Culture

Announcing a new article publication for BIO Integration journal. In this research article the authors Vered Aharonson, Nabeel Seedat, Simon Israeli-Korn, Sharon Hassin-Baer, Michiel Postema and Gilad Yahalom from the University of the Witwatersrand, Johannesburg, South Africa, Tel Aviv Academic College of Engineering, Tel Aviv, Israel, Chaim Sheba Medical Center, Tel Aviv, Israel and Tel Aviv University, Israel consider automated stage discrimination of Parkinson's Disease.

Treatment plans for Parkinson's disease (PD) are based on a disease stage scale, which is generally determined using a manual, observational procedure. Automated, sensor-based discrimination saves costs in clinical settings and may offer augmented stage determination accuracy. Previous automated devices were either cumbersome or costly and were not suitable for individuals who cannot walk without support.

Since 2017, a device has been available that successfully detects PD and operates for people who cannot walk without support. In this study, the suitability of this device for automated discrimination of PD stages was tested. The authors conclude that stage discrimination of PD can be automated, even in patients who cannot support themselves. A similar method might also be successfully applied to other gait disorders BIO Integration is fully open access journal which will allow for the rapid dissemination of multidisciplinary views driving the progress of modern medicine.

KINGSTON, R.I. - June 26, 2020 -- In a new study, scientists from around the world - including a professor at the University of Rhode Island - warn that the threats posed by invasive alien species are increasing. They say that urgent action is required to prevent, detect and control invaders at both local and global levels.

Alien species are plants, animals and microbes that are introduced by people, accidentally or intentionally, into areas where they do not naturally occur. Many of them thrive, spreading widely with harmful effects on the environment, economy, or human health.

The study, published in the journal Biological Reviews, was carried out by a team of researchers from 13 countries across Africa, Asia, Australasia, Europe, and North and South America. It states that the number of invasive alien species is increasing rapidly, with more than 18,000 currently listed around the world.

According to Laura Meyerson, URI associate professor of natural resources science, the escalation in biological invasions is due to the increase in the number and variety of pathways along which species spread, and to the increasing volume of traffic associated with those pathways. For example, she notes the role played by emerging pathways such as the online trade in unusual pets and the transport of species across oceans on rafts of plastic.

The researchers note that the scale of the problem is enormous. A 2017 analysis of global extinctions revealed that alien species contributed to 25 percent of plant extinctions and 33 percent of terrestrial and freshwater animal extinctions. Meanwhile, annual environmental losses caused by introduced species in the United States, United Kingdom, Australia, South Africa, India and Brazil have been calculated at more than $100 billion.

The study also shows how drivers of global change, such as climate change, land-use change, and international trade, are exacerbating the impacts of biological invasions. Species transported through shipping can now thrive in new regions, for instance, owing to climate warming. And the permanent opening of the Arctic Ocean due to global warming is allowing marine species to move between the Atlantic and Pacific Oceans.

The research paper is part of an initiative called World Scientists' Warning to Humanity: A Second Notice, which calls for urgent change in stewardship of the Earth and the life on it. The first notice, in 1992, was supported by 1,700 eminent scientists from around the globe who warned that humanity was on a collision course with the rest of the natural world. Twenty-five years later, a follow-up evaluation supported by 15,000 scientists declared that humanity had failed to make sufficient progress in dealing with the environmental challenges. Indeed, they found that most of these problems had worsened.

The authors of the new paper stress that biological invasions can be managed and mitigated. They point to approaches that are working around the world and make specific recommendations for improved management. For example, the introduction of more stringent border controls, including X-ray machines and detector dogs, has led to a progressive decline in the rate of fungal plant pathogens entering New Zealand.

Professor Petr Pyšek of the Czech Academy of Sciences and Charles University in Prague, lead author of the study, said: "As our knowledge about invasive alien species increases, the problems associated with biological invasions are becoming clearer. The threats posed by invasive alien species to our environment, our economies and our health are very serious, and getting worse. Policy makers and the public need to prioritize actions to stem invasions and their impacts."

Professor David Richardson of the Centre for Invasion Biology at Stellenbosch University in South Africa, the other lead author, added: "Nations such as Australia and New Zealand have made biosecurity a national priority. South Africa has invested heavily in a massive national programme focussed on reducing the negative impacts of widespread invaders on ecosystem services, especially the delivery of water from catchments invaded by alien trees. But action is needed more widely at both national and international levels in order to tackle the challenges effectively."

Meyerson, who contributed to the paper and is leading the chapter on trends in invasions for a report on invasive alien species for the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, said, "It has been so exciting to see developments in our knowledge and understanding of biological invasions in recent decades, achieved through truly inspiring global collaborations. It is so important that we continue to share our knowledge and engage with relevant stakeholders across sectors and borders."

SALT LAKE CITY, UT - Over the last three decades, colorectal cancer survival in the United States has improved significantly. But in young people--particularly men diagnosed with colorectal cancer before age 50--incidence and mortality due to colorectal cancer are on the rise. Even among patients with early-stage colorectal cancer, racial disparities have grown more pronounced, with survival after colorectal cancer diagnosis poorer among African Americans compared with whites.

Charles R. Rogers, PhD, MPH, MS, Huntsman Cancer Institute (HCI) cancer researcher and assistant professor of public health at the University of Utah (U of U), is working to better understand these factors in young people with colorectal cancer in order to help improve outcomes and reduce related disparities from this preventable disease. A study led by Rogers and his colleagues, published in the American Journal of Cancer Research, found many of these new diagnoses are occurring in counties in the lower Mississippi Delta, west-central Appalachia, and eastern Virginia/North Carolina. These "hotspot" areas--where colorectal cancer is on the rise and actually killing young men at high rates--revealed several trends about who these men are and how their cancer progresses. The researchers found that young adult non-Hispanic Black men living in these areas are part of a group in which there is an alarming trend of increasing rates of early-onset colorectal cancer, and that these men are more likely to die of the disease as compared to other racial groups.

Rogers and his colleagues developed an analysis of counties with a high rate of early-onset colorectal cancer using data from Centers for Disease Control and Prevention during the years 1999 to 2017. They then linked this to Surveillance, Epidemiology, and End Results (SEER) Program data from the National Cancer Institute for men aged 15 to 49. This revealed 232 hotspot counties for early-onset colorectal cancer in the U.S. The majority of these counties are in the south.

The team then studied a variety of factors of the diagnoses in these hotspot counties. These included age, race, tumor stage and grade, treatment approach, and marital status. In the hotspot counties, they identified that death rates in non-Hispanic Black and Hispanic men with early-onset colorectal cancer outpaced other racial groups studied. In addition, Rogers's team examined many other health and social factors, such as smoking. The team observed that although roughly 14% of all U.S. adults are current smokers, 24% of the adult population residing in hotspot counties reported currently smoking and having smoked at least 100 cigarettes in their lifetime. "After identifying these geographic disparities, the focus of our study was to better understand the role of individual and county-level characteristics in explaining regional variations in early-onset colorectal cancer survival among these men," Rogers explained.

Rogers said, "If young men are not already doing so, adults younger than 50 should have conversations with health care providers about early detection screening for colorectal cancer. This is especially the case if they have any symptoms of colorectal cancer, a family history of the disease, or if they live in the 'hotspot' counties we have identified for early-onset colorectal cancer."

Rogers plans to identify early-onset colorectal cancer hotspots in Utah, where his lab is located. The lab studies the health and well-being of underrepresented men through community engagement, research, and education.

Rogers' team is also working to develop a community-based intervention to increase awareness while reducing incidence and death due to early-onset colorectal cancer in Utah and areas of the country where rates are on the rise.

The brains of millions of people suffering from Alzheimer´s disease (AD) are slowly and inescapably being depleted of neurons, which leads to the characteristic loss of memory and cognitive function associated with this condition. However, the cause of neuronal death is still unknown. The treatments available are aimed at slowing down the development of dementia and only help to improve quality of life for short periods. Therefore, treatments to actually cure AD are an unmet medical need.

Researchers led by Natalia Carulla, IRB Barcelona Alumni, former group leader at the Institut Européen de Chimie et Biologie (IECB) in Bordeaux, and currently project manager at Grup CIEF have revealed for the first time the atomic structure of amyloid-beta (Aβ) protein assemblies. The knowledge of this structure reveals a new mechanism of toxicity for these assemblies, with the capacity to disrupt the neuronal membrane, allowing water and ions to pass through it and causing the death of these cells. Several studies have proposed that the interaction of the Aβ protein with the neuronal membrane is responsible for the neuronal death observed in AD. However, the Aβ protein is a difficult therapeutic target because it is "sticky" and self-assembles, adopting distinct shapes and sizes.

"Knowing the features that characterise these protein ensembles, such as the number of molecules that make them and the shape they adopt, is crucial to design effective therapeutic strategies that target the forms of Aβ ensembles responsible for the neurotoxicity in AD," Carulla explains.

An in vitro approach to ensure stable Aβ forms

To tackle the instability of the different conformations, the team first studied the Aβ protein in vitro--in simplified model systems that mimic the neuronal membrane--to develop conditions to prepare stable Aβ forms of uniform composition and shape. Once the different compositions had been identified, they studied their structure and mode of neurotoxicity, establishing a 3D arrangement of all the atoms making up the Aβ ensemble.

"Our study suggests that some Aβ associations can perforate the membrane of neurons, alter their osmotic equilibrium, and consequently trigger their death," say Sonia Ciudad and Eduard Puig, first authors of the paper. Ciudad is an IRB Barcelona Alumni, currently R&D Scientist at Biokit, a Werfen Company; while Puig is now a postdoctoral fellow in Research Unit on Asymmetric Synthesis at IRB Barcelona.

Targeting membrane pores to avoid neurotoxicity

This study has highlighted two Aβ protein ensembles, one formed by four Aβ proteins and the other by eight, whose arrangement has the capacity to disrupt cell membrane, proposing them as candidates for causing neurodegeneration in AD.

Further work should focus on approaches to prevent the formation of this ensemble-thus preventing membrane disruption. Currently, the drug discovery pipeline in this field does not include any drug targeting membrane-associated Aβ assemblies, so this finding could make a significant breakthrough in the treatment of AD.

Researchers at the Beckman Institute for Advanced Science and Technology have developed a new method to improve the detection ability of nanoscale chemical imaging using atomic force microscopy. These improvements reduce the noise that is associated with the microscope, increasing the precision and range of samples that can be studied.

The study "Closed-Loop Atomic Force Microscopy-Infrared Spectroscopic Imaging for Nanoscale Molecular Characterization" was published in Nature Communications.

Atomic force microscopy is used to scan the surfaces of materials to generate an image of their height but the technique cannot easily identify the molecular composition. Researchers have previously developed a combination of AFM and infrared spectroscopy called AFM-IR. The AFM-IR microscope uses a cantilever, which is a beam that is connected to a support at one end and a sharp tip at the other, to measure subtle movements of the sample introduced by shining an IR laser. The absorption of light by the sample causes it to expand and deflect the cantilever, generating an IR signal.

"Although the technique is widely used, there is a limit to its performance," said Rohit Bhargava, a Founder Professor of Engineering and the director of the Cancer Center at the University of Illinois at Urbana-Champaign. "The problem is that there were unknown sources of noise that limited the quality of the data."

The researchers created a theoretical model to understand how the instrument works and therefore identify the sources of noise. Additionally, they developed a new way to detect the IR signal with improved precision.

"The cantilever deflection is susceptible to noise which becomes worse as the deflection increases," said Seth Kenkel, a graduate student in the Chemical Imaging and Structures Laboratory, which is led by Bhargava. "Instead of detecting cantilever deflection, we used a piezo component as a stage to maintain zero deflection. By applying a voltage to the piezo material, we can maintain small deflection with low noise while recording the same chemical information which is now encoded in the piezo voltage."

Instead of moving the cantilever, the researchers use the movement of the piezo crystal to record the IR signal. "This is the first time anyone has controlled a piezo actuator to detect the signal. Other researchers work around challenges such as noise by using more complex detection systems that don't address the underlying problems associated with AFM-IR," Kenkel said.

"People have only been able to use this technique to measure samples that have a strong signal because of the noise problem," Bhargava said. "With the improved sensitivity, we can image a much smaller volume of samples, like cell membranes."

In addition to measuring more diverse samples, the researchers also hope to use this technique to measure smaller sample volumes. "We could use this technique to look at complex mixtures that are present in small volumes, like a single lipid bilayer," Bhargava said.

"The new technique developed by the Bhargava lab is exciting. Our group is interested in using this technique immediately to learn about protein deformation on complex surfaces," said Catherine Murphy, the head of the Department of Chemistry and the Larry Faulkner Endowed Chair in Chemistry.

Tsukuba, Japan - When most of us think of dinosaurs, we envision large, lumbering beasts, but these giants shared their ecosystems with much smaller dinosaurs, the smaller skeletons of which were generally less likely to be preserved. The fossilized egg shells of these small dinosaurs can shed light on this lost ecological diversity.

Led by the University of Tsukuba, researchers scoured an exceptional fossil egg site first discovered in 2015 in Hyogo Prefecture, southwestern Japan, and reported their findings in a new study published in Cretaceous Research.

The Kamitaki Egg Quarry, found in a red-brown mudstone layer of the Ohyamashimo Formation, deposited in an Early Cretaceous (about 110 million years old) river flood plain, was carefully and intensively excavated in the winter of 2019, and yielded over 1300 egg fossils. Most were isolated fragments, but there were a few partial and almost complete eggs.

According to lead author Professor Kohei Tanaka, "our taphonomic analysis indicated that the nest we found was in situ, not transported and redeposited, because most of the eggshell fragments were positioned concave-up, not concave-down like we see when egg shells are transported."

Most of these fossil eggs belong to a new egg genus and species, called Himeoolithus murakamii, and are exceptionally small, with an estimated mass of 9.9 grams--about the size of a modern quail egg. However, biological classification analysis implies that the eggs belonged not to early birds, but to their cousins, the non-avian theropod dinosaurs (the group that includes well-known carnivores like Tyrannosaurus and Velociraptor). That puts Himeoolithus murakamii among the smallest non-avian theropod eggs reported to date. These tiny eggs were notably elongated in shape--unusual for similarly small eggs among Cretaceous birds, but typical among larger non-avian theropod eggs.

In addition to the abundant Himeoolithus murakamii egg shells, five more ootaxa (distinct types of egg fossils) were recognized in the Kamitaki locality. All of these ootaxa belonged to small non-avian theropods.

As Professor Tanaka explains, "the high diversity of these small theropod eggs makes this one of the most diverse Early Cretaceous egg localities known. Small theropod skeletal fossils are quite scarce in this area. Therefore, these fossil eggs provide a useful window into the hidden ecological diversity of dinosaurs in the Early Cretaceous of southwestern Japan, as well as into the nesting behavior of small non-avian theropods."

AURORA, Colo. (June 26, 2020) - Researchers at the University of Colorado College of Nursing at the Anschutz Medical Campus found that an 18-month pilot project that trained Nurse Practitioners and Physician Assistants to prescribe Medication for Opioid Use Disorders (MOUD) was successful in increasing availability and access of services to residents of two rural Colorado counties experiencing high overdose rates. As a result of the success of the pilot project, the state legislature passed a second bill to expand MOUD into 17 counties.

The study, out in the July issue of the Journal of Substance Abuse Treatment, reviewed the 18-month pilot project funded by the original Senate Bill 17-074 that focused on supporting NP- or PA MOUD prescribing in Substance use treatment programs up and running rapidly in areas with significant needs. The University of Colorado College of Nursing oversaw the project.

Project goals were two-fold. "Increase the number of NP/PA providers waivered to prescribe MOUD, and to increase the availability of services for patient access in these rural counties, with some of the highest opioid overdose rates in the state," said lead author Associate Professor Tanya Sorrell, PhD, PMHNP-BC. Traditionally, NPs and PAs are successful front-line primary care providers in rural areas. "This program provided the training and support for them to lead as MOUD providers as well. By adding nurse practitioners and physician assistants confident in prescribing MOUDs, we were able to increase availability of services for Pueblo and Routt counties. We went from two clinical providers at three sites to 15 MOUD waivered providers, and from caring for 99 clients to more than 1000 in less than two years."

The state of Colorado is ranked 12th nationally for self-reported non-medical use of opioids. According to the Colorado Office of Behavioral Health, only one in three Coloradans with OUD reported that they had access to treatment; and one in five Coloradans said that even if they wanted help no services would be available in their home county. The pilot program grew out of a formal statewide collaborative, focused on rural counties with limited MOUD services and high opioid death rates, and capitalized on current trends in treatment of opioid use disorder (OUD). New legislation in the Comprehensive Addiction and Recovery Act of 2016 allowed NPs and PAs to begin prescribing MOUD. "This opened up a unique opportunity for Colorado to expand MOUD services across the state and potentially reduce the impact of the opioid epidemic in our state," said Sorrell.

Due to the success of the pilot, the state passed SB19-001 in 2019 to expand MOUD into 17 counties. However, there were barriers, which included transportation, MOUD reimbursement from Medicaid or other insurances, and continued stigma. "One agency, initially framed their services as pain management versus substance abuse treatment to help overcome some of the stigma associated with substance abuse. Thankfully, with the notable care and treatment provided to clients in that area, now that agency is a leader in the community, and known for its substance use treatment services," said Sorrell.

Recursion -- the computational capacity to embed elements within elements of the same kind -- has been lauded as the intellectual cornerstone of language, tool use and mathematics. A multi-institutional team of researchers for the first time show this ability is shared across age, species and cultural groups in a new study published in the June 26 issue of the journal Science Advances.

"Recursion is a way to organize information that allows humans to see patterns in information that are rich and complex, and perhaps beyond what other species see," said Jessica Cantlon, the Ronald J. and Mary Ann Zdrojkowski Professor of Developmental Neuroscience at CMU and senior author on the paper. "We try to trace the origins of our complex and rich intellectual activities to something in our evolutionary past to understand what makes our thinking similar to and distinct from other species."

The team set up a series of experiments with U.S. adults, adults from an indigenous group in Bolivia that largely lacks formal education, U.S. children and non-human primates. After training on the task, the researchers provided each group with sequences to order. They studied how each group conducted this task, either in a recursive or non-recursive way (listing) and looked to see which order they naturally chose.

The researchers found that the human participants from all age and cultural groups spontaneously ordered content from a recursive approach by building nested structures. The non-human primate subjects more commonly used a simpler listing strategy but with additional exposure began using the recursive strategy, eventually ending up in the range of performance of human children.

"This ability to represent recursive structures is present in children as young as three years old, which suggests it is there even before they use it in language," said Stephen Ferrigno, a post-doctoral fellow at Harvard University and first author on the paper. "We also saw this ability across people from widely different human cultures. Non-human primates also have the capacity to represent recursive sequences, given the right experience. These results dispel the long-held belief that only humans have the capacity to use this rule."

The team found that working memory was an important factor affecting the sequencing abilities of participants. A strong correlation exists between working memory and the use of the hierarchical strategy.

"Some of the errors were due to working memory, because participants had to remember which objects went first and relate that to other objects later in the list," said Ferrigno. "Children and non-human primates had more errors, which may be due to lower working memory capacity."

The authors note that this work offers a simplified version of a recursive task using visual cues. A more complex series of tasks may not yield the same results.

"There is something universal of being a human that lets our brains think this way spontaneously, but primates have the ability to learn it to some degree," said Cantlon. "[This research] really gives us a chance to sort out the evolutionary and developmental contributions to complex thought."

(Boston) -- Scientists have long believed that a single traumatic brain injury (TBI) earlier in life may contribute to problems with memory, thinking and depression later in life. In most previous studies, however, research failed to examine the possible role of having a history of exposure to repetitive head impacts, including those leading to "subconcussive" injuries, in these later-life problems. In the largest study of its kind, an association has been found in living patients exposed to repetitive head impacts and difficulties with cognitive functioning and depression years or decades later.

Scientists from the Boston University (BU) Alzheimer's Disease and Chronic Traumatic Encephalopathy (CTE) Centers, the University of California, San Francisco (UCSF), and San Francisco VA Healthcare System teamed up to analyze the records of 13,323 individuals age 40 and older (average age 62) who participate in the internet-based Brain Health Registry. Of those, 725 or 5 percent of participants reported exposure to previous repetitive head impacts through contact sports, abuse or military service. In addition to repetitive head impact history, the scientists also examined the effects of having a TBI with and without loss of consciousness.

Along with self-report questionnaires of repetitive head impact and TBI history, participants completed measures of depressive symptoms and computerized cognitive tests. The findings, published in the journal Neurology, reveal that participants with a history of both repetitive head impacts and TBI reported greater depression symptoms than those who did not have such history. In addition, when repetitive head impacts and TBI were examined separately, a history of repetitive head impacts had the strongest effect on later-life symptoms of depression. The findings were independent of age, sex, racial identity and education level.

"The findings underscore that repetitive hits to the head, such as those from contact sport participation or physical abuse, might be associated with later-life symptoms of depression. It should be made clear that this association is likely to be dependent on the dose or duration of repetitive head impacts and this information was not available for this study," said Michael Alosco, PhD, associate professor of neurology at BU School of Medicine (BUSM) and co-director of the BU Alzheimer's Disease Center Clinical Core.

There was a dose-response-like pattern between head trauma and depression symptoms. Specifically, participants without any history of either TBI or repetitive head impacts had the fewest symptoms. While depression symptoms increased when a history of TBI alone was present, depression symptoms were highest for the groups who had a history of both repetitive head impacts and TBI. Indeed, the group that had a history of repetitive head impacts and TBI with loss of consciousness reported the most depressive symptoms.

A similar cumulative effect was seen among those exposed to repetitive head impacts and TBI on tests of memory, learning, processing speed, and reaction time. Participants with a history of repetitive head impacts or TBI had worse performance on some of the tests compared to those without any head trauma history, and those with both a history of repetitive head impacts and TBI with loss of consciousness had worse performance on almost all of these computerized cognitive tests.

"These findings add to the growing knowledge about the long-term neurological consequences of brain trauma," said Robert Stern, PhD, professor of neurology, neurosurgery and anatomy & neurobiology at BUSM and director of clinical research at the BU CTE Center. "It should be noted that not all people with a history of repetitive hits to the head will develop later-life problems with cognitive functioning and depression. However, results from this study provide further evidence that exposure to repetitive head impacts, such as through the routine play of tackle football, plays an important role in the development in these later-life cognitive and emotional problems," added Stern, one of the senior authors of the study.

A major limitation of the study is that the researchers did not have access to measurements or estimates of the degree of repetitive impact exposure nor TBI frequency. In October, BU researchers reported a dose-response relationship between the number of years of exposure to tackle football (regardless of the number of concussions) and the presence and severity of the degenerative brain disease chronic traumatic encephalopathy (CTE). In a sample of 266 deceased football players, each year of exposure to tackle football was associated with 30 percent increased odds of having CTE and 17 percent increased odds of having severe CTE. It is unknown if any subjects in this study have CTE or any other neurodegenerative disease.

The research team plans to extend their work through continued collaboration between BU and UCSF investigators utilizing data from the Brain Health Registry. "We are excited to partner with BU on this important study that used the Brain Health Registry to increase our understanding on the long-term effects of repetitive head impacts and TBI," said Michael Weiner, MD, PI of the Brain Health Registry and professor-in-residence in radiology and biomedical imaging, medicine, psychiatry and neurology at UCSF. "The Brain Health Registry is a novel and exciting resource for both the scientific community and the general public. It allows for large-scale recruitment, screening and study of dementia, and more than 60,000 individuals across the world are enrolled. It offers a way for the general public to track their thinking, memory, mood, and behavior over time, and also serves as a readiness registry for future research and clinical trials of prevention and treatment." You can visit the BHR here: http://bit.ly/brainhealthreg.

5pm on June 26, 2020 - Kawasaki/Japan: The Innovation Center of NanoMedicine (iCONM), the National Institute for Quantum Science and Technology (QST), and the University of Tokyo jointly announced that a reagent for the selective and safe coating of the liver sinusoidal walls to control the clearance of gene therapy drugs was successfully developed. The contents of this research will be published in Science Advances by the American Association for the Advancement of Science (AAAS) at 2:00 pm on June 26, east coast of the United States (Japan standard time: 3:00 am on 27th): A. Dirisala, S. Uchida, K. Toh, J. Li, S. Osawa, T. A. Tockary, X. Liu, S. Abbasi, K. Hayashi, Y. Mochida, S. Fukushima, H. Kinoh, K. Osada, Kazunori Kataoka, "Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines".

Recently, gene therapies have been successively approved in Europe, US, and Japan, and are expected to provide novel therapeutic options for cancer, chronic diseases, acquired and inherited genetic disorders. Whilst this is promising, in reality, when gene therapy drugs are systemically administered to living organisms, they are rapidly eliminated and metabolized in the liver, thus impeding the delivery of a sufficient amount to the target organs and raising the toxicity concerns. This elimination by the liver is caused by the adsorption of the gene therapy drugs to the vascular wall of the liver sinusoid, which is an intrahepatic capillary. To overcome this issue, we conceived to selectively coat the liver sinusoidal wall using polyethylene glycol (PEG). However, a long-term coating may impair the normal physiological functions of the liver, and therefore the coating should be transient. In addition, coating needs to be selective for liver sinusoids, as coating the blood vessels throughout the body would not only cause adverse effects but also decrease the delivery amount of gene therapy drugs to target organs. Towards this end, we have developed a coating agent with two-armed PEG conjugated to positively charged oligolysine, which demonstrated the selective coating on the liver sinusoidal wall, the first-of-its-kind strategy in the world. Interestingly, the coating with two-armed PEG was excreted into bile within 6 hours after binding to sinusoidal walls, while the coating with single chain of linear PEG bound to oligolysine persisted in the walls for a long time. In this way, the precise molecular design was necessary to achieve a transient coating.

This coating was subsequently applied to boost the delivery efficacy of gene therapy drugs. Adeno-associated virus (AAV) is widely used for viral gene therapy drugs, and its serotype 8 (AAV8) targets myocardium and skeletal muscles. When AAV8 was administered after prior coating of two-armed PEG to the liver sinusoidal wall, the transfer of AAV8 to the liver was suppressed, and as a result, the gene transfer efficiency into the myocardium and skeletal muscles was improved by 2 to 4 times. This approach is promising for the treatment of muscular dystrophy. In addition, we expanded the use of our strategy to virus-free gene delivery systems, which allows more economically attractive and safe gene therapy. We have been working on non-viral gene therapy for malignant tumors using plasmid DNA-equipped smart nanomachine for over 10 years. When the coating agent was used for this system, the adsorption of nanomachines to the sinusoidal wall was suppressed, resulting in an approximately 10-fold improvement in DNA transfer efficiency to colon cancer. As described above, we have succeeded in boosting the activity of gene therapy drugs while ensuring safety by using the coating agent developed this time.

The above findings are summarized as follows:

- The coating agent with two-armed PEG selectively coated the liver sinusoid wall for several hours and was then excreted in the bile.

- The coating agent with single chain of linear PEG is not excreted in bile and coated the liver sinusoidal wall for more than 9 hours, which raises a safety concern.

- The coating agent with two-armed PEG had selectivity for the liver sinusoid wall, without coating the blood vessels in the connective tissues.

- The coating agent improved the gene transfer efficacy to the myocardium and skeletal muscles using the AAV vector by 2 to 4 times, and the gene transfer efficiency to colorectal cancer using DNA-loaded smart nanomachines by 10 times.

- As a result, our approach is expected to allow for improving the effect of gene therapy drugs and reducing their dose needed to obtain therapeutic outcome, which will lead to the reduction of medical cost and adverse event opportunities.

Boston, MA - Strengthening U.S. air quality standards for fine particulate pollution to be in compliance with current World Health Association (WHO) guidelines could save more than 140,000 lives over the course of a decade, according to a new study from Harvard T.H. Chan School of Public Health.

The study, published June 26, 2020 in Sciences Advances, provides the most comprehensive evidence to date of the causal link between long-term exposure to fine particulate (PM2.5) air pollution and premature death, according to the authors.

"Our new study included the largest-ever dataset of older Americans and used multiple analytical methods, including statistical methods for causal inference, to show that current U.S. standards for PM2.5 concentrations are not protective enough and should be lowered to ensure that vulnerable populations, such as the elderly, are safe," said doctoral student Xiao Wu, a co-author of the study.

The new research builds on a 2017 study that showed that long-term exposure to PM2.5 pollution and ozone, even at levels below current U.S. air quality standards, increases the risk of premature death among the elderly in the U.S.

For the new study, researchers looked at 16 years' worth of data from 68.5 million Medicare enrollees--97% of Americans over the age of 65--adjusting for factors such as body mass index, smoking, ethnicity, income, and education. They matched participants' zip codes with air pollution data gathered from locations across the U.S. In estimating daily levels of PM2.5 air pollution for each zip code, the researchers also took into account satellite data, land-use information, weather variables, and other factors. They used two traditional statistical approaches as well as three state-of-the-art approaches aimed at teasing out cause and effect.

Results were consistent across all five different types of analyses, offering what authors called "the most robust and reproducible evidence to date" on the causal link between exposure to PM2.5 and mortality among Medicare enrollees--even at levels below the current U.S. air quality standard of 12 μg/m3 (12 micrograms per cubic meter) per year.

The authors found that an annual decrease of 10 μg/m3 in PM2.5 pollution would lead to a 6%-7% decrease in mortality risk. Based on that finding, they estimated that if the U.S. lowered its annual PM2.5 standard to 10 μg/m3--the WHO annual guideline--143,257 lives would be saved in one decade.

The authors included additional analyses focused on causation, which address criticisms that traditional analytical methods are not sufficient to inform revisions of national air quality standards. The new analyses enabled the researchers, in effect, to mimic a randomized study--considered the gold standard in assessing causality--thereby strengthening the finding of a link between air pollution and early death.

"The Environmental Protection Agency has proposed retaining current national air quality standards. But, as our new analysis shows, the current standards aren't protective enough, and strengthening them could save thousands of lives. With the public comment period for the EPA proposal ending on June 29, we hope our results can inform policymakers' decisions about potentially updating the standards," said co-author Francesca Dominici, Clarence James Gamble Professor of Biostatistics, Population, and Data Science.

Patients suffering from severe respiratory symptoms as a result of SARS-CoV-2 infection can rapidly generate virus-attacking T cells, and can increase this production over time, suggests a new study of T cells from 10 COVID-19 patients under intensive care treatment. In addition, 2 out of 10 healthy individuals without prior exposure to the virus harbored SARS-CoV-2-reactive T cells, the researchers found, possibly indicating that these T cells can cross-react to the novel coronavirus due to past infection with related coronaviruses that cause common cold symptoms. Together, these new data address the poorly understood question of whether SARS-CoV-2-specific T cell responses vary in patients over time depending on disease severity, and helps to answer whether patients with more severe symptoms can generate protective virus-specific T cells at all. The study also provides new clues regarding the cells responsible for excessive immune responses, including life-threatening "cytokine storms," and may also help inform vaccine design. Daniela Weiskopf and colleagues extracted blood cells from 10 patients at weekly intervals starting soon after they were admitted to the ICU for COVID-19 and exposed these cells to "megapools" of known SARS-CoV-2 epitopes - a technique meant to capture a large fraction of total viral-reactive T cells. They found SARS-CoV-2-specific CD4+ helper T cells in all 10 patients and CD8+ "killer" T cells in 8 out of 10 patients, and characterized the cells' production of specific inflammation-triggering cytokines. The strongest T cell responses were directed to the virus' spike (S) surface glycoprotein, supporting prior work that has pointed to the S protein as a promising target to induce virus-specific T cells. Furthermore, screening all patients at 0, 7, and 14 days after inclusion in the study revealed that SARS-CoV-2-specific T cells were present relatively early during the course of infection and increased in these patients over time. Using the same T cell stimulation technique in age-matched healthy controls, the researchers found SARS-CoV-2-reactive T cells in 2 out of the 10 individuals. Based on their findings, the authors note promising areas for future work, including an investigation of how preexisting SARS-CoV-2-specific T cells in healthy controls correlate to protection against COVID-19 disease, as well as identification of T cell types responsible for cytokine storms.

Reservoirs in the heart of an ancient Maya city were so polluted with mercury and algae that the water likely was undrinkable.

Researchers from the University of Cincinnati found toxic levels of pollution in two central reservoirs in Tikal, an ancient Maya city that dates back to the third century B.C. in what is now northern Guatemala.

UC's findings suggest droughts in the ninth century likely contributed to the depopulation and eventual abandonment of the city.

"The conversion of Tikal's central reservoirs from life-sustaining to sickness-inducing places would have both practically and symbolically helped to bring about the abandonment of this magnificent city," the study concluded.

A geochemical analysis found that two reservoirs nearest the city palace and temple contained toxic levels of mercury that UC researchers traced back to a pigment the Maya used to adorn buildings, clayware and other goods. During rainstorms, mercury in the pigment leached into the reservoirs where it settled in layers of sediment over the years.

But the former inhabitants of this city, made famous by its towering stone temples and architecture, had ample potable water from nearby reservoirs that remained uncontaminated, UC researchers found.

The study was published in the Nature journal Scientific Reports.

UC's diverse team was composed of anthropologists, geographers, botanists, biologists and chemists. They examined layers of sediment dating back to the ninth century when Tikal was a flourishing city.

Previously, UC researchers found that the soils around Tikal during the ninth century were extremely fertile and traced the source to frequent volcanic eruptions that enriched the soil of the Yucatan Peninsula.

"Archaeologists and anthropologists have been trying to figure out what happened to the Maya for 100 years," said David Lentz, a UC professor of biological sciences and lead author of the study.

For the latest study, UC researchers sampled sediment at 10 reservoirs within the city and conducted an analysis on ancient DNA found in the stratified clay of four of them.

Sediment from the reservoirs nearest Tikal's central temple and palace showed evidence of toxic algae called cyanobacteria. Consuming this water, particularly during droughts, would have made people sick even if the water were boiled, Lentz said.

"We found two types of blue-green algae that produce toxic chemicals. The bad thing about these is they're resistant to boiling. It made water in these reservoirs toxic to drink," Lentz said.

UC researchers said it is possible but unlikely the Maya used these reservoirs for drinking, cooking or irrigation.

"The water would have looked nasty. It would have tasted nasty," said Kenneth Tankersley, an associate professor of anthropology in UC's College of Arts and Sciences. "There would have been these big algae blooms. Nobody would have wanted to drink that water."

But researchers found no evidence of the same pollutants in sediments from more distant reservoirs called Perdido and Corriental, which likely provided drinking water for city residents during the ninth century.

Today, Tikal is a national park and a UNESCO World Heritage site. Researchers believe a combination of economic, political and social factors prompted people to leave the city and its adjacent farms. But the climate no doubt played a role, too, Lentz said.

"They have a prolonged dry season. For part of the year, it's rainy and wet. The rest of the year, it's really dry with almost no rainfall. So they had a problem finding water," Lentz said.

Co-author Trinity Hamilton, now an assistant professor of biology at the University of Minnesota, worked on the analysis of ancient DNA from algae that sank to the reservoir bottom and was buried by centuries of accumulated sediment.

"Typically, when we see a lot of cyanobacteria in freshwater, we think of harmful algal blooms that impact water quality," Hamilton said.

Finding some reservoirs that were polluted and others that were not suggests the ancient Maya used them for different purposes, she said.

Reservoirs near the temple and palace likely would have been impressive landmarks, much like the reflecting pool at the National Mall is today.

"It would have been a magnificent sight to see these brightly painted buildings reflected off the surface of these reservoirs," said co-author Nicholas Dunning, head of geography in UC's College of Arts and Sciences.

"The Maya rulers conferred to themselves, among other things, the attribute of being able to control water. They had a special relationship to the rain gods," Dunning said. "So the reservoir would have been a pretty potent symbol."

UC's Tankersley said one popular pigment used on plaster walls and in ceremonial burials was derived from cinnabar, a red-colored mineral composed of mercury sulfide that the Maya mined from a nearby volcanic feature known as the Todos Santos Formation.

A close examination of the reservoir sediment using a technique called energy dispersive X-ray fluorescence spectrometry found that mercury did not leach into the water from the underlying bedrock. Likewise, Tankersley said, UC ruled out another potential source of mercury -- volcanic ash that fell across Central America during the frequent eruptions. The absence of mercury in other nearby reservoirs where ash would have fallen ruled out volcanoes as the culprit.

Instead, Tankersley said, people were to blame.

"That means the mercury has to be anthropogenic," Tankersley said.

With its bright red color, cinnabar was commonly used as a paint or pigment across Central America at the time.

"Color was important in the ancient Maya world. They used it in their murals. They painted the plaster red. They used it in burials and combined it with iron oxide to get different shades," Tankersley said.

"We were able to find a mineral fingerprint that showed beyond a reasonable doubt that the mercury in the water originated from cinnabar," he said.

Tankersley said ancient Maya cities such as Tikal continue to captivate researchers because of the ingenuity, cooperation and sophistication required to thrive in this tropical land of extremes.

"When I look at the ancient Maya, I see a very sophisticated people with a very rich culture," Tankersley said.

UC's team is planning to return to the Yucatan Peninsula to pursue more answers about this remarkable period of human civilization.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving Antiretroviral Therapy

Researchers from the Ministry of Health and the HIV Network of Excellence in Madrid, Spain, and Harvard T.H. Chan School of Public Health describe the incidence and severity of COVID-19 among 77,590 HIV-positive patients receiving antiretroviral therapy (ART). These authors conclude HIV-positive patients receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) have a lower risk for COVID-19 and related hospitalization than those receiving other therapies. The authors' findings warrant further investigation of HIV ART in HIV preexposure prophylaxis studies and randomized trials among persons without HIV. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-3689.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Julia del Amo, MD, PhD, can be reached through mlorenzo@mscbs.es.

An innovative, interactive cloud-based data portal debuted this week that lets academic researchers mine the world's largest and most comprehensive collection of scientific resources for studying pediatric solid tumors and their related biology. The Childhood Solid Tumor Network (CSTN) data portal on St. Jude Cloud was created to improve access to the detailed data available through the network, stimulating the research and development of novel, lifesaving therapies.

The CSTN includes wide-ranging data on 170 patient-derived samples representing 21 different childhood solid tumors, including neuroblastoma, rhabdomyosarcoma and rare tumors. The samples are orthotopic patient-derived xenografts, meaning the human tumor samples are implanted and grown in the corresponding location in mice.

The CSTN includes wide-ranging data on 170 patient-derived samples representing 21 different childhood solid tumors, including neuroblastoma, rhabdomyosarcoma and rare tumors. The samples are orthotopic patient-derived xenografts, meaning the human tumor samples are implanted and grown in the corresponding location in mice.

Tumor samples and related data are shared with academic researchers at no charge and with no obligation to collaborate. Michael Dyer, Ph.D., chair of the St. Jude Developmental Neurobiology department, and Alberto Pappo, M.D., of the St. Jude Oncology department, launched the network in 2013. The goal was to accelerate discoveries in the field. "There had been no significant improvement in outcomes for children with solid tumors in the past three decades," said Dyer, who is a Howard Hughes Medical Institute investigator. Pediatric solid tumors are developmental tumors. To understand how the tumor begins, grows and spreads, they need to be studied in the environment in which they develop.

"As interest in the network grew, we realized scientists needed to dig deeper into the data," Dyer said. "We created the interactive browser to make that possible." The CSTN data portal was unveiled this week at the annual meeting of the American Association for Cancer Research, which was held virtually.

Web-based data

The portal makes it easier for researchers to download and analyze the data themselves.

Available data and analytic tools include:

Next-generation, whole genome sequencing of the patient tumors, germline and the orthotopic patient-derived xenografts. These are presented as an interactive application, allowing for customized heatmaps to represent mutations and individual gene searches. Raw genomic sequences are also uploaded and available.

Interactive browsers for epigenetic and, in some cases, proteomic data

Histology images with tissue-specific stains and electron microscopy images at three magnifications for each sample

Clonal analysis of the matched patient samples and
orthotopic xenografts

Sample-level search and visualization of specific characterization data that let users filter by factors such as patient's age at diagnosis or primary versus recurrent tumors

Preclinical pharmacokinetic reports, tumor propagation protocols and more

Single-cell RNA sequencing of patient and patient derived-orthotopic xenografts is underway. Additional tumor samples and data are added to the network as they become available.

Academic researchers can also request cryopreserved cells from orthotopic patient-derived xenografts as well as fresh frozen tissue or cells and formalin-fixed paraffin-embedded tissue blocks.

As of June 2020, more than 200 researchers from more than 100 institutions worldwide have requested and received more than 1,500 tumor samples from the network.

"We feel the network and data portal are the best way to make the most of the tumor tissue samples that children and their parents have donated to provide resources to speed cures and understand the diseases," said Asa Karlstrom, Ph.D., of Developmental Neurobiology. She was co-first author of a report on the network data portal that was included in an AACR poster session.