Culture

Biological organisms (such as elephant trunks, octopus tentacles, and human tongues) show remarkable dexterity and self-adaptation in unstructured environments, relying on the multiple-mode actuations of the skeleton-free muscular hydrostats. In general, muscular hydrostats mainly consist of well-ranged active 3D muscle-fiber arrays bundled by passive connective tissues (Fig. 1A). By selectively actuating the active 3D muscle-fiber arrays, muscular hydrostats can generate elongation, bending, contraction and twisting. Producing such multiple-mode actuation of muscular hydrostats is an interesting but long-lasting challenge in the field of robotics.

During past decades, many artificial muscles (such as dielectric elastomer actuators, pneumatic elastomer actuators, shape memory alloy/polymers) have been well developed to generate various actuations, which have been widely used in soft robotic systems. However, existed artificial muscles usually suffer from single actuation mode, such as elongation, bending, contraction, or twisting. Therefore, the development of artificial muscles with multiple-mode actuations remains elusive.

To address this challenge, inspired by the 3D muscle-fiber arrays in muscular hydrostats, a group from Shanghai Jiao Tong University, led by Professors Guoying Gu and Xiangyang Zhu, reported a class of multiple-mode pneumatic artificial muscles, called MAIPAMs, that are capable of multiple-mode actuations, like muscular hydrostats. The MAIPAMs mainly consist of active 3D elastomer-balloon arrays bundled by a passive elastomer membrane (Fig. 1B). When the compressed air is applied, each active elastomer balloon can generate an elongation while the passive elastomer membrane can transform the elongation into multiple-mode actuations, including elongation, bending, and spiraling (Fig. 1C). For the design and fabrication, a planar design and one-step rolling fabrication approach (Fig. 1D-E) is proposed to build the active 3D elastomer-balloon arrays of the MAIPAMs. In this sense, different MAIPAMs can be created to achieve complex actuation modes, such as parallel elongation-bending-spiraling actuations, parallel 10 bending actuations for omnidirectionally recording videos in a confined space, and cascaded elongation-bending-spiraling actuations for gripping. Owing to the scalable advantages of the planar design and rolling fabrication approach, MAIPAMs can also integrate limiting layers for contraction and twisting actuation modes, or compliant electrodes for self-sensing. They finally demonstrate that the MAIPAMs shows promising potentials in the field of soft robotics, such as detecting environments, manipulating or gripping objects, and climbing inside a pipe-line.

A Pediatric Policy Council state of the art plenary session during the Pediatric Academic Societies (PAS) 2021 Virtual Meeting explored the role of public health research in iterative policymaking to reduce gun violence in America.

The toll of gun violence on young people represents one of the most significant public health challenges facing contemporary America. In recent years, firearm-related injury and death has made headlines routinely, including mass shootings at schools, public festivals, and places of worship, while daily occurrences of gun violence affect local communities.

Gun violence touches young people directly, impacting them, their family members and friends. Additionally, the ongoing threat of gun violence, reinforced through regular active shooter drills in schools and media reports, extends the detrimental effects of gun violence further through biological stress mechanisms.

Despite the frequency of these tragic events, too little research into interventions and public policies to reduce gun violence has been conducted in over two decades due in large part to a reticence on the part of the federal government to fund such work.

In 2019, the Pediatric Policy Council engaged in successful advocacy efforts that helped to appropriate $25 million to the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) to administer grants for firearm research. Still, the U.S. has lagged behind its peers in identifying and implementing policies to address this problem.

"I'm eager to speak candidly with our expert panel about the challenges of advocating for firearm policy and the unique position of pediatricians to engage in this critical work," said Shale Wong, MD, MSPH. "Our president has charged Congress to act. Together with the power of youth advocates, we must garner the energy, confidence and perseverance to put our children first and decrease access to firearms. Our actions can save lives."

Presentations included:

Policies that work to reduce gun violence; presenter: Joshua Sharfstein, MD - Johns Hopkins Bloomberg School of Public Health

Research and evidence to reduce firearm injuries; presenter: Lois Lee, MD, MPH - Boston Children's Hospital/Harvard Medical School

Role of physician advocacy for gun violence prevention; presenter: Benjamin Hoffman, MD - OHSU

Dr. Wong and Shetal Shah, MD, chaired the session, "The Role of Research in Reducing Gun Violence: A Pediatric Policy Council State of the Art Plenary," on Sunday, May 2 at 10 a.m. EDT. Reporters interested in an interview with the presenters should contact PAS2021@piercom.com.

The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. For more information about the PAS Meeting, please visit http://www.pas-meeting.org.

Researchers at University of California San Diego School of Medicine, with colleagues elsewhere, have used gene therapy to prevent learning and memory loss in a mouse model of Alzheimer's disease (AD), a key step toward eventually testing the approach in humans with the neurodegenerative disease.

The findings are published online in advance of the June 11, 2021 issue of Molecular Therapy-Methods & Clinical Development.

AD is characterized by the accumulation of clumps of misfolded proteins called amyloid plaques and neurofibrillary tau tangles, both of which impair cell signaling and promote neuronal death. Current AD treatments targeting plaques and tangles address only symptoms, which the study's authors say suggests a reversal and cure of AD will likely require a combination of interventional approaches that both decrease aggregating toxins and promote neuronal and synaptic plasticity.

Gene therapy is based on the premise that introducing a therapeutic compound to a precisely targeted region of the brain may restore or protect normal neural function and/or reverse neurodegenerative processes. In this case, researchers used a harmless adeno-associated viral vector to introduce synapsin-Caveolin-1 cDNA (AAV-SynCav1) into the hippocampus region of three-month-old transgenic AD mice.

The mice had been genetically modified to exhibit learning and memory deficits at 9 and 11 months, respectively. These deficits are associated with decreased expression of Caveolin-1, a scaffolding protein that builds the membranes housing cellular signaling tools, such as neurotrophin receptors that receive the critical extracellular signals, which govern all cellular life and function. With decay and destruction of these membranes, cell dysfunction and neurodegeneration follow.

"Our goal was to test whether SynCav1 gene therapy in these AD mouse models might preserve neuronal and synaptic plasticity in targeted parts of the membrane, and improve higher brain function," said senior author Brian P. Head, PhD, adjunct professor in the Department of Anesthesiology at UC San Diego School of Medicine and research health scientist at the VA San Diego Healthcare System.

And, in fact, that's what happened after mice received a single injection of AAV-SynCav1 to their hippocampus, which is a complex region deep within the brain that plays a major role in learning and memory. In AD, the hippocampus is among the first areas of the brain to be impaired.

At 9- and 11-months, said Head, hippocampal learning and memory in the mice were preserved. Moreover, researchers found that critical membrane structures and associated neurotrophin receptors also remained intact. Furthermore, these neuroprotective effects from SynCav1 gene delivery occurred independent of reducing amyloid plaque depositions.

"These results suggest SynCav1 gene therapy is an attractive approach to restore brain plasticity and improve brain function in AD and potentially in other forms of neurodegeneration caused by unknown etiology," wrote the authors.

Head's laboratory is currently testing SynCav1 gene delivery in other AD models at symptomatic stages as well as in a mouse model of amyotrophic lateral sclerosis (Lou Gehrig's disease). He hopes to advance this work to human clinical trials soon.

During the next 10 years, an estimated half-million individuals in the U.S. with autism spectrum disorder (ASD) are expected to transition from adolescence to adulthood, according to the Centers for Disease Control and Prevention.

That means thousands of these young adults will likely fall into a widening and potentially devastating gap in a variety of services--because they're too old for high school, but may not qualify for Medicaid-funded services, social work researchers at Case Western Reserve University predict in a new study.

The team of researchers from the Jack, Joseph and Morton Mandel School of Applied Social Sciences interviewed 174 families from Northeast Ohio to examine the use of health, medical and social services for youth with autism--from 16 to 30 years old--and their family caregivers. The study was funded by the International Center for Autism Research and Education (ICARE) through a Mt. Sinai Health Care Foundation catalytic grant and a grant from the Mandel School.

The findings, recently published in the Journal of Autism and Developmental Disorders, show that having a Medicaid waiver and high school enrollment emerged as "the most robust and consistent" predictors of youth with autism and their families using available services.

Those services include improved job training and access to medical care, speech and occupational therapy and transportation. Autism, a neurological condition typically diagnosed by age 3, often affects a person's communication abilities and social skills.

Having ample services available is vital, said Karen Ishler, a senior research associate at the Mandel School and the study's lead author.

"These findings provide a snapshot of the 'service cliff' faced by families and highlight the need for additional research," she said. "It reaffirms that once individuals leave high school, they are less likely to receive services. But having a Medicaid waiver provides a gateway to receiving all sorts of services."

David Biegel, the Henry L. Zucker Professor of Social Work Practice Emeritus at the Mandel School and a co-author of the study, noted that how states administer Medicaid waivers varies widely. Ohio has been generous in some regards, he said, but other states have done better for those with autism.

"Pennsylvania, for example, has a Medicaid waiver available specifically for those with autism," he said. "So when you apply, you don't have to compete with individuals with other health conditions."

Ishler said states like Ohio could take a lead role to address the issue, "but that also takes dollars and some motivation."

That would involve finding other options for funding services, changing eligibility requirements for Medicaid waivers and reducing the wait list, the researchers said. "Autism spectrum disorder affects the entire family," Biegel said.

"Many young people with ASD are at risk for reduced quality of life in adulthood," he said. "Additionally, families of adolescents and young adults with ASD face all kinds of stressors--especially during those critical, post-high school transition years."

Take, for example, finding a job. Students with autism are allowed to stay in Ohio public schools until age 22. When they finish, though, employment training and supports often dry up, according to the study.

It's something only made more challenging by the global COVID-19 pandemic.

"I think about some of these families, about how difficult it must be at home--especially for those whose youth have complex service needs," Ishler said.

ORLANDO, Fla. (May 3, 2021) - Researchers have identified a gene expressed in children with acute myeloid leukemia (AML) that could serve as a new immunotherapy treatment target, according to a new study published today in Blood Advances, a journal of the American Society of Hematology. The study, co-authored by researchers with Nemours Children's Health System, outlines the process and potential path for new immunotherapy drugs that improve survival and reduce treatment-related toxicity in children with AML.

Leukemia is the most common cancer in children and teens, and AML accounts for nearly one-fourth of those cases. AML is a fast-growing cancer that typically starts in immature bone marrow cells.

"Using genomic sequencing data, we identified novel targets for children's cancer and worked with collaborators to engineer new therapies for children with AML, rather than repurpose drugs from the adult cancer realm that don't work well in children," said E. Anders Kolb, MD, director of Nemours' Center for Childhood Cancer Research and a senior author of the study.

The researchers obtained genomic data from more than 2,000 pediatric patients with leukemia, to identify associated gene variants. Through genomic sequencing, they found that the gene mesothelin (MSLN) is abnormally expressed in more than one-third of childhood and young adult AML cases but was absent in normal bone marrow cells.

After this discovery, the researchers chose new immunotherapy drugs that would target MSLN to test in cell lines and animal models, to gauge pre-clinical effectiveness of leukemia therapies. Two experimental immunotherapy drugs were tested: anetumab ravtansine (Bayer), which is being tested in adult cancers, and a new compound, anti-MSLN-DGN462 (ImmunoGen). Each drug, in lab testing and in mouse models, produced potent destruction of leukemia cells. These drugs belong to a new class of cancer treatments known as anti-body drug conjugates (ADCs), which combine an antibody with a cancer-killing toxin. The antibody targets specific types of cancer cells and delivers the toxin directly to them, minimizing damage to healthy cells.

"We are working to show a proof of principle that we can create custom therapies for pediatric malignancies and turn the drugs we're testing in the lab into clinical trials," said Sonali P. Barwe, PhD, the study's co-lead author and head of the Preclinical Leukemia Testing Laboratory in Nemours' Center for Childhood Cancer Research.

The rapid evolution of genomic sequencing funded by the National Institutes of Health has led to the identification of new gene targets that are relevant for a significant number of patients. In addition, local organizations, such as the Leukemia Research Foundation of Delaware, have funded efforts like this study by Nemours to find new treatments.

Coronavirus (CoVs) infection in animals and humans is not new. The earliest papers in the scientific literature of coronavirus infection date to 1966. However, prior to SARS-CoV, MERS-CoV, and SARS-CoV-2, very little attention had been paid to coronaviruses.

Suddenly, coronaviruses changed everything we know about personal and public health, and societal and economic well-being. The change led to rushed analyses to understand the origins of coronaviruses in humans. This rush has led to a thus far fruitless search for intermediate hosts (e.g., civet in SARS-CoV and pangolin in SARS-CoV-2) rather than focusing on the important work, which has always been surveillance of SARS-like viruses in bats.

To clarify the origins of coronavirus' infections in humans, researchers from the Bioinformatics Research Center (BRC) at the University of North Carolina at Charlotte (UNC Charlotte) performed the largest and most comprehensive evolutionary analyses to date. The UNC Charlotte team analyzed over 2,000 genomes of diverse coronaviruses that infect humans or other animals.

"We wanted to conduct evolutionary analyses based on the most rigorous standards of the field," said Denis Jacob Machado, the first author of the paper. "We've seen rushed analyses that had different problems. For example, many analyses had poor sampling of viral diversity or placed excessive emphasis on overall similarity rather than on the characteristics shared due to common evolutionary history. It was very important to us to avoid those mistakes to produce a sound evolutionary hypothesis that could offer reliable information for future research."

The study's major conclusions are:

1) Bats have been ancestral hosts of human coronaviruses in the case of SARS-CoV and SARS-CoV-2. Bats also were the ancestral hosts of MERS-CoV infections in dromedary camels that spread rapidly to humans.

2) Transmission of MERS-CoV among camels and their herders evolved after the transmission from bats to these hosts. Similarly, there was transmission of SARS-CoV after the bat to human transmission among human vendors and their civets. These events are similar to the transmission of SARS-CoV-2 by fur farmers to their minks. The evolutionary analysis in this study helps to elucidate that these events occurred after the original human infection from lineages of coronaviruses hosted in bats. Therefore, these secondary transmissions to civet or mink did not play a role in the fundamental emergence of human coronaviruses.

3) The study corroborates the animal host origins of other human coronaviruses, such as HCoV-NL63 (from bat hosts), HCoV-229E (from camel hosts), HCoV-HKU1 (from rodent hosts) and HCoV-OC43 and HECV-4408 (from cow hosts).

4) Transmission of coronaviruses from animals to humans occurs episodically. From 1966 to 2020, the scientific community has described eight human-hosted lineages of coronaviruses. Although it is difficult to predict when a new human hosted coronavirus could emerge, the data indicate that we should prepare for that possibility.

"As coronavirus transmission from animal to human host occurs episodically at unpredictable intervals, it is not wise to attempt to time when we will experience the next human coronavirus," noted professor Daniel A. Janies, Carol Grotnes Belk Distinguished Professor of Bioinformatics and Genomics and team leader for the study. "We must conduct research on viruses that can be transferred from animals to humans on a continuous rather than reactionary basis."

Many miles of streams and rivers in the United States and elsewhere are polluted by toxic metals in acidic runoff draining from abandoned mining sites, and major investments have been made to clean up acid mine drainage at some sites. A new study based on long-term monitoring data from four sites in the western United States shows that cleanup efforts can allow affected streams to recover to near natural conditions within 10 to 15 years after the start of abatement work.

The four mining-impacted watersheds--located in mountain mining regions of California, Colorado, Idaho, and Montana--were all designated as Superfund sites under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), which helps fund the cleanup of toxic-waste sites in the United States. They are among the few acid mine drainage sites where scientists have conducted extended studies to monitor the effectiveness of the remediation efforts.

"The good news from them all is that Superfund investments can restore the water quality and ecological health of the streams," said David Herbst, a research scientist at UC Santa Cruz and coauthor of a paper on the new findings to be published in the June issue of Freshwater Science. The paper is currently available online.

For the past two decades, Herbst has been monitoring streams affected by acid mine drainage from the Leviathan mine in the central Sierra Nevada. The new study developed out of discussions he had with other scientists involved in long-term studies of similar sites.

"There are not many of these long-term studies of impacted watersheds, and by combining our data we could identify the common threads of recovery between these different sites," Herbst said.

To assess the recovery of aquatic life in streams and rivers severely polluted by the abandoned mines, the researchers combined data from long-term monitoring over periods of 20 years or more. They used aquatic insects and other diverse invertebrate life (such as flatworms and snails) as indicators of the restoration of ecological health, with nearby unpolluted streams serving as standards for comparison.

Even with differing mixes of toxic metals and different treatment practices used to control the pollution at each site, the studies documented successful recovery to near natural conditions within 10 to 15 years. Much of the recovery was rapid, occurring within the first few years of treatment.

"These promising results and shared paths suggest that even daunting environmental problems can be remedied given the effort and investment," Herbst said.

The research also revealed that the sites shared common responses despite differences in the species of aquatic life occurring across this broad geographic region. Shared feeding habits, patterns of development, and behavioral characteristics unified how stream invertebrates responded to the alleviation of metal pollutants.

Species with traits such as feeding on algae, long life cycles, and clinging to the surfaces of stones became increasingly common as toxicity declined over time. Species that were more prevalent when metal concentrations were higher had traits such as rapid development, short life cycles, feeding on deposits of organic matter, and an ability to escape quickly off the bottom by drifting into the flow of water.

The species most sensitive to toxic metals are the mayflies, stoneflies, and caddisflies. Across all streams, the loss of these sensitive insects occurred at a toxicity level predicted by lab bioassays based on the combined levels of the toxic metals present.

"The convergence of these responses across streams and at a level consistent with how water quality criteria are established lends support to guidelines established for what chemical conditions are protective of stream and river ecosystems," Herbst said.

The additive toxicity of the metals present determined the response to pollutants, he noted, showing that water quality standards should be based on combined metals present rather than singly for each metal. In other words, even if a metal is below its toxic level, when it is present with other metals the combined effect may exceed the tolerance of aquatic life.

"It is vital to account for this factor in how water quality standards for metals are applied," Herbst said.

BOSTON -- Immunity often calls to mind the adaptive immune response, made up of antibodies and T cells that learn to fight specific pathogens after infection or vaccination. But the immune system also has an innate immune response, which uses a set number of techniques to provide a swift, non-specialized response against pathogens or support the adaptive immune response.

In the past few years, however, scientists have found that certain parts of the innate immune response can, in some instances, also be trained in response to infectious pathogens, such as HIV. Xu Yu, MD, a Core Member of the Ragon Institute of MGH, MIT and Harvard, and colleagues recently published a study in the Journal of Clinical Investigation which showed that elite controllers, a rare subset of people whose immune system can control HIV without the use of drugs, have myeloid dendritic cells, part of the innate immune response, that display traits of a trained innate immune cell.

"Using RNA-sequencing technology, we were able to identify one long-noncoding RNA called MIR4435-2HG that was present at a higher level in elite controllers' myeloid dendritic cells, which have enhanced immune and metabolic states," says Yu. "Our research shows that MIR4435-2HG might be an important driver of this enhanced state, indicating a trained response."

Myeloid dendritic cells' primary job is to support T cells, which are key to the elite controllers' ability to control HIV infection. Since MIR4435-2HG was found in higher levels only in cells from elite controllers, Yu explains, it may be part of a learned immune response to infection with HIV. Myeloid dendritic cells with increased MIR4435-2HG also had higher amounts of a protein called RPTOR, which drives metabolism. This increased metabolism may allow the myeloid dendritic cells to better support the T cells controlling the HIV infection.

"We used a novel sequencing technology, called CUT&RUN, to study the DNA of these cells," says postdoctoral fellow Ciputra Hartana, MD, PhD, the paper's first author. "It allowed us to study epigenetic modifications like MIR4435-2HG, which are molecules that bind to the DNA and change how, or if, the DNA is read by the cell's machinery."

The team found that MIR4435-2HG might work by attaching to the DNA near the location of the RPTOR gene. The bound MIR4435-2HG would then encourage the cell's machinery to make more of the RPTOR protein, using the instructions found in the RPTOR gene. This type of epigenetic modification, a trained response to HIV infection, would allow the myeloid dendritic cells to stay in an increased metabolic state and therefore provide long-term support to the T cells fighting the virus.

"Myeloid dendritic cells are very rare immune cells, accounting for only 0.1-0.3% of cells found in human blood," says Yu. "We were fortunate and thankful to have access to hundreds of millions of blood cells from the many study participants who have donated their blood to support our HIV research. These donations were key to making this discovery."

Understanding exactly how elite controllers' immune systems can control HIV is a key part of HIV cure research. If scientists can understand how elite controllers suppress this deadly virus, they may be able to develop treatments that allow other people living with HIV to replicate the same immune response, removing the need for daily medication to control the virus and achieving what is known as a functional cure.

In the field of molecular epidemiology, the worldwide scientific community has been steadily sleuthing to solve the riddle of the early history of SARS-CoV-2. Despite recent efforts by the World Health Organization, no one to date has identified the first case of human transmission, or "patient zero" in the COVID-19 pandemic.

Finding the earliest possible case is needed to better understand how the virus may have jumped from its animal host first to infect humans as well as the history of how the SARS-CoV-2 viral genome has mutated over time and spread globally.

Since the first SARS-CoV-2 virus infection was detected in December 2019, well over a million genomes of SARS-CoV-2 have been sequenced worldwide, revealing that the coronavirus is mutating, albeit slowly, at a rate of 25 mutations per genome per year. The sheer number of emerging variants, including the UK (B.1.1.1.7), South African (B.1.351), South American (P.1) and now, Indian (B.1.617) have not only come to replace prior dominant strains in their respective regions, but still threaten world health due to their potential to escape today's vaccines and therapeutics.

"The SARS-CoV-2 virus has already infected more than 145 million people and caused 3 million deaths across the world," said Sudhir Kumar, director of the Institute for Genomics and Evolutionary Medicine, Temple University. "We set out to find the genetic common ancestor of all these infections, which we call the progenitor genome."

This progenitor genome (proCoV2) is the mother of all SARS-CoV-2 coronaviruses that has infected and continue to infect people today.

In the absence of patient zero, Kumar and his research team now may have found the next best thing to aid the worldwide molecular epidemiology detective work. "We reconstructed the genome of the progenitor and its early pedigree by using a big dataset of coronavirus genomes obtained from infected individuals since December 2019," said Kumar, the lead author of a new study, appearing in advanced online edition of the journal Molecular Biology and Evolution.

They found that the progenitor gave rise to a family of coronavirus strains, whose members included the strains found in Wuhan, China, in December 2019. "In essence, the events in December in Wuhan, China, represented the first superspreader event of a virus that had all the tools necessary to cause a worldwide pandemic right out of the box." said Kumar.

Kumar's group estimates that the SARS-CoV-2 progenitor was already circulating with an earlier timeline--at least 6 to 8 weeks prior to the first genome sequenced in China, known as Wuhan-1. "This timeline puts the presence of proCoV2 in late October 2019, which is consistent with the report of a fragment of spike protein identical to Wuhan?1 in early December in Italy, among other evidence," said Sayaka Miura, a senior author of the study.

"We have found progenitor genetic fingerprint in January 2020 and later in multiple coronavirus infections in China and the USA. The progenitor was spreading worldwide months before and after the first reported cases of COVID-19 in China," said Pond.

Besides their findings on SARS-CoV-2's early history, Kumar's group also has developed intuitive mutational fingerprints and Greek symbol classification (ν, α, β, γ, δ, and ε) to simplify the categorization of the major strains, sub-strains and variants infecting an individual or colonizing a global region. This may help scientists better trace and provide context for the order of emergence of new variants.

"Overall, our mutational fingerprinting and nomenclature provide a simple way to glean the ancestry of new variants as compared to phylogenetic designations, e.g., B.1.351 and B.1.1.7," said Kumar.

For example, an α fingerprint refers to genomes that one or more of the α variants and no other subsequent major variants, and αβ fingerprint refers to genomes that contain all α, at least one β variant, and no other major variants.

"With our tools, we observed the spread and replacement of prevailing strains in Europe (αβε with αβζ) and Asia (α with αβε), the preponderance of the same strain for most of the pandemic in North America (αβ?δ), and the continued presence of multiple high?frequency strains in Asia and North America," said Pond.

Getting to the root of the problem

To identify the progenitor genome, they used a approach not applied to SARS-CoV-2 previously, called mutation order analysis. The technique, which is used extensively in cancer research, relies on a clonal analysis of mutant strains and the frequency in which pairs of mutations appear together to find the root of the virus.

Many previous attempts in analyzing such large datasets were not successful because of "the focus on building an evolutionary tree of SARS-CoV-2," says Kumar. "This coronavirus evolves too slow, the number of genomes to analyze is too large, and the data quality of genomes is highly variable. I immediately saw parallels between the properties of these genetic data from coronavirus with the genetic data from the clonal spread of another nefarious disease, cancer."

Kumar and Miura have developed and investigated many techniques for analyzing genetic data from tumors in cancer patients. They adapted and innovated these techniques to build a trail of mutations that traced back to the progenitor genetic fingerprint. "The mutation tracking approach produced the progenitor and the family history of its major mutation. It is a great example of how big data coupled with biologically-informed data mining reveals important patterns," said Kumar.

An earlier timeline emerges
"This progenitor genome had a sequence very different from what some folks are calling the reference sequence, which is what was observed first in China and deposited into the GISAID SARS-CoV-2 database," said Kumar.

The closest match was to eight genomes sampled 26 to 80 days after the earliest sampled virus from 24 December 2019. Multiple close matches were found in all sampled continents and detected as late as June 2020 (pandemic day 181) in South America. Overall, 140 genomes Kumar's group analyzed all contained only synonymous differences from proCoV2. That is, all their proteins were identical to the corresponding proCoV2 proteins in the amino acid sequence. A majority (93 genomes) of these protein-level matches were from coronaviruses sampled in China and other Asian countries.

These spatiotemporal patterns suggested that proCoV2 already possessed the full repertoire of protein sequences needed to infect, spread and persist in the global human population.

They found the proCoV2 virus and its initial descendants arose in China, based on the earliest mutations of proCoV2 and their locations. Furthermore, they also demonstrated that a population of strains with at least three mutational differences from proCoV2 existed at the time of the first detection of COVID-19 cases in China. With estimates of SARS-CoV-2 acquiring 25 mutations per year, this meant that the virus must already have been infecting people several weeks before the December 2019 cases.

Mutational signatures

Because there was strong evidence of many mutations before the ones found in the reference genome, Kumar's group had to come up with a new nomenclature of mutational signatures to classify SARS-CoV-2 and account for these by introducing a series of Greek letter symbols to represent each one.

For example, they found that the emergence of α SARS-CoV-2 genome variants came before the first reports of COVID-19. This strongly implies the existence of some sequence diversity in the ancestral SARS-CoV-2 populations. All 17 of the genomes sampled from China in December 2019, including the designated SARS-CoV-2 reference genome, carry all three α variants. But, 1,756 genomes without α variants were sampled across the world until July 2020. Therefore, the earliest sampled genomes (including the designated reference) were not the progenitor strains.

It also predicts the progenitor genome had offspring that were spreading worldwide during the earliest phases of COVID-19. It was ready to infect right from the start.

"The progenitor had all the ability it needed to spread," said Pond. "There is an overabundance of non-synonymous changes in the population. What happened between bats and humans remains unclear, but proCoV2 could already infect at pandemic scales."

A global spread

Altogether, they have identified seven major evolutionary lineages and the episodic nature of their global spread. The proCoV2 genome gave rise to many major offspring lineages, some of which arose in Europe and North America after the likely genesis of the ancestral lineages in China.

"Asian strains founded the whole pandemic," said Kumar. "But over time, many variants
that evolved elsewhere are now infecting Asia much more."

Their mutational-based analyses also established that North American coronaviruses harbor very different genome signatures than those prevalent in Europe and Asia.

"This is a dynamic process," said Kumar. "Clearly, there are very different pictures of spread that are painted by the emergence of new mutations, the three εs, γ&delta, which we found to occur after the spike protein change (a β mutation). Scientists are still figuring out if any functional properties of these mutations have sped up the pandemic."

Remarkably, the mutational signature of αβ?δ has remained the dominant lineage in North America since April 2020, in contrast to the turn?over seen in Europe and Asia. More recently, novel fast?spreading variants including an S protein variant (N501Y) from South Africa and the UK (B.1.1.17) have rapidly increased. Coronaviruses with N501Y variant in South Africa carry the αβγδ genetic fingerprint, whereas those in the UK carry the αβε genetic fingerprint, according to their classification scheme. "Therefore, αβ ancestor continues to give rise rise to many major offshoots of this coronavirus." Said Kumar.

Real-time updates

The MBE study relied on three snapshots were retrieved from GISAID on July 7, 2020, (a dataset of 60,332 genomes), October 12, 2020, (contained 133,741 genomes), and finally, an expanded dataset of 172,480 genomes sampled on December 30, 2020.

Moving forward, they will continue to refine their results as new data becomes available.

"More than a million SARS-CoV-2 genomes are sequenced now," said Pond. "The power of this approach is that the more data you have, the more easily you can tell the precise frequency of individual mutations and mutation pairs. These variants that are produced, the single nucleotide variants, or SNVs, their frequency, and history can be told very well with more data. Therefore, our analyses infer a credible root for the SARS-CoV-2 phylogeny."

The MBE study is part of their effort to maintain a continuous, live real-time monitoring of SARS-CoV-2 genomes, which has now grown to include more than 350,000 genomes.

"We have set up a live dashboard showing regularly updated results because the processes of data analysis, manuscript preparation, and peer?review of scientific articles are much slower than the pace of expansion of SARS?CoV?2 genome collection," said Pond. "We also provide a simple "in?the? browser" tool to classify any SARS?CoV?2 genome based on key mutations derived by the MOA analysis.

"These findings and our intuitive mutational fingerprints and barcodes of SARS-CoV-2 strains have overcome daunting challenges to develop a retrospective on how, when and why COVID-19 has emerged and spread, which is a prerequisite to creating remedies to overcome this pandemic through the efforts of science, technology, public policy and medicine," said Kumar.

DALLAS, May 4, 2021 -- A meta-analysis of 14 air pollution studies from around the world found that exposure to high levels of air pollutants during childhood increases the likelihood of high blood pressure in children and adolescents, and their risk for high blood pressure as adults. The study is published in a special issue on air pollution in the Journal of the American Heart Association, an open access journal of the American Heart Association.

Other studies look at: the effects of diesel exhaust on the muscle sympathetic nerve; the impact of pollutants on high blood pressure; rates of hospital readmission for heart failure among those exposed to high levels of ambient air pollution; and risk of stroke and heart attack after long-term exposure to high levels of particulate matter. The studies include health outcomes of people who were exposed to pollutants in the United States, China and Europe.

High blood pressure during childhood and adolescence is a risk factor for hypertension and heart disease in adulthood. Studies on air pollution and blood pressure in adolescents and children, however, have produced inconsistent conclusions. This systematic review and meta-analysis pooled information from 14 studies focused on the association between air pollution and blood pressure in youth. The large analysis included data for more than 350,000 children and adolescents (mean ages 5.4 to 12.7 years of age).

"Our analysis is the first to closely examine previous research to assess both the quality and magnitude of the associations between air pollution and blood pressure values among children and adolescents," said lead study author Yao Lu, M.D., Ph.D., professor of the Clinical Research Center at the Third Xiangya Hospital at Central South University in Changsha, China, and professor in the department of life science and medicine at King's College London. "The findings provide evidence of a positive association between short- and long-term exposure to certain environmental air pollutants and blood pressure in children and adolescents."

The analysis included 14 studies published through September 6, 2020, exploring the impact of long-term exposure (?30 days) and/or short-term exposure (

The studies were divided into groups based upon length of exposure to air pollution and by composition of air pollutants, specifically nitrogen dioxide and particulate matter with diameter ?10 μm or ?2.5 μm. (The majority of research linking heart disease with particulate matter focuses on particle matter mass, which is categorized by aerodynamic diameter - μm or PM.) Fine particles are defined as PM2.5 and larger; coarse particles are defined at PM10; and the concentrations of particulate matter are typically measured in their mass per volume of air (μg/m3).

The meta-analysis concluded:

Short-term exposure to PM10 was significantly associated with elevated systolic blood pressure in youth (the top number on a blood pressure reading).

Periods of long-term exposure to PM2.5, PM10 and nitrogen dioxide were also associated with elevated systolic blood pressure levels.

Higher diastolic blood pressure levels (the bottom number on a blood pressure reading) were associated with long-term exposure to PM2.5 and PM10.

"To reduce the impact of environmental pollution on blood pressure in children and adolescents, efforts should be made to reduce their exposure to environmental pollutants," said Lu. "Additionally, it is also very important to routinely measure blood pressure in children and adolescents, which can help us identify individuals with elevated blood pressure early."

The results of the analysis are limited to the studies included, and they did not include data on possible interactions between different pollutants, therefore, the results are not generalizable to all populations. Additionally, the analysis included the most common and more widely studied pollutants vs. air pollutants confirmed to have heart health impact, of which there are fewer studies.

Durham, NC - A study released today in STEM CELLS Translational Medicine offers hope for those suffering from a chronic, difficult to treat condition called non-tuberculous mycobacteria (NTM) lung infection. The study describes how researchers at Case Western University developed a new model of NTM lung infection and then used it to show how effective human mesenchymal stem cells (hMSCs) are in treating this condition - and even which donor cells might be best for doing so.

"The potential to use human mesenchymal stem cells to treat difficult lung infections is promising," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine. "This study shows the ability of using optimal donors to obtain maximum treatment success."

NTMs are naturally occurring, and everyone inhales them into their lungs as part of daily life. For most people, they are harmless. But in a small number of vulnerable individuals, such as older people or those with cystic fibrosis (CF) or COPD, NTM bacteria can settle in the lungs and cause infection. While not contagious, more than 100,000 people are living with NTM lung disease in the U.S. alone, and that rate appears to be increasing.

"NTM infections can be very difficult to resolve," said Tracey L. Bonfield, Ph.D., the study's corresponding author. "Treatment typically requires taking multiple antibiotics, often for years. Patients who suffer from chronic NTM infection not only deal with the consequences of the disease, but also the toxicity, as well as inefficiency and side effects of the antibiotics used to treat it."

In the search for better therapies, some researchers are focusing on hMSCs, which are collected from adults and can be coaxed into becoming a variety of cells types. hMSCs have significant potential for treating infection and inflammation, Dr. Bonfield said. "They are dynamic storehouses of anti-microbial activity. They are unique in their capacity to respond to infection by secreting multiple bioactive factors, contributing to the host environment. That gives hMSCs a clinical advantage over traditional pharmaceuticals."

Previous studies by the Bonfield team described the potential for hMSCs and their secreted products ("supernatants") to treat other types of lung infections including Pseudomonas aeruginosa and Staphylococcus aureus, but these studies are the first to describe the ability of hMSCs to manage two of the most problematic groups of NTMs, Mycobacterium avium (M. avium) and Mycobacterium intracellulare (M. intracellulare). Like these current studies, hMSCs demonstrated significant anti-microbial, anti-inflammatory and anti-fibrotic potential, both in culture medium (in vitro) and in animals (in vivo). Further, they also documented that hMSC treatment improves the effectiveness of antibiotics, leading to a decrease in the dose necessary for eradicating bacteria.

At the same time, those studies pointed out that not all hMSC preparations have the same level of potency or sustainability. "This suggested to us that it is essential to identify the appropriate hMSC donor and subsequent preparation for disease specific applications. That was the goal of our current study," said Dr. Bonfield.

Both M. avium and M. intracellulare are slow growing bacteria, so researchers have found it difficult to study what happens in sustained NTM infections because in small animals the bacteria clear up quickly, while larger animals are too expensive for defining dosing, timing and duration of a new treatment, Dr. Bonfield noted. So, her team first needed to develop new models of M. avium and M. intracellulare lung infections that would effectively allow them to study this issue.

"In the earlier studies we had developed an innovative protocol in which M. avium and M. intracellulare can be evaluated over the course of a week instead of the typical four to six weeks," Dr. Bonfield explained. To sustain infection in vivo for chronic disease required an additional innovation "We did this by embedding NTMs into beads of a polysaccharide extracted from seaweed called agarose, and then injecting them into mice with CF. The beads degrade gradually, releasing the NTM into the mice and thus extending the time of infection and inflammatory response. This modeling system has been very efficient in generating acute and chronic scenarios of infection in all of our models."

The researchers then went on to identify donor-specific hMSC potency against M. avium and M. intracellulare, once again in vitro and in vivo using CF mice. "Every donor hMSC preparation has a unique profile in terms of how the cells respond to pathogens, which likely translates into their successful potency and how the patient responds to hMSC treatment," Dr. Bonfield said.

"Focusing on hMSC response to NTMs and efficiency of in vitro and in vivo anti-NTM activity provides direction for identifying the optimal hMSC signature for anti-NTM therapy. Data gained from our study begins to define this unique hMSC fingerprint."

Osaka, Japan —Straight-line constant-speed propagation in free space is a basic characteristic of light. In a recent study published in Communications Physics, researchers from Osaka University discovered the phenomenon of reciprocating propagation of laser pulse intensity in free space.

Spatiotemporal couplings have been recently used to produce light with tunable group-velocity, direction, and trajectory in free space. For example, the flying focus (a moving laser pulse intensity in the extended Rayleigh length), where longitudinal chromatism and temporal chirp are combined to control the spectrum-dependent focus-separation in space and spectrum-dependent pulse-location in time, respectively, has arbitrarily tunable propagating group-velocity and direction in space and time.

However, in the previous result, the flying focus can only propagate along a certain direction either forward or backward, although the propagating group-velocity can be freely controlled.

In this study, by dramatically increasing the Rayleigh length in space and the temporal chirp in time, the newly created flying focus propagates along a reciprocating straight-line trajectory in free space. A clear reciprocating flying focus with a high spatial resolution is also possible by further increasing the temporal chirp.

"The newly created flying focus propagates along the longitudinal axis first forward, then backward, and lastly forward again, showing a reciprocating straight-line trajectory in space and time. The forward-propagating velocity is the light speed in the vacuum, while the backward-propagating velocity is subluminal," explains corresponding author Zhaoyang Li.

This intriguing phenomenon changes the traditional understanding of light propagation and may be applied in both fundamental and applied physics.

"For example, in our radiation pressure simulation, it can produce an on-axis reciprocating trapping or pushing force for a small or big sphere, respectively, in the Rayleigh scattering regime," says Zhaoyang Li.

Cancer of the colon and rectum is one of the deadliest forms of cancer, and has in recent years affected growing numbers of young people. In the largest registry study to date, researchers at Karolinska Institutet in Sweden and Harvard University in the USA demonstrate a possible connection between colorectal polyps in close relatives and the risk of developing colorectal cancer. The study, which is published in the British Medical Journal, is of potential consequence for different countries' screening procedures.

Colorectal cancer is the second deadliest form of cancer in the world, according to the World Health Organisation (WHO). While lifestyle factors, such as overweight and sedentariness, increase the disease risk, there is also a known hereditary factor.

Most people diagnosed with the disease are over 65, but in a growing number of countries the proportion of young people affected is increasing.

Local colorectal cancer can be treated with a good prognosis; prospects are much worse, however, for patients with metastases.

In Sweden, people over 65 are offered colonoscopy screening, but more knowledge is needed about which individuals should be offered this prophylactic examination.

The disease is preceded by polyps in the mucosa of the colon. Researchers at Karolinska Institutet and Harvard University have now conducted the largest registry study to date on the relationship between colorectal cancer, and having a first-degree relative (i.e. parents and siblings) with a colorectal polyp.

The study included 68,060 patients with colorectal cancer and 333,753 healthy controls matched for parameters such as age and sex. Data on colorectal cancer and polyps were sourced from the ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden) cohort.

All other patient data were drawn from Swedish healthcare registries. The researchers also took the hereditariness of colorectal cancer into account.

They found that approximately 8.4 per cent of the participants with colorectal cancer had a sibling or parent with colorectal polyps, as opposed to 5.7 per cent of the control group.

The results show that heredity for colorectal polyps had a 40 per cent increased risk of colorectal cancer. The researchers found what appear to be several hereditary risk relationships.

"The risk was double in people with at least two first-degree relatives with polyps or a first-degree relative who had a colorectal polyp diagnosed before the age of 60." says the study's first author Mingyang Song, researcher at Harvard University.

A weakness of the study is the lack of information on other risk factors of colorectal cancer, such as lifestyle factors as well as the size and spread of the polyps. More research is now needed to corroborate the results.

"If additional studies reveal a link between a family history of polyps and the risk of colorectal cancer, it is something to take into account in the screening recommendations, especially for younger adults," says Jonas F. Ludvigsson, paediatrician at Orebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. "I really hope that this study can help doctors in Sweden and elsewhere identify patients at a higher risk of colorectal cancer."

The study was financed by the National Institutes of Health and the American Cancer Society. Jonas F. Ludvigsson heads an unrelated study commissioned by the Swedish IBD Quality Registry (SWIBREG) financed by Janssen. There are no other reported conflicts of interest.

PULLMAN, Wash. -- Professor Arda Gozen looks to a future someday in which doctors can hit a button to print out a scaffold on their 3-D printers and create custom-made replacement skin, cartilage, or other tissue for their patients.

Gozen, George and Joan Berry associate professor in the Washington State University School of Mechanical and Materials Engineering, and a team of researchers have developed a unique scaffolding material for engineered tissues that can be fine-tuned for the tricky business of growing natural tissue. They report on their research in the journal, Bioprinting. The team also includes researchers from WSU's Gene and Linda Voiland School of Chemical Engineering and Bioengineering as well as from the University of Texas-San Antonio (UTSA), Morehouse College, and University of Rochester. The lead author is Mahmoud Amr, who received his PhD at UTSA.

In recent decades, researchers have been working to use biological material in 3D printing to create tissue or organs for patients recovering from injury or disease. Using 3D printing, or additive manufacturing, makes it possible to print complex, porous, and personalized structures and could allow doctors someday to print out tissue for a patient's particular body and needs. To create biological structures, biological materials known as "bioinks" are dispensed out of a nozzle and deposited layer-by-layer, creating complex "scaffolds" for real biological material and providing a nice place for cells to grow.

Nature, however, has so far been more complicated than researchers can keep up with. Real biological cells like to grow on a scaffold that approaches their own properties. So, for instance, a skin cell wants to grow on a scaffold that feels like skin while a muscle cell will only develop on a scaffold that feels like muscle.

"The success of this method in manufacturing functional tissues relies heavily on how well the fabricated structures mimic the native tissues," Gozen said. "If you want to grow cells and turn them into functional tissue, you need to match the mechanical environment of the native tissue."

The way that researchers have traditionally varied their scaffolds was to simply remove trusses to make them softer or stiffer - a method that is too simple to address all the needed complexity in tissue engineering.

"We don't have a lot of knobs to turn," Gozen said. "You need more degrees of freedom - to create something softer or harder without changing the structure."

The team of researchers developed a new bioink material that allows for customizing properties to closer approach what cells might need. The ingredients for their scaffold include gelatin, gum Arabic, and sodium alginate, which are all common thickening agents used in many processed foods.

Similar to the way a thick rope is made of braided strands, the researchers used three separate chemical processes to tie their three ingredients together into one scaffold material for printing.

Playing with the separate chemical processes then provides a way to finely tune the mechanical properties of the material, allowing them to make a softer or stiffer final scaffold.

"That gives you the capability of tuning the properties without changing the scaffold design and gives you an additional degree of freedom that we are seeking."

By adjusting the chemical bonds between the rope strands, they didn't change the material significantly, and it was amenable for growing cartilage cells.

The work is still in its early stages, and the researchers would like to figure out how to more precisely tune the process and final material. They might look at varying the composition of their three materials or printing at different temperatures, for instance.

Trying to imitate the vast complexity of natural tissue remains a challenge. Even a simple millimeter-sized piece of cartilage on the knee for instance, has three separate and distinct layers, each with different mechanical properties and functions.

"You're not assembling Legos here. It's always about replicating nature that works with the body," Gozen said. "You can make living structures, but they look nothing like the native tissue. Precision is key because there is no single mechanical property target for a single piece of tissue."

Dating violence - physical, sexual, psychological or emotional within a relationship, including stalking - is pervasive on college campuses with far-reaching health implications. One in five women experience a sexual assault in college and students living in sorority houses are three times more likely to experience rape. College students are vulnerable to dating violence because of the influence of their social and living environments.

Researchers from Florida Atlantic University's College of Education in collaboration with Sacred Heart University conducted a study to understand the dating violence experience and perpetration of college-age women, as well as how they conceptualize violence in dating relationships. They also wanted to learn more about the role of technology within their lived experiences, which infuses most areas of American life, especially in dating and romantic relationships. Mobile technology allows 24-hour access, which also facilitates stalking and controlling behaviors.

Results of the study, published in the journal Violence Against Women, illuminate the span of dating violence knowledge among the participants and point to a lack of understanding of what constitutes emotional violence. Findings reveal normalization of unhealthy violent behaviors where sexual pressure or sexualized verbal harassment are viewed as an innate part of men, supporting the idea that "boys will be boys."

"Physically forcing you to have intercourse," was endorsed at 100 percent by participants as violent, while "emotionally pressuring you to have intercourse until you give in," was endorsed at 73.9 percent. Both scenarios indicate rape, yet one of them introduced physical dating violence, which was not acceptable to any participant. The other item introduced coercive sex, which was acceptable to about 25 percent of the participants.

Fifty-eight percent of the study participants reported not knowing how to help someone experiencing dating violence, 57 percent reported difficulty identifying what constitutes dating violence, and 38 percent noted not knowing how to get help for themselves if experiencing dating violence.

A substantially lower percentage of participants reported not experiencing in-person violence, but did report the experience of intimate partner "cyber" violence. Almost every respondent who noted having experienced intimate partner sexual, physical and emotional violence also documented experiencing intimate partner cyber violence.

Participants expressed a decreased sense of personal control over impulsivity and retaliatory behaviors when using technology in relationships, while often justifying the use of this form of violence because of the accessibility of technology. They also described ways in which they were controlled and monitored by partners.

"Unfortunately, the college students in our study demonstrated a lack of knowledge of the forms of dating violence and its consequences. They also had a tendency to normalize these behaviors, which led to acceptance, rationalizing and providing excuses for these acts of violence. Furthermore, they lacked awareness of support systems that are available," said Kelly Emelianchik-Key, Ph.D., senior author and an associate professor in the Department of Counselor Education within the College of Education.

Study participants failed to mention any resources for psychological services, therapy, prevention programming or dating violence support groups. Only 21.6 percent endorsed the desire to seek help specifically from a counselor, traditionally one of the primary services provided on most college campuses. Instead, study participants turned to peers for help. However, research has shown that peers do not know how to help and fear intruding into someone's relationship.

"Our study findings underscore the need for education and early prevention programs on campuses that give a clear message that violence - in all forms - is not acceptable or normal in relationships," said Carman S. Gill, Ph.D., co-author, professor and department chair in the clinical mental health program, FAU College of Education. "Moreover, women should recognize emotional violence as a predictor of low quality of life over time and emotional well-being. The importance of understanding emotional abuse cannot be understated, as research findings illustrate that emotional violence is just as detrimental as physical violence."

The researchers say that because it is evident that peers play a critical role in student growth and development, interventions such as peer training initiatives, need to be appropriately targeted across college campuses. They also note that to break this cycle, students could benefit from a university/college statement or policy of zero tolerance for all forms of dating violence perpetration, along with clear definitions of the forms of violence.

"By gaining a critical understanding of college women's unique experiences, we can tailor early intervention to meet the individual needs of this population before the violence becomes pervasive and affects their physical and emotional health," said Emelianchik-Key.