Culture

The Research Group on Synthetic Biology for Biomedical Applications at Pompeu Fabra University in Barcelona, Spain, has designed a cellular device capable of computing by printing cells on paper. For the first time, they have developed a living device that could be used outside the laboratory without a specialist, and it could be produced on an industrial scale at low cost. The study is published in Nature Communications and was carried out by Sira Mogas-Díez, Eva Gonzalez-Flo and Javier Macía.

We currently have many electronic devices available to us such as computers and tablets whose computing power is highly efficient. But, despite their power, they are very limited devices for detecting biological markers, such as those that indicate the presence of a disease. For this reason, a few years ago "biological computers" began to be developed, in other words, living cellular devices that can detect multiple markers and generate complex responses. In them, the researchers leverage biological receptors that allow detecting exogenous signals and, by means of synthetic biology, modify them to emit a response in accordance with the information they detect.

So far, cellular devices have been developed that must operate in the laboratory, for a limited time, under specific conditions, and must be handled by a specialist in molecular biology. Now, a team of researchers from Pompeu Fabra University has developed new technology to "print" cellular devices on paper that can be used outside the laboratory.

Interestingly, they use "ink" of different cell types with nutrients to "draw" the circuits. The cells remain trapped in the paper, alive and functional, and there, they continue growing and are able to release signals that travel through the paper and reach other cells. The reason for doing this on paper (or other surfaces such as fabrics) is principally practical; it is cheap and easy to adapt to industrial use, and large quantities could be produced at a very low cost. "We wanted to design a scalable model and we thought about using a printing system like the one for printing T-shirts", details Sira Mogas-Díez, first author of the study. "We make moulds with our drawing, we soak it with the different cellular inks like a buffer, put it on paper and the cells are deposited", she adds. One strong point is that these devices on paper can be kept in the refrigerator or can even be frozen, since the cellular ink incorporates cryoprotectors that so permit. Thus, unlike previous devices, they can be stored for long periods of time before use.

In this new approach, each element of the device is a group of cells, in this case bacteria, with minimal genetic modifications that can detect different signals. The cells live in the strip of paper and communicate with each other, integrate signals and generate one response or another depending on the different combinations of signals detected. The elements do not vary, but changing their arrangement in space by means of the drawing they make on paper, devices can be built with different functionalities. "Therefore, the order in which the cells are placed is the software, the cells are the hardware, and the paper is the physical substrate hosting these cells", Javier Macía, coordinator of the work, illustrates.

The research team has designed various biosensors, one with a specific application to detect mercury. The system's contribution compared to other existing ones is that it makes a visual estimate of the concentration of mercury without requiring a device in the laboratory that measures it. Depending on the amount of mercury present, more or less dots appear on the reactive strip that can be counted with the naked eye.

Another application being developed is based on detecting cholera in polluted water. "Settlements where there is a risk of cholera often do not have a laboratory or a specialist. Hence, our idea was to develop a new method that would allow us to get living technology outside the laboratory and use it in the field. Our approach is interesting to tackle this kind of problem because it is inexpensive and enables the production of cellular devices in industrial quantities", Sira explains.

Another potential use would be to identify, for example, the risk of preeclampsia. Its detection depends not only on a single marker but a complex combination of markers. A strip with the cellular device with the appropriate configuration could detect biomarker combinations, analyse them and determine a pregnant woman's risk of suffering from this disease.

"Certainly there is much work to do, but these initial results suggest that the methodology developed may be the means to facilitate the creation of commercial products based on living devices", Javier Macía concludes.

DALLAS, March 19, 2021 -- Mechanical removal of blood clots causing a stroke is increasing, yet racial differences in treatment persist, according to late-breaking science presented today at the American Stroke Association's International Stroke Conference 2021. The virtual meeting is March 17-19, 2021 and is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Mechanical clot-removal or endovascular therapy is a non-surgical treatment that uses tiny tubes, or catheters, to remove a blood clot. In 2015, several major clinical trials confirmed that endovascular therapy effectively treated stroke caused by a blockage in a large blood vessel (ischemic stroke). In 2018, the American Heart Association's stroke treatment guidelines were updated to recommend endovascular therapy to improve the odds that certain stroke patients could have functional recovery. However, previous research has indicated members of some under-represented racial/ethnic groups are less likely to receive recommended treatments such as endovascular therapy.

This study compared the use of endovascular therapy and post-stroke recovery among patients of different races/ethnicities before and after 2015. Between April 2012 and June 2019, investigators also reviewed data in the American Heart Association's Get With The Guidelines®- Stroke program, which includes a large, database of information about stroke treatment at hospitals across the U.S. Since 2003, over 2,000 hospitals have entered more than 5 million patient records into the program's database.

Researchers found:

Overall, 14% of 302,965 potentially eligible patients received endovascular therapy and, in all groups, endovascular therapy increased over the course of the study.

However, Black patients were 32% less likely to receive endovascular therapy before 2015 and still 17% less likely to receive it after 2015 when compared to non-Hispanic white patients.

Differences also emerged related to stroke recovery. In terms of short-term outcomes, patients from under-represented racial and ethnic groups fared better than non-Hispanic white patients. In addition, Black, Hispanic and Asian patients were more likely to return home and less likely to die while hospitalized or to be discharged to hospice care.

Three months later, however, Black patients were 16% less likely and Asian patients were 30% less likely to be able to function independently, compared to non-Hispanic white patients.

"It is reassuring that the treatment gap for Black patients has narrowed since 2015, yet it remains significant and is concerning. The most surprising finding was the discrepancy between short- and long-term outcomes in non-Hispanic white patients versus the patients in other race and ethnicity groups," said study lead author Faheem G. Sheriff, M.D., assistant professor of neurology at Texas Tech University Health Science Center of El Paso, Texas. "There is a lot of work that remains in terms of figuring out the root causes for these differences and how best to improve equitable access and care for all patients."

Sheriff continued, "Once these root causes are identified, we can focus on formulating an action plan to reduce these differences, for both access to endovascular therapy and recovery afterwards, particularly post-discharge care."

DALLAS, March 19, 2021 -- New research found patients hospitalized with COVID-19 had a higher risk of stroke, compared with patients who had similar infectious conditions such as influenza and sepsis in prior studies. Those who had an ischemic stroke were more likely to be older, male, Black race, or have high blood pressure, Type 2 diabetes or an irregular heartbeat (atrial fibrillation) compared with other COVID-19 patients, according to late-breaking science presented today at the American Stroke Association's International Stroke Conference 2021. The meeting is being held virtually, March 17-19, 2021 and is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

For this analysis, researchers accessed the American Heart Association's COVID-19 Cardiovascular Disease Registry to investigate stroke risk among patients hospitalized for COVID-19, their demographic characteristics, medical histories and in-hospital survival. The COVID-19 Registry data pulled for this study included more than 20,000 patients hospitalized with COVID-19 across the U.S. between January and November 2020.

"These findings suggest that COVID-19 may increase the risk for stroke, though the exact mechanism for this is still unknown," said lead study author Saate S. Shakil, M.D., a cardiology fellow at the University of Washington in Seattle. "As the pandemic continues, we are finding that coronavirus is not just a respiratory illness, but a vascular disease that can affect many organ systems."

Two hundred eighty-one people (1.4%) in the COVID-19 CVD Registry had a stroke confirmed by diagnostic imaging during hospitalization. Of these, 148 patients (52.7%) experienced ischemic stroke; 7 patients (2.5%) had transient ischemic attack (TIA); and 127 patients (45.2%) experienced a bleeding stroke or unspecified type of stroke.

The analysis of COVID-19 patients also found:

Those with any type of stroke were more likely to be male (64%) and older (average age 65) than patients without stroke (average age 61);

44% of patients who had an ischemic stroke also had Type 2 diabetes vs. about one-third of patients without stroke, and most of the ischemic stroke patients had high blood pressure (80%) compared to patients without stroke (58%);

18% of ischemic stroke patients had atrial fibrillation, while 9% of those without stroke also had atrial fibrillation;

Patients who had a stroke spent an average of 22 days in the hospital, compared to 10 days of hospitalization for patients without stroke; and

In-hospital deaths were more than twice as high among stroke patients (37%) compared to patients without stroke (16%).

In addition, stroke risk varied by race. Black patients accounted for 27% of the patients in the COVID-19 CVD Registry pool for this analysis; however, 31% of ischemic stroke cases were among Black patients.

"We know the COVID-19 pandemic has disproportionately affected communities of color, but our research suggests Black Americans may have higher risk of ischemic stroke after contracting the virus, as well," Shakil said. "Stroke on its own can have devastating consequences and recovering from COVID-19 is often a difficult path for those who survive. Together, they can exact a significant toll on patients who have had both conditions."

Shakil added, "It is more important than ever that we curb the spread of COVID-19 via public health interventions and widespread vaccine distribution."

In-school COVID-19 transmission is rare - even among close school contacts of those who test positive for the virus - when schools heed public health precautions such as mandatory masking, social distancing and frequent hand-washing, according to results of a pilot study in Missouri aimed at identifying ways to keep elementary and secondary schools open and safe during the pandemic. A close contact is anyone who has been within 6 feet for more than 15 minutes in a 24-hour period with someone infected with COVID-19.

The study is part of a larger, ongoing collaboration involving the Centers for Disease Control and Prevention (CDC), Washington University School of Medicine in St. Louis, the Missouri Department of Health and Senior Services, the Missouri Department of Elementary and Secondary Education, Saint Louis University, the Springfield-Greene and St. Louis County health departments, and school districts in the St. Louis and Springfield, Mo., areas.

The findings are published March 19 in the CDC's journal, Morbidity and Mortality Weekly Report. The Missouri school findings mirror those of schools in other states, demonstrating that COVID-19 prevention efforts can significantly curb the spread of SARS-CoV-2 among students, teachers and staff.

"This work is imperative because keeping kids in school provides not only educational enrichment but also social, psychological and emotional health benefits, particularly for students who rely on school-based services for nutritional, physical and mental health support," said senior author Johanna S. Salzer, DVM, PhD, a veterinary medical officer with the CDC's National Center for Emerging and Zoonotic Infectious Diseases.

The pilot study involved 57 schools in the Pattonville School District in St. Louis County and the Springfield Public School District in Greene County in southwest Missouri, as well as two private schools in St. Louis County. All schools in the pilot study required students, teachers, staff and visitors to wear masks while on campus or buses.

Other safety measures included a focus on hand hygiene, deep cleaning of facilities, physical distancing in classrooms, daily symptom screenings for COVID-19, installing physical barriers between teachers and students, offering virtual learning options, and increasing ventilation.

For two weeks in December, the schools involved in the pilot project notified the research team of students, teachers and staff who were either infected with COVID-19 or quarantined due to being considered a close contact of someone who had tested positive. In St. Louis, close contacts of students or teachers who had tested positive were placed in quarantine, meaning they were not to leave their homes for 14 days from when last exposed to a positive case. In Springfield, however, some of the close contacts of those who had tested positive were placed in modified quarantine - meaning they could stay in school if they and the infected person were wearing masks when in close contact; in this scenario, the infected person still isolated at home.

Participants in the pilot study included 193 persons across 22 of the 57 schools -- 37 who tested positive for COVID-19 and 156 of their close contacts. Among participants who were COVID-19 positive, 24 (65%) were students, and 13 (35%) were teachers or staff members. Of the close contacts, 137 (88%) were students, and 19 (12%) were teachers or staff members.

Among the 102 close contacts who agreed to testing for COVID-19 using saliva tests, only two people received positive test results indicating probable school-based SARS-CoV-2 secondary transmission. Further, no outbreaks were identified in participating schools despite the high rates of community spread in December, even among the Springfield schools that followed modified quarantine protocols allowing some close contacts of positive individuals to remain in school.

"Schools can operate safely during a pandemic when prevention strategies are followed," said one of the study's leading researchers, Jason Newland, MD, a Washington University professor of pediatrics, who treats patients at St. Louis Children's Hospital. Newland led the pilot program with the CDC and has advised multiple school districts in Missouri on plans for reopening schools. "The pilot study demonstrates low transmission in schools and no student-to-teacher transmission -- and this was during the height of the pandemic in December, with high rates of community spread."

Added Randall Williams, MD, director of the Missouri Department of Health and Senior Services: "Schools with proper prevention strategies remain a safe environment for students and teachers during the pandemic."

Since mid-January, the CDC, Washington University and Saint Louis University researchers, and the St. Louis County and Springfield-Greene County health departments, along with three school districts from St. Louis County, and three school districts in Greene County have been participating in a larger study to further examine the COVID-19 prevention strategies and quarantine policies. The St. Louis County school districts involved are Rockwood, Pattonville and University City; the Greene County school districts involved are Springfield, Republic and Logan-Rogersville.

In addition, the researchers are going into classrooms to measure the distances between desks to evaluate whether the 6-foot social distancing rule can be relaxed in school settings. They're also sending surveys to parents, teachers and staff to assess the stress and mental health challenges surrounding quarantine. In Springfield, the researchers are continuing to study modified quarantine policies.

"We are pleased to continue to work on this joint project with the CDC, Washington University, and the Springfield-Greene County Health Department," said Jean Grabeel, director of health services for Springfield Public Schools. "The initial results helped verify that our mitigation strategies have been successful in the school setting. This continued work will help to further guide the full-time return of students to in-person learning, five days a week, in a safe manner. We deeply appreciate this unique opportunity to collaborate on such a meaningful, impactful project."

Added Mark T. Miles, PhD, superintendent of the Rockwood School District, the largest school system in St. Louis County and one of the largest in the state, with 22,268 students: "I am grateful for Rockwood's opportunity to participate in this collaboration. We all share the same priority: keeping schools safe for students, teachers and staff as well as the community at large."

Notwithstanding last month's cold snap in Texas and Louisiana, climate change is leading to warmer winter weather throughout the southern U.S., creating a golden opportunity for many tropical plants and animals to move north, according to a new study appearing this week in the journal Global Change Biology.

Some of these species may be welcomed, such as sea turtles and the Florida manatee, which are expanding their ranges northward along the Atlantic Coast. Others, like the invasive Burmese python -- in the Florida Everglades, the largest measured 18 feet, end-to-end --maybe less so.

Equally unwelcome, and among the quickest to spread into warming areas, are the insects, including mosquitoes that carry diseases such as West Nile virus, Zika, dengue and yellow fever, and beetles that destroy native trees.

"Quite a few mosquito species are expanding northward, as well as a lot of forestry pests: bark beetles, the southern mountain pine beetle," said Caroline Williams, associate professor of integrative biology at the University of California, Berkeley, and a co-author of the paper. "In our study, we were really focusing on that boundary in the U.S. where we get that quick tropical-temperate transition. Changes in winter conditions are one of the major, if not the major, drivers of shifting distributions."

That transition zone, northward of which freezes occur every winter, has always been a barrier to species that evolved in more stable temperatures, said Williams, who specializes in insect metabolism -- in particular, how winter freezes and snow affect the survival of species.

"For the vast majority of organisms, if they freeze, they die," she said. "Cold snaps like the recent one in Texas might not happen for 30 or 50 or even 100 years, and then you see these widespread mortality events where tropical species that have been creeping northward are suddenly knocked back. But as the return times become longer and longer for these extreme cold events, it enables tropical species to get more and more of a foothold, and even maybe for populations to adapt in situ to allow them to tolerate more cold extremes in the future."

The study, conducted by a team of 16 scientists led by the U.S. Geological Survey (USGS), focused on the effects warming winters will have on the movement of a broad range of cold-sensitive tropical plants and animals into the Southern U.S., especially into the eight subtropical U.S. mainland states: Florida, Alabama, Mississippi, Louisiana, Texas, New Mexico, Arizona and California. Williams and Katie Marshall of the University of British Columbia in Vancouver co-wrote the section on insects for the study.

The team found that a number of tropical species, including insects, fish, reptiles, amphibians, mammals, grasses, shrubs and trees, are enlarging their ranges to the north. Among them are species native to the U.S., such as mangroves, which are tropical salt-tolerant trees; and snook, a warm water coastal sport fish; and invasive species such as Burmese pythons, Cuban tree frogs, Brazilian pepper trees and buffelgrass.

"We don't expect it to be a continuous process," said USGS research ecologist Michael Osland, the study's lead author. "There's going to be northward expansion, then contraction with extreme cold events, like the one that just occurred in Texas, and then movement again. But by the end of this century, we are expecting tropicalization to occur."

The authors document several decades' worth of changes in the frequency and intensity of extreme cold snaps in San Francisco, Tucson, New Orleans and Tampa - all cities with temperature records stretching back to at least 1948. In each city, they found, mean winter temperatures have risen over time, winter's coldest temperatures have gotten warmer, and there are fewer days each winter when the mercury falls below freezing.

Temperature records from San Francisco International Airport, for example, show that before 1980, each winter would typically see several sub-freezing days. For the past 20 years, there has been only one day with sub-freezing temperatures.

Changes already underway or anticipated in the home ranges of 22 plant and animal species from California to Florida include:

Continuing displacement of temperate salt marsh plants by cold-sensitive mangrove forests along the Gulf and southern Atlantic coasts. While this encroachment has been happening over the last 30 years, with sea-level rise, mangroves may also move inland, displacing temperate and freshwater forests.

Buffelgrass and other annual grasses moving into Southwestern deserts, fueling wildfire in native plant communities that have not evolved in conjunction with frequent fire.

The likelihood that tropical mosquitos that can transmit encephalitis, West Nile virus and other diseases will further expand their ranges, putting millions of people and wildlife species at risk of these diseases.

Probable northward movement, with warming winters, of the southern pine beetle, a pest that can damage commercially valuable pine forests in the Southeast.

Recreational and commercial fisheries' disruption by changing migration patterns and the northward movement of coastal fishes.

The changes are expected to result in some temperate zone plant and animal communities found today across the southern U.S. being replaced by tropical communities.

"Unfortunately, the general story is that the species that are going to do really well are the more generalist species -- their host plants or food sources are quite varied or widely distributed, and they have relatively wide thermal tolerance, so they can tolerate a wide range of conditions," Williams said. "And, by definition, these tend to be the pest species -- that is why they are pests: They are adaptable, widespread and relatively unbothered by changes in conditions, whereas, the more specialized or boutique species are tending to decline as they get displaced from their relatively narrow niche."

She cautioned that insect populations overall are falling worldwide.

"We are seeing an alarming decrease in total numbers in natural areas, managed areas, national parks, tropical rain forests -- globally," she said. " So, although we are seeing some widespread pest species increasing, the overall pattern is that insects are declining extremely rapidly."

The authors suggest in-depth laboratory studies to learn how tropical species can adapt to extreme conditions and modeling to show how lengthening intervals between cold snaps will affect plant and animal communities.

"On a hopeful note, it is not that we are heading for extinction of absolutely everything, but we need to prepare for widespread shifts in the distribution of biodiversity as climate, including winter climate, changes," Williams said. "The actions that we take over the next 20 years are going to be critical in determining our trajectory. In addition to obvious shifts, like reducing our carbon footprint, we need to protect and restore habitat for insects. Individuals can create habitat in their own backyards for insects by cultivating native plants that support pollinators and other native insects. Those are little things that people can do and that can be important in providing corridors for species to move through our very fragmented habitats."

Researchers looking at miniscule levels of plutonium pollution in our soils have made a breakthrough which could help inform future 'clean up' operations on land around nuclear power plants, saving time and money.

Publishing in the journal Nature Communications, researchers show how they have measured the previously 'unmeasurable' and taken a step forward in differentiating between local and global sources of plutonium pollution in the soil.

By identifying the isotopic 'fingerprint' of trace-level quantities of plutonium in the soil which matched the isotopic fingerprint of the plutonium created by an adjacent nuclear reactor, the research team was able to estimate levels of plutonium in the soil which were attributable to reactor pollution and distinguish this from plutonium from general global pollution.

This is important to provide key information to those responsible for environmental assessment and clean up.

Plutonium formed in the big bang decayed away long ago, but miniscule quantities can be found in the environment as a result of reactions in naturally occurring uranium in the ground, and due to human activity. The latter occur local to their source of production, for example, from nuclear plant effluents, reactor accidents, accidents involving nuclear weapons and plutonium-powered space probes. They also occur globally from fallout from atmospheric nuclear weapon tests which took place between the 1950s and 1980.

In the absence of human intervention, the amount of plutonium in the earth varies very slowly with time due to the long half-lives of most plutonium isotopes and relatively slow natural transport mechanisms.

The ability to differentiate between local sources of plutonium and global fallout is important to inform decisions concerning nuclear legacies, particularly the clean-up of contaminated land.

Given this context, the study set out to determine whether the local contribution to trace plutonium levels on the site of a fast breeder nuclear reactor might be discerned from the global contribution.

Using accelerator mass spectrometry (one of the most sensitive ways to measure plutonium), the researchers, from Lancaster University, ETH Zürich, and Dounreay Site Restoration Ltd, were able to demonstrate this was possible and say their research findings could help inform the extent to which clean-up of the local plutonium might be necessary.

Professor Malcolm Joyce, of Lancaster University and Principal Investigator, said: "Plutonium is primordially extinct but that does not mean we don't find it in the earth. Up until 1980 many nuclear weapons were tested in the atmosphere - this coupled with other forms of pollution, has resulted in trace levels of pollution.

"Our study showed we've measured what one might have assumed was 'unmeasureable', differentiating between two very different sources of trace amounts of plutonium, hence demonstrating that it is possible to measure this extraordinarily low-level indicator of human activity if we need to do so."

OSAKA, Japan. If you were given the option to eat a delicious meal by yourself, or share that meal with your loved ones, you would need as very good excuse ready if you chose the former. Turns out, fish share a similar inclination to look after each other.

For the first time ever, a research group led by researcher Shun Satoh and Masanori Kohda, professor of the Graduate School of Science, Osaka City University, have shown these altruistic tendencies in fish through a series of prosocial choice tasks (PCT) where they gave male convict cichlid fish two choices: the antisocial option of receiving food for themselves alone and the prosocial option of receiving food for themselves and their partner.

"As a result, it can be said that the convict cichlid fish properly distinguish between paired females, unknown females, and rival males, and change their choices according to the situation", states Dr. Satoh.

However, what exactly happened?

An experimental male fish was placed in a tank, and a fish was presented to the male fish in another tank. When a partner with whom the male fish had experience in raising children was in the presentation tank, the male fish actively made a prosocial choice and both fish received food. On the other hand, when there was no one in the presentation tank, the male fish preferred neither the prosocial nor antisocial option. To understand how the social context affected the fish's prosocial nature, the team changed the partners to rival males or females the experimental male fish had never met before. Results showed the male fish actively choose the antisocial option of not feeding the rival male, while choosing the prosocial option of feeding the unknown female as if it was their own breeding partner. In the latter experiment, the team also presented the original paired female near the experimental tank holding the male fish. In the absence of the paired female, the male fish made the prosocial choice which provided food for the unknown female, but in the presence of the paired female, they made the antisocial choice.

"These PCT results mirror those from similar experiments with primates", states Dr. Satoh. "However, this is the first time that caring and misbehaving behavior has been observed in fish. No one had ever expected such delicate and exquisite social behavior from such a small fish."

Yet, there is still much work to do. "Through more rigorous behavioral experiments, we hope to clarify whether these fish really have psychosociality and the motivation to produce it and also how the mind of this type of fish evolved to produce it" states Prof. Kohda.

There are hypotheses floating around as to the origin of this desire to care. Could it be a link that connects us past our primate ancestors, ultimately back to fish? Let us wait and see what else Prof. Kohda and his team find out.

In a recent study led by the University of Bristol, scientists have shown how to simultaneously harness multiple forms of regulation in living cells to strictly control gene expression and open new avenues for improved biotechnologies.

Engineered microbes are increasingly being used to enable the sustainable and clean production of chemicals, medicines and much more. To make this possible, bioengineers must control when specific sets of genes are turned on and off to allow for careful regulation of the biochemical processes involved.

Their findings are reported today in the journal Nature Communications.

Veronica Greco, lead author and a Royal Society funded PhD student at Bristol's School of Biological Sciences, said: "Although turning on or off a gene sounds simple, getting a living cell to do it on command is a real challenge. Every cell is slightly different, and the processes involved are not 100 percent reliable."

To solve this issue, the team took inspiration from nature where key events are often controlled by multiple processes simultaneously.

Veronica Greco added: "If you look at a Venus flytrap you find that a trap will only close when multiple hairs are triggered together. This helps reduce the chance of a trap closing by accident. We wanted to do something similar when controlling the expression of a gene inside a cell, adding multiple-levels of regulation to ensure it only comes on precisely when we want it to."

Professor Claire Grierson, co-author and Head of the School of Biological Sciences at Bristol, added: "What was wonderful about this project was how well it worked to harness two of the core processes present in every cell and underpinning all of life - transcription and translation."

The team showed that by using this type of multi-level regulation, they could create some of the most high-performance switches for gene expression built to date.

Moreover, working in collaboration with Dr Amir Pandi and Prof Tobias Erb from Bristol's Max Planck Institute for Terrestrial Microbiology, the team were able to go a step further. They demonstrated that even when used outside of living cells, these multi-level systems offered some of the most stringent control over gene expression yet seen.

Dr Thomas Gorochowski, senior author and a Royal Society University Research Fellow at Bristol, said: "When we engineer microbes, we often try to simplify our systems as much as possible, thinking we'll have better control over what is happening. But what we've shown is that embracing some of the inherent complexity of biology might be the key to fully unlocking its potential for the high-precision biotechnologies of tomorrow."

Key takeaways

Nearly half of gastrointestinal cancer operations in this study were performed at 42 U.S. News & World Report "Best Hospitals."

These top-ranked hospitals performed more than four times the annual case volume of unranked hospitals.

Higher hospital case volume was associated with better outcomes, even after accounting for patient characteristics and complicating factors.

Patients with complex gastrointestinal (GI) cancers may fare better by seeking surgical care at high-volume, top-ranked hospitals.

CHICAGO (March 19, 2021, 9 a.m. CDT): A new study reinforces the principle that "practice makes perfect" when it comes to complex GI cancer operations. Patients whose procedures for gastrointestinal malignancies were performed by a surgical team at a hospital ranked as one of America's "best" by U.S. News & World Report were nearly two and half times more likely to survive the operation than those who had the same procedure done at an unranked hospital. These new research findings are published online in advance of print on the website of the Journal of the American College of Surgeons.

Every year, U.S. News & World Report releases a list ranking the top 50 hospitals for specialty and overall care. These rankings, made available to the public, are based on measures in patient outcomes, patient experience, care-related factors, and expert opinion.

The annual issue plays a role in guiding patients and providers to high quality health care centers. Still, the reliability and accuracy of these rankings for high-risk gastrointestinal surgery is not known.

"Our study demonstrates the U.S. News & World Report ranking is a very appropriate resource," said study coauthor Ninh T. Nguyen, MD, FACS, chair, department of surgery, University of California, Irvine. "Now that we've actually done this analysis, we see the ranking does make sense when you look at surgical case volume and other related issues. Patients who seek surgical care at the top-ranked hospitals actually fare better, particularly if they are treated for the complex surgical conditions examined in this study."

Study details

Using data from the Vizient clinical database, the researchers assessed 6,662 patients who underwent elective esophagectomy, gastrectomy, or pancreatectomy for malignancies in 2018 at U.S. academic centers and their affiliated community hospitals. The study findings include the following:

Of the 6,662 gastrointestinal cancer operations performed, nearly half (3,054) were performed at 42 top-ranked hospitals, compared with 3,608 performed at 198 non-ranked hospitals.

The average annual case volume for these high-risk conditions was four times higher at top-ranked hospitals, compared with non-ranked hospitals (72 cases versus 18 cases).

Compared with non-ranked hospitals, top-ranked hospitals had a much lower in-hospital death rate. Specifically, that rate was almost 1 percent at top ranked hospitals compared with 2.26 percent at non-ranked.

Top ranked hospitals had a lower in-hospital mortality index compared to non-ranked hospitals (0.71 versus 1.53). A score of less than 1 means less patients died than expected based on their characteristics and preexisting comorbidities, and a score of more than 1 means more patients died than expected.

For patients who developed serious complications after their operations, top-ranked hospitals had a much lower in-hospital death rate compared with non-ranked hospitals (8.19 percent versus 16.79 percent).

"Anastomotic or pancreatic leaks are a serious postoperative complication that can be associated with an exceedingly high risk of death. Based on our study findings, surgical teams at top-ranked hospitals are likely better at detecting and managing these serious complications, and more likely to save patients from dying from the complication," Dr. Nguyen said. "For patients, that means if you had your operation performed at a non-ranked center, you are 2.35 times more likely to die than if you had it performed at a top-ranked hospital."

Benefits for high- and low-risk patients

After the researchers factored in patient characteristics such as severity of illness, the death rates were still, on average, lower in the high-volume, ranked hospitals versus non-ranked hospitals.

"When we think of top-ranked hospitals, we imagine these hospitals would perform better for patients who are higher risk, older, or have more comorbidities, but our analysis also examined outcomes based on severity of illness, and we found that even younger, low-risk patients fare better when they go to a top-ranked hospital," Dr. Nguyen said. "So even if you are healthy, and you're dealing with a complex GI condition requiring surgical resection, you are probably better off also obtaining care at a top-ranked hospital."

Accurate decision-making data empowers patients

"Deciding where to go for treatment is a collaborative decision that should be made between the patient and their physician. But one of the resources you can use is the annual U.S. News & World Report list," Dr. Nguyen said. "These are complex GI operations with a much higher risk of mortality. Therefore, you really want to go to a hospital where the surgical team performs a lot of these operations."

UNIVERSITY PARK, Pa. -- A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study led by researchers at Penn State and Emory University. The compound targets a molecular pathway found in bacteria but not humans and could lead to new treatments for gonorrhea and infections from other bacteria, such as tuberculosis and MRSA.

The research team, which also includes scientists from the biopharmaceutical company Microbiotix, the Uniformed Services University, and Florida State, published their results in a paper appearing March 19 in the journal Nature Communications.

Gonorrhea infects more than 500 thousand people in the United States each year, and several strains of the bacteria that causes the disease, Neisseria gonorrhoeae, are resistant to multiple antibiotics in use today. For this reason, the Centers for Disease Control and Prevention (CDC) lists multi-drug resistant gonorrhea as one of the five most dangerous urgent threats today.

"Many current antibiotics target the process of translation--when proteins are made based on information in genetic material--within the bacteria," said Ken Keiler, professor of biochemistry and molecular biology at Penn State and an author of the paper. "Over the last decade, we have been investigating a family of compounds that instead inhibit the trans-translation pathway in bacteria, which bacteria use to fix certain kinds of errors during protein synthesis. In this paper, we provide a proof-of-concept that inhibiting the trans-translation pathway can effectively clear multi-drug resistant gonorrhea in animals."

The researchers previously identified a promising trans-translation inhibitor that clears gonorrhea infection in lab cultures but is ineffective in animals because the compound breaks down. In this study, members of the research team at Microbiotix strategically altered the compound to identify which portions of its structure were necessary to inhibit the pathway and which could be changed to improve its stability.

"Our iterative optimization campaign evaluated over 500 versions of the compound to assess their potency, toxicity, and other pharmacological properties," said Zachary Aron, director of chemistry at Microbiotix and an author of the paper. "We determined that the central region of the compound plays a critical role in blocking the trans-translation pathway, however modifications at the periphery could be altered to modulate its pharmacological properties. By altering a functional group to sidestep the primary mechanism of metabolism, we can create versions of the compound that are much more stable in animals."

Members of the research team at the Uniformed Services University then tested one of these modified compounds, MBX-4132, in mice. Their experiments utilized the gonorrhea strain WHO-X, an extremely virulent pathogen that is resistant to almost all approved antibiotics. A single oral dose of the compound completely cleared the infection in 80% of mice within six days, and the bacterial load in the remaining 20% was dramatically reduced.

"Developing a single dose therapy for gonorrhea is incredibly important," said Keiler. "In some cases, bacteria can develop resistance to a drug when additional doses are skipped, for example when a patient starts to feel better and stops taking antibiotics. With a single dose therapy, a patient could complete the treatment during a visit to their health provider."

To better determine how the compound inhibits the trans-translation pathway, members of the research team at Emory University and Florida State University used cryo-electron microscopy (cryo-EM) to produce high-resolution images of the compound as it binds to the bacterial ribosome--the macromolecule where proteins are synthesized.

"A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites," said Christine Dunham, associate professor of biochemistry at Emory University and an author of the paper. "The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix."

The research team plans to further optimize the compound before pursuing preclinical trials.

"This type of compound is actually a broad-spectrum inhibitor," said Keiler. "It is effective against most Gram-positive bacteria--including tuberculosis and difficult-to-treat staph infections (MRSA)--and some Gram-negative bacteria and could be a promising candidate for future treatments. In this study, we lay the groundwork for using this type of compound and demonstrate that inhibiting the trans-translation pathway in bacteria is a viable antibiotic strategy."

A new imaging technique is shining a light on immune responses and setting the scene for enhancing immune memory to optimise vaccine strategies.

By imaging intact lymphoid organs in three dimensions, researchers have been able to identify specialised niches, which can determine how immune T cells function.

The research, published in Nature Immunology, is a step forward in understanding the differentiation of T cells - critical cells for developing strong immune responses - and how we can use these crucial findings to inform and optimise vaccine strategies.

At a glance

Three-dimensional imaging has enabled researchers to identify the factors that play a role in determining where immune memory cells locate to in the lymph node, in response to infection or cancer.

The research identified avenues to therapeutically target effector and memory cells for a host of applications, including vaccine development.

The findings will help inform and optimise future vaccination strategies.

Keeping memory cells at the ready

WEHI researchers Ms Brigette Duckworth and Dr Joanna Groom said the imaging technique could be applied to many different settings.

"By using this type of three-dimensional imaging, we have the power to visualise how and where immune cells decide their fate. There is real interest in understanding these mechanisms, as that gives us clues about how we can therapeutically target them and harness them for a host of applications, including vaccine development," Ms Duckworth said.

The team studied two types of immune cell: effector cells, which fight infections, and memory cells, which 'remember' how to fight specific infections, like viruses, so they can be rapidly cleared if they return in the future.

"These memory cells are particularly important because they keep chronic infections and cancers in check and act rapidly if we see the virus a second time," Ms Duckworth said.

"This work opens the door to harnessing extrinsic factors like vaccines to alter immune cell positioning in the lymph node and potentially direct the exact type of immune response we would like to generate."

Understanding vaccine strategies

Dr Groom said COVID-19 had put vaccines and vaccination strategies in the spotlight and had highlighted the importance of having a better understanding of our immune response to vaccination.

"These memory cells are what we want to generate when we vaccinate. Previously, we have focussed on the overall immune response, but our data suggests that may not be the best strategy," she said.

"A more efficient response might be to specifically direct vaccines towards memory formation because we want those cells to remain long after vaccination and to react when we come in contact with a virus."

Using T cell differentiation to improve the immune response

Dr Groom said the research team had identified factors that played a role in determining where the memory cells locate to in the lymph node.

"We have identified several ways we can modify the direction of the T cell differentiation," she said.

"These modifiers can be used as a lever to control whether we want more effector cells, which is good to overcome an immediate threat, such as cancer; or whether we want to switch to memory cells for longer lasting immunity benefits."

"We are now looking at these targets to identify the therapeutic window of opportunity and pinpointing which cells will be most effective and have the most impact in future vaccination strategies."

Professor Chunghun Lim and his research team in the Department of Biological Sciences unveiled a neuroprotective pathway that suppresses Lou Gehrig's Disease (ALS).

Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases, such as C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). In this study, the research team has identified a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by the C9ORF72-derived poly (glycine-arginine) protein.

The research team found that the LSM12-EPAC1 pathway is an important suppressor of the NCT-related pathologies in C9-ALS/FTD. The EPAC1 protein, which was expressed in this genetic pathway, normalizes the abnormal RAN gradient that determines the transport direction between the cell nucleus and the cytoplasm, thereby restoring its cellular function.

In general, the RAN proteins are more abundant in the cell nucleus, but in patients with Lou Gehrig's disease, they begin to leak out into the cytoplasm, thereby resulting in abnormal concentration differences. Their findings revealed that the EPAC1 protein, which was expressed through the LSM12-EPAC1 pathway, indeed helped EPAC1 return to the cell nucleus, thereby restoring the RAN gradient.

The research team also identified that the EPAC1 protein, which was expressed through the LSM12-EPAC1 pathway, regulates the distribution of RAN proteins. The EPAC1 protein increases the binding force between the nuclear pore complex (NPC) and the RAN proteins. Because of this, RAN proteins lost within the cytoplasm are, then, captured by the NPC and returned to the nucleus.

"Although the distribution of RAN proteins is critical for the nucleocytoplasmic transport (NTC), its molecular biological mechanism has relatively been unknown," says Professor Lim. "In this study, we have identified that LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient."

He adds, "Our findings are expected to contribute greatly to the prediction and treatment of neurodegenerative diseases, such as frontotemporal dementia and Lou Gehrig's disease, as well as for the understanding of the molecular mechanisms underlying aging."

For the first time researchers from Hebrew University of Jerusalem, Radboudumc, Maastricht UMC+ and international colleagues have gained insight into the "hidden genetic defects" of the general European population. This is important because these defects, if inherited from both father and mother, can lead to all kinds of illnesses in their children. Research in the Dutch and Estonian population shows that every person has two to four such hidden genetic defects. In 1 in 100 couples, this leads to a situation with an increased risk of a genetic disease for future children. In the case of consanguinity, even 20 percent of the couples appear to be at high risk. This research is published in The American Journal of Human Genetics and Genetics in Medicine.

The genes of a every person are half maternal, half paternal. Therefor you have two copies of each gene. Sometimes one of those two copies is defective, without making you sick because the other gene still functions properly. In this case we call it a 'hidden genetic defect' (in scientific terms: an autosomal recessive gene). Such a hidden genetic defect can cause problems if a child inherits the same hidden defect, the same mutated gene, from both father and mother. Both parents are healthy and have never suffered from the hidden genetic defect. But when these two hidden genetic defects (maternal en paternal) come together in the child, the disease manifests itself.

Hidden defects in sight

How often such hidden genetic defects occur in the general population has been unclear. By screening all the genes of nearly 6,500 people in the Dutch and Estonian population researchers from Radboudumc and Maastricht UMC+ have now obtained insight into how often such hidden defects that can lead to disease are present in a single individual. Christian Gilissen, researcher at Radboudumc: "Every human being appears to have on average 2 to 4 such hidden genetic defects. Therefore the chance that a European couple is at risk of having a sick child due to two such defects is about 1 percent. The risk increases sharply in consanguineous couples. In a relationship of cousins, about sixteen percent of the couples are at high risk, with a particularly increased risks for skeletal disorders or intellectual disabilities."

Higher risk with consanguinity

In addition to this research, published in The American Journal of Human Genetics, research was also conducted in the hospital's clinical practice coordinated by Maastricht UMC+, together with Radboudumc and Amsterdam UMC. This study, published in Genetics in Medicine, addresses the question of risk determination of hidden genetic defects in cousin relationships prior to a desired pregnancy. Clinical Molecular Geneticist Aimee Paulussen of Maastricht UMC+: "We mapped the risk in 100 consanguineous couples. About 20 percent of these couples were found to have an increased risk of serious disorders in their offspring through these hidden genetic defects. These results from clinical practice confirm the data already found in the population study mentioned above."

Valuable testing

Professor Han Brunner, head of the Department of Clinical Genetics Maastricht as well as the Department of Genetics Nijmegen, is involved in both studies. He sees them as a clear incentive to make genetic testing available to couples with a possible increased risk because of such hidden genetic defects: "Certainly for these couples, this information can help them to make an informed decision when starting a family. They can consider pre-implantation diagnostics and IVF to allow selection of embryos without these defects."

Aspergillus fumigatus kills as many people as malaria and tuberculosis, but is less known. It is found "everywhere", for example in the soil or in our compost, but is not normally dangerous to healthy people.

Those who die from it often have a poor immune system or are hospitalized for lung infections, such as covid-19.

Aspergillus also constitutes an increasing problem in agriculture, because the fungus causes deadly infections in both plants and animals. In the same way that many bacteria are resistant to antibiotics, also this fungus is now becoming more and more resistant to the limited repertoire of treatments. It is therefore important to find new ways to fight fungal infections.

Researchers at the Department of Biomedicine at the Faculty of Medicine, UiB, together with researchers at the Faculty of Mathematics and Natural Sciences and a German research team, have now discovered an enzyme on the surface of the fungus.

The newly discovered enzyme breaks down a vital molecule that is important for the cells' energy metabolism: the NAD molecule, which is formed in our body from vitamin B3.

Without NAD, cells cannot survive. Therefore, the breakdown of NAD could affect immune cells and weaken our immune system to fight the fungal infection.

Recollected old scientific observations

Similar enzymes are found in bacteria that cause infections such as tuberculosis, streptococci or cholera. The idea that also fungi may have an NAD-degrading enzyme on their surface has been raised already in the 1950's:

"Enzyme activity that degrades NAD had been detected on the surface of a fungus, only the identity of the enzyme was never established. However, that fungus is commonly used in research laboratories and not known to be pathogenic. Probably, this discovery therefore went into the archive", says Professor Mathias Ziegler, leader of the study.

They want to re-examine the hypothesis that an enzyme, which breaks down NAD, may contribute to pathogenic mechanisms in fungi such as Aspergillus fumigatus.

"We measured strong enzyme activity on the surface of spores from Aspergillus fumigatus. It surprised us", says researcher and first author Øyvind Strømland.

Modern technology makes it possible to study the enzyme

"Using an elegant biochemical method, we identified fragments of the protein sequence from this enzyme. Since the entire genome of the fungus is known, we could then use these fragments to identify the gene that encodes the enzyme", says Ziegler.

"The next step was to use the genetic information and create a version of this gene that can be used by laboratory cell lines "trained" to produce sufficient amounts of the protein for detailed molecular studies", he continues.

In this way, researchers have been able to study how the enzyme breaks down NAD.

"There are two things that are central here. Highly sensitive analytical technology enabled identification of enzyme fragments. The other important element is that we now have the genome sequence and could easily identify the gene. That was not possible in the 50s", says Ziegler.

May design new drugs against the fungus

The researchers are clear that even though it is known from other diseases that similar bacterial enzymes break down NAD in infected cells, it cannot be said for sure that this is the case with the enzyme from Aspergillus fumigatus.

However, they know a lot more about the enzyme now through their research, and the hope is that the knowledge can help to discover new treatments for fungal infections.

Intriguingly, their bioinformatics analyses revealed that this type of enzyme is predominantly present in pathogenic fungi.

"If we could make a drug with molecules that resemble NAD, they might block the enzyme in our cells", the researchers suggest.

March 19, 2021, Bristol, UK - A new peer-reviewed study published in the journal Toxicological Research & Application shows acute exposure of a 3D human bronchial tissue model to e-cigarette aerosol has minimal impact on gene expression compared to smoke from combustible cigarettes.

The research involved sub-cytotoxic exposure to cells in a 3D human bronchial model (MucilAirTM) to nicotine-containing vape aerosol, combustible cigarette smoke and fresh air control under strict laboratory conditions.

The highly sensitive Toxicity Testing in the Twenty-First Century (TT21C)-based technique allows researchers to gain a mechanistic understanding of the potential effects of exposure to vape aerosol and 3R4F (reference cigarette) smoke, without experiencing other processes that may be triggered by significantly higher exposures - including cell death - that could potentially make interpretation of results difficult.

After cell 'recovery' periods of 4 and 48 hours, scientists assessed the expression of a variety of genes to determine if any were increased or decreased by the single exposure.

"Within this model, exposure to combustible cigarette smoke triggered significant changes in gene expression, indicating - amongst other effects - changes in oxidative stress and inflammation markers," confirmed Matt Stevenson, Pre-Clinical Toxicology Manager at Imperial Brands. "Conversely, the vape aerosol generated only a minimal response, similar to that observed in the air control."

Principal Toxicologist at Imperial Dr Liam Simms added: "Gene set enrichment analysis examining those genes most over/under expressed were compared across five key pathways - cell cycle, apoptosis, p53 signaling, cell death and NF-KappaB signaling [a protein complex that controls transcription of DNA, cytokine production and cell survival].

Focusing on the 3R4F reference cigarette, no pathways were activated after four hours exposure, but at 48 hours the cells had both genes associated with cell cycle and cell death pathways activated. Conversely, those cells exposed to vape aerosol demonstrated slightly elevated NF-KappaB signaling pathways after four hours exposure. However, at 48 hours no pathways were activated."

The results from this study show, that under the conditions of test, acute exposure to vape aerosol had less impact on gene expression in human lung cells in vitro than the equivalent dose of cigarette smoke.

"This latest research adds to the growing body of research gathered by both Imperial Brands and others, demonstrating the considerable harm reduction potential of Next Generation Products (NGPs) like vapes compared to continued combustible cigarette smoking," said Dr Grant O'Connell, Head of Tobacco Harm Reduction Science at Imperial.

"We encourage regulators and policy makers to consider the weight of evidence that shows the clear scientific differences between combustible cigarettes, which burn tobacco, and potentially harm-reduced NGPs that do not," he concluded.