in the inner ear and transmitted to the brain.

Without treatment, Beethoven mice typically are completely deaf by 6 months of age. By comparison, mice without the genetic defect retain normal hearing throughout life and can detect sounds at around 30 decibels--a level similar to a whisper.

Two months after receiving the gene-editing therapy, Beethoven mice exhibited markedly better hearing than untreated siblings carrying the genetic mutation. The treated animals were capable of detecting sounds at about 45 decibels--the level of a normal conversation--or about 16 times quieter than untreated mice. The Beethoven mouse with the greatest hearing preservation was capable of hearing sounds at 25 to 30 decibels, virtually indistinguishable from its healthy peers.

Taken together, the findings demonstrate that the novel gene therapy effectively silenced the defective copy of the gene and salvaged the animals' hearing from the rapid demise typically seen in the disease.

Because the disease is marked by progressive hearing loss, the researchers assessed the effect of therapy on the progression over several months. Researchers administered treatment shortly after birth and tested hearing levels in treated and untreated mice with and without the mutation every four weeks for up to six months. In month one, untreated Beethoven mice could hear low-frequency sounds but had notable hearing loss at high frequencies. By month six after birth, untreated Beethoven mice had lost all their hearing. In contrast, treated Beethoven mice retained near-normal hearing at low frequencies, with some showing near-normal hearing even at high frequencies.

Notably, treated animals that didn't carry the genetic defect did not experience any hearing loss as a result of the gene therapy--a finding that demonstrated the safety of the procedure and its ability to selectively target the aberrant copy of the gene. Even more encouragingly, a small subset of treated Beethoven mice that were followed for nearly a year retained stable, near-normal hearing.

Because the Beethoven defect is marked by the progressive deterioration and death of hearing cells in the inner ear, the researchers used electron microscopy to visualize the structure of these critical hearing cells. As expected, in the untreated Beethoven mice, the researchers saw gradual loss of hearing cells along with deterioration in their structure. By contrast, treated Beethoven mice and treated healthy mice both retained a normal number of hearing cells with intact or near-intact structure.

In a final experiment, the scientists tested the effect of the treatment in a line of human cells carrying the Beethoven mutation. DNA analysis revealed that treatment caused editing exclusively in the mutant copy of the Tmc1 gene and spared the normal one.

Because of its ability to target single-point genetic mutations, the approach holds promise for 15 other forms of inherited deafness also caused by a single-letter mutation in the DNA sequence of other hearing genes.

Additionally, the team said, their technique could be adapted for use in other dominantly inherited genetic disease caused by single-point mutations. To determine its hypothetical utility, the scientists scanned the federal ClinVar database--a national repository of all known genetic mutations linked to human diseases. The analysis showed that based on the tool's specificity, it could correctly identify 3,759 defective gene variants collectively responsible for one-fifth of dominant human genetic mutations.

"To be sure, this is the first step in a long journey," Holt said. "But what we have here is proof of principle that demonstrates this highly specific, highly targeted treatment could be developed to selectively silence genes that carry single-point mutations and potentially treat many other forms of human disease."

Rearing its head in infancy, Christianson Syndrome is a rare disorder whose symptoms include intellectual disability, seizures and difficulty standing or walking. Although it is becoming increasingly diagnosed, with little being known about the neural mechanism behind the disease, therapeutic options for patients remain limited.

Now, researchers at McGill University focusing on the intellectual disability aspect of the disease, have shown for the first time how a specific mutant form of the SLC9A6 encoding gene for the NHE6 protein affects the ability of neurons to form and strengthen connections. The findings, which the researchers hope could eventually lead to new treatments for patients, are published online in the journal Neurobiology of Disease.

"NHE6 functions like a GPS inside of brain cells, helping other proteins navigate to the correct location to allow the neurons to function properly and remodel the connections they form between themselves during learning and memory situations," explains Dr. Anne McKinney, Professor in the Department of Pharmacology and Therapeutics at McGill's Faculty of Medicine and the study's senior author. "This protein regulates pH of the vesicles, which contain the cargo that moves inside the brain cell. It prevents it from becoming too acidic or too alkali. We now show that if this protein loses its function because of a mutation, then other proteins can no longer be sent to the right places, and thus these neurons are unable to properly undergo learning-type mechanisms. Using methods to regulate the pH of the vesicles we can rescue the cargo trafficking and learning of the neuron."

Using mouse models to study the hippocampus

To make their discovery, the researchers grew mouse neurons on a dish, expressing a mutant version of SLC9A6 discovered in patients. Using high-resolution microscopy and electrophysiology they examined changes in appearance of these brain cells as well as how they responded to artificial learning and memory-type stimulations in a dish.

"We found that by attempting to rescue the 'GPS' function of the protein by compensating with other pharmacological agents, we were able to restore at least some of the proper mechanisms to allow other proteins to be trafficked around the cell normally and thus restore their ability to 'learn'," notes Andy Gao a PhD student in Dr. McKinney's lab and the study's first author.

A hope for potential therapies

The first study to clearly demonstrate that mutations in SLC9A6 can lead to changes in synaptic function that could be related to the cognitive deficits associated with Christianson Syndrome, the researchers hope that these insights will eventually provide more clues as to how to modify the impact of the mutation in order to provide clinical benefit.

"Interestingly enough, other groups are starting to show that the implicated protein is actually expressed less as well in other more common neurodegenerative disorders, such as Parkinson's and Alzheimer's Diseases," notes Dr. McKinney, who is also Associate Dean, Academic Affairs at the Faculty of Medicine. "Through our work, we can start to develop potential therapeutic targets to improve the quality of life, not only for those suffering from Christianson Syndrome, but from other disorders as well where NHE6 is perturbed."

New York, NY--July 3, 2019--The emerging field of synthetic biology--designing new biological components and systems--is revolutionizing medicine. Through the genetic programming of living cells, researchers are creating engineered systems that intelligently sense and respond to diverse environments, leading to more specific and effective solutions in comparison to current molecular-based therapeutics.

At the same time, cancer immunotherapy--using the body's immune defenses to fight cancer--has transformed cancer treatment over the past decade, but only a handful of solid tumors have responded, and systemic therapy often results in significant side effects. Designing therapies that can induce a potent, anti-tumor immune response within a solid tumor without triggering systemic toxicity has posed a significant challenge.

Researchers at Columbia Engineering and Columbia University Irving Medical Center (CUIMC) announced today that they are addressing this challenge by engineering a strain of non-pathogenic bacteria that can colonize solid tumors in mice and safely deliver potent immunotherapies, acting as a Trojan Horse that treats tumors from within. The therapy led not only to complete tumor regression in a mouse model of lymphoma, but also significant control of distant, uninjected tumor lesions. Their findings are published today in Nature Medicine.

"Seeing untreated tumors respond alongside treatment of primary lesions was an unexpected discovery. It is the first demonstration following a bacterial cancer therapy of what is termed an 'abscopal' effect," says Tal Danino, assistant professor of biomedical engineering. "This means that we'll be able to engineer bacteria to prime tumors locally, and then stimulate the immune system to seek out tumors and metastases that are too small to be detected with imaging or other approaches."

The study was led in collaboration with Nicholas Arpaia, assistant professor of microbiology & immunology at CUIMC, and co-senior author on the publication. The team combined their expertise in synthetic biology and immunology to engineer a strain of bacteria able to grow and multiply in the necrotic core of tumors. When bacteria numbers reach a critical threshold, the non-pathogenic E. coli are then programmed to self-destruct, allowing for effective release of therapeutics and preventing them from wreaking havoc elsewhere in the body. Subsequently, a small fraction of bacteria survive lysis and reseed the population, allowing for repeated rounds of drug delivery inside treated tumors. The proof of concept in programming the bacteria in this way was originally developed a few years ago (Din & Danino et al. Nature 2016). In the current study, the authors chose to release a nanobody that targets a protein called CD47.

CD47, a "don't-eat-me" signal, protects cancer cells from being eaten by innate immune cells such as macrophages and dendritic cells. It is found in abundance on a majority of human solid tumors and has recently become a popular therapeutic target.

"But CD47 is present elsewhere in the body, and systemic targeting of CD47 results in significant toxicity as evidenced by recent clinical trials. To solve this issue, we engineered bacteria to target CD47 exclusively within the tumor and avoid systemic side-effects of treatment," adds Sreyan Chowdhury, the paper's lead author and a PhD student co-mentored by Arpaia and Danino.

The combined effect of bacterially induced local inflammation within the tumor and the blockade of CD47 leads to increased ingestion, or phagocytosis of tumor cells and subsequently to enhanced activation and proliferation of T cells within the treated tumors. The team found that treatment with their engineered bacteria not only cleared the treated tumors but also reduced the incidence of tumor metastasis in multiple models.

"Treatment with engineered bacteria led to priming of tumor-specific T cells in the tumor that then migrated systemically to also treat distant tumors," Arpaia says. "Without both live bugs lysing in the tumor and the CD47 nanobody payload, we were not able to observe the therapeutic or abscopal effects."

The team is now performing further proof-of-concept tests, as well as safety and toxicology studies, of their engineered immunotherapeutic bacteria in a range of advanced solid tumor settings in mouse models. Positive results from those tests may lead to a clinical trial in patients. They are also collaborating with Gary Schwartz, CUIMC's chief of hematology/oncology and deputy director of the Herbert Irving Comprehensive Cancer Center, on clinical translation aspects of their work, and have started a company to translate their promising technology to patients.

July 3, 2019 - There are two kinds of age: chronological age, which is the number of years one has lived, and biological age, which is influenced by our genes, lifestyle, behaviour, the environment and other factors. Biological age is the superior measure of true age and is the most biologically relevant feature, as it closely correlates with mortality and health status. The search for reliable predictors of biological age has been ongoing for several decades, and until recently, largely without success.

Since 2016 the use of deep learning techniques to find predictors of chronological and biological age has been gaining popularity in the aging research community. Advances in artificial intelligence, combined with the availability of large datasets, have led to a boom in the field, increasing the variety of biomarkers that could be considered candidates as potential age predictors. One promising development that considers multiple combinations of these different predictors could shed light on the aging process and provide further understanding of what contributes to healthy aging.

In the paper titled "Deep Aging Clocks: The Emergence of AI-Based Biomarkers of Aging and Longevity" in Cell Trends in Pharmacological Sciences, Polina Mamoshina, Senior Scientist at Insilico Medicine, and Alex Zhavoronkov, the Founder of Insilico Medicine, summarise current findings on the main types of deep aging clocks and their broad range of applications in pharmaceutical industry.

"Humans are very good at guessing each other's age using images, videos, voice, and even smell. Deep neural networks can do it better and we can now interpret what factors are most important. Very often when someone looks older than their chronological age, they are sick. A trained doctor can guess the health status of a patient just by looking at him or her. At Insilico we developed a broad range of deep biomarkers of aging that can be used by the pharmaceutical and insurance companies, as well as by the longevity biotechnology community. In this paper we describe the recent progress in this emerging field and outline a range of non-obvious applications," said Alex Zhavoronkov, Ph.D, Founder and CEO of Insilico Medicine.

Deep biological aging clocks can be used for data quality control, biological target identification and even the evaluation of the biological relevance and value of various data types and combinations. The recent perspective on the value of human data recently appeared in Cell Trends in Molecular Medicine.

"Deep biomarkers of aging developed utilizing a variety of data types of aging are rapidly advancing the longevity biotechnology industry. Using biomarkers of aging to improve human health, prevent age-associated diseases and extend healthy life span is now facilitated by the fast-growing capacity of data acquisition, and recent advances in AI. They hold a great potential for changing not only aging research, but healthcare in general," said Polina Mamoshina, Senior Scientist at Insilico Medicine.

New research on the autoimmune disease systemic lupus erythematosus (SLE) provides hints to the origins of the puzzling disorder. The results were published in Nature Immunology.

In people with SLE, their B cells - part of the immune system - are abnormally activated. That makes them produce antibodies that react against their own tissues, causing a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems.

Scientists at Emory University School of Medicine could discern that in people with SLE, signals driving expansion and activation are present at an earlier stage of B cell differentiation than previously appreciated. They identified patterns of gene activity that could be used as biomarkers for disease development.

"Our data indicate a disease signature across all cell subsets, and importantly on mature resting B cells, suggesting that such cells may have been exposed to disease-inducing signals," the authors write.

The paper reflects a collaboration between the laboratories of Jeremy Boss, PhD, chairman of microbiology and immunology, and Ignacio (Iñaki) Sanz, MD, head of the division of rheumatology in the Department of Medicine. Sanz, recipient of the 2019 Lupus Insight Prize from the Lupus Research Alliance, is director of the Lowance Center for Human Immunology and a Georgia Research Alliance Eminent Scholar. The first author is Christopher Scharer, PhD, assistant professor of microbiology and immunology.

The researchers studied blood samples from 9 African American women with SLE and 12 healthy controls. They first sorted the B cells into subsets, and then looked at the DNA in the women's B cells, analyzing the patterns of gene activity. Sanz's team had previously observed that people with SLE have an expansion of "activated naïve" and DN2 B cells, especially during flares, periods when their symptoms are worse.

By examining epigenetic parameters - inherited traits not encoded in the DNA sequence -- and patterns of gene activity, the researchers could see signs of activation in "resting naïve" B cells, which precede the activated naïve cells. They were able to surmise that resting naïve cells are being stimulated through particular receptor pathways. This "provides an important window to understand early antigenic triggers," the authors write. The authors were also able to identify regulatory networks that drive the disease phenotype in SLE B cells. Together, these their results open up new avenues for future investigation and therapeutic interventions.

New research published in Respirology suggests that some respiratory symptoms may predict an earlier death in older adults. Also, such predictions differ by smoking status.

In the study of 2087 older Australians with 22 years of follow-up, shortness of breath predicted a shorter life expectancy irrespective of smoking status. Cough in former smokers and wheeze in current smokers predicted shorter life expectancy.

The estimated remaining life expectancy of a 70-year-old male never smoker with no symptoms was 16.6 years. The years of life lost for a 70-year-old male current smoker with cough, shortness of breath, and wheeze compared with a never smoker with no symptoms was 4.93 years with 2.99 years being attributed to their current smoking and the remainder to their respiratory symptoms.

"If older people are experiencing even mild respiratory symptoms, they may benefit from visiting their general practitioner for further investigations," said lead author Kate Petrie, of Monash University, in Australia.

BETHESDA, MD (July 3, 2019) -- As hospitals look for ways to stem the opioid crisis, a survey of health-system pharmacy directors released today found that most large health systems have active stewardship programs to prevent the misuse of opioids -- with pharmacists playing a key role in detecting drug diversion and identifying strategies to encourage appropriate opioid prescribing. The findings are part of the National Survey of Pharmacy Practice in Hospital Settings, published in the AJHP, the journal of ASHP (American Society of Health-System Pharmacists). The survey also explores the expanding role of hospital and health-system pharmacists in drug therapy monitoring and providing care in outpatient clinics.

"Hospital and health-system pharmacists play a major role as patient care providers on the interprofessional team in managing medication therapy, educating patients and other providers, and helping to solve public health issues like the opioid crisis and drug shortages," said Michael Ganio, Pharm.D., M.S., ASHP's Director of Pharmacy Practice and Quality and an author of the study. "Pharmacists possess unique knowledge, skills, and abilities that make them critical team members to help ensure that medication use is optimal, safe, and effective. That is why hospitals and health systems rely on them to take a leading role in addressing the opioid crisis and many other medication-related areas."

The National Survey of Pharmacy Practice in Hospital Settings -- 2018 analyzes pharmacy's role in drug therapy monitoring and patient education. In addition to opioid stewardship programs, the survey covers several contemporary pharmacy practice issues, including management of medication therapy activities, and pharmacist participation in outpatient clinics. The study includes responses from pharmacy directors in 811 general and children's hospitals in the U.S.

The most common strategies that health systems employ for preventing opioid misuse include providing clinician education and guidelines (71.4 percent), followed by using prescription drug monitoring database searches to track prescribing practices and patient behaviors that can lead to abuse (65.3 percent), and opioid diversion detection programs (55.6 percent).

In opioid stewardship, pharmacists most commonly play a role in diversion detection (70.8 percent). Pharmacists are also likely to be involved in clinical utilization review (57.2 percent), leadership and accountability (54.8 percent), and prescribing support (34.5 percent).

Other health-system strategies to prevent opioid misuse include limiting supplies of opioid prescriptions on home discharge, naloxone dispensing or education, opioid medication reconciliation during transitions of care, prescription opioid takeback programs, and medication-assisted opioid addiction management. Strategies employed to encourage appropriate prescribing include monitoring opioid prescribing practices to identify outliers among clinicians, using clinical decision-support, imposing restrictions on specific opioids or doses, and providing daily feedback to prescribers.

Medication Monitoring

The survey also shows that pharmacists are integral to drug therapy management, a comprehensive and proactive approach to medication monitoring that involves selecting appropriate drug therapies, educating and monitoring patients, and assessing patient outcomes. More than 60 percent of hospitals routinely assign pharmacists to provide drug therapy management services to a majority of patients.

Pharmacists are managing medication therapy activities that include, but are not limited to, monitoring therapeutic drug levels, patient outcomes and laboratory results, adverse drug event monitoring, adjusting medication regimens, and monitoring medication errors - for a growing portion of their patients. More than 75 percent of patients were monitored in more than 60 percent of hospitals in 2018 compared to just 20 percent of hospitals in 2000. A third of hospitals have pharmacists monitor all medication therapy, while 47 percent use electronic health records or clinical surveillance software to identify patients in need of additional pharmacist monitoring. Less than 8 percent, typically smaller hospitals, use a paper-based screening process to identify patients whose medication should be monitored by pharmacists.

A third of health-systems have pharmacists practicing in primary or specialty care clinics, including anticoagulation, oncology, family medicine, diabetes, cardiovascular disease, and infectious disease.

Survey responses were collected online between July 2018 and September 2018 from general and children's medical-surgical hospitals in the United States in the IMS Health hospital database.

In a study of 375 adults who have successfully maintained weight loss and who engage in moderate-to-vigorous intensity physical activity, most reported consistency in the time of day that they exercised, with early morning being the most common time.

The Obesity study also found that being consistent in the timing of physical activity was associated with higher physical activity levels, regardless of whether people exercised consistently during the morning, afternoon, or evening.

"Our findings warrant future experimental research to determine whether promoting consistency in the time of day that planned and structured physical activity is performed can help individuals achieve and sustain higher levels of physical activity," said senior author Dale Bond, PhD of the Brown Alpert Medical School. "It will also be important to determine whether there is a specific time of day that is more advantageous for individuals who have initial low physical activity levels to develop a physical activity habit," added first author Leah Schumacher, PhD.

'Grandmother, why do you have such big ears?' is one of the most well-known questions in literature, posed of course by Red Riding Hood as she hesitantly observes the wolf dressed in her Grandmother's clothes. Had Red Riding Hood been a physicist, she might well have asked: 'Grandmother, why are your two ears exactly the same length?' Scientists have been aware of this 'length problem' for a long time, but it was largely overlooked for most of the twentieth century. Robert B. Laughlin, who won the Nobel Prize for physics in 1998, wrote an interesting paper on the topic. In 'Critical waves and the length problem of biology' Laughlin states that for a long period of time no significant progress was made into understanding how organisms regulate their length. He proposed that living things can size themselves and that once they have acquired this information, they can respond accordingly - for example, by ceasing to grow their arms or legs once these limbs have reached their 'desired' size.

Physicists at Saarland University have picked up on these ideas and have developed a mathematical model that can be used to describe how biological systems can measure their length. Graduate student, Frederic Folz, who addressed the problem in his Master's thesis, has now published the results in the highly ranked journal Physical Review E in a paper co-authored by Giovanna Morigi, Professor of Theoretical Quantum Physics, Karsten Kruse, Professor of Theoretical Biological Physics, and Lukas Wettmann, a PhD student in Kruse's group.

The scientists chose to study axons as their model system. Axons are key components of nerve cells (neurons). Axons act as a link between nerve cells and enable electrical signals to pass from one neuron to another. As the length of an axon can vary from a few micrometres to several metres, organisms must obviously have some means of controlling how long specific axons should grow. 'We have managed to develop a model of a mechanism that explains how an organism can do just that. The model not only explains how neurons can determine their own length, it can also be generalized to other biological systems,' explains Frederic Folz.

The chemical signalling molecules that regulate growth in biological systems behave in the following manner: 'The molecules spread through the system as chemical waves until they reach the end of the axon,' says Folz. If the frequency at which this 'molecular wave' returns to its point of origin is high, the biological structure through which the wave has passed is short; if the frequency of such a cycle is low, then it has taken longer for the chemical to return and the structure is correspondingly large. A molecule needs less time to travel a few micrometres within a bacterium than it does to travel from the root to the crown of an oak tree. The physicists have described this mechanism using a mathematical model.

The researchers surmise that a biological system, such as a tree, a human or a cell, can 'measure' the frequency of these cycles and can therefore determine and hence control the length of, say, a leaf or a leg.

Their work could be of fundamental importance to future research into a variety of diseases. 'Our model can also be used in the electronics sector to regulate different physical quantities,' says Folz. The model also incorporates elements that can describe the dynamics of the internet and, more generally, other artificial networks and could well form the basis for further developments and improvements in these areas.

A study from the University of Exeter has found that mycoprotein, the protein-rich food source that is unique to Quorn products, stimulates post-exercise muscle building to a greater extent than milk protein.

The study evaluated the digestion of protein, which allows amino acids (the building blocks of protein) to increase in the bloodstream and then become available for muscle protein building in 20 healthy, trained young men at rest and following a bout of strenuous resistance exercise.

The young men performed the exercise and were then given either milk protein or mycoprotein.

Their muscle building rates were then measured using stable isotope labelled "tracers" in the hours following protein consumption.

Animal proteins like milk are an excellent source for muscle growth, so they provide a useful comparison for testing other protein sources.

The results showed that while those who ingested milk6 protein increased their muscle building rates by up to 60%, those who had mycoprotein increased their muscle growth rates (MGRs) by more than double this - showing that mycoprotein, the main ingredient in all Quorn products, is a more effective source of protein to promote muscle growth.

"These results are very encouraging when we consider the desire of some individuals to choose non-animal derived sources of protein to support muscle mass maintenance or adaptations with training," said Dr Benjamin Wall, Associate Professor of Nutritional Physiology, University of Exeter.

"Our data show that mycoprotein can stimulate muscles to grow faster in the hours following exercise compared with a typical animal comparator protein (milk protein) - we look forward to seeing whether these mechanistic findings translate to longer term training studies in various populations."

Tim Finnigan, Chief Scientific Adviser for Quorn Foods, said "We're excited to see this data being presented by the University of Exeter at ECSS. In a world where many people are trying to cut back on their meat consumption, either for environmental or health reasons, we're happy to be able to offer an alternative protein that can provide exceptional nutrition and muscle growth, all while being meat-free."

Recent research has suggested that current recommendations for protein intake are too low - some scientists have calculated that minimum protein requirements could have been underestimated by as much as 30-50% in some populations.1

The British Nutrition Foundation already recommends mycoprotein as a good source of dietary protein, both for everyday life and for sport and exercise.

However, in the UK roughly a third of total protein consumption comes from meat products - and increasing meat intake may have serious consequences for public health and for the environment.

A pivot to "alternative" sources of protein therefore may be advisable - and mycoprotein is well placed to fill the gap.