Culture

It is known that the tumour microenvironment plays an important role in the progression of cancer. But could estrogen present in this microenvironment facilitate the growth of liver metastases in women affected by colon, pancreatic and lung cancers? This is what a team of researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) suggests, in a study that shows for the first time that the liver immune microenvironment reacts to metastatic cells differently in male and in female mice and that, indeed, the main female hormone estrogen can indirectly contribute to the growth of metastases. Their findings, recently published in Nature Communications, provide a rationale for further exploration of the role of sex hormones in female cancer patients and the potential benefits of anti-estrogen drugs such as tamoxifen in the treatment of hormone-independent cancers that metastasize to the liver.

"What prompted us to begin this investigation was our finding that the immune microenvironments of liver metastases in male and female mice are regulated differently," says Dr. Pnina Brodt, senior scientist in the Cancer Research Program at the RI-MUHC and lead author of the study. "We were also aware of reports based on recent immunotherapy clinical trials that female patients do not respond to immunotherapy as well as male patients and that overall, patients with liver metastases respond more poorly to such treatments than patients without liver metastases."

"We therefore wanted to identify factors unique to male and female responses to liver metastatic disease that could explain these findings and could eventually lead to improved immunotherapy outcomes for patients," adds Dr. Brodt.

Dr. Brodt and her team looked at the interaction between metastatic cells entering the liver and the unique microenvironment of this organ, in mouse models of colon, pancreatic and lung carcinoma, malignant diseases that do not have a clear sex bias and are not depended on sex hormones for growth.

By increasing and decreasing the levels of estrogen in their mouse models, the team discovered that estrogen plays a role in the expansion of liver metastases--a major cause of cancer-associated death. Specifically, they found that this hormone regulates the accumulation in the liver of bone marrow-derived innate immune cells such as the myeloid-derived suppressor cells (or MDSC) and immunosuppressive macrophages.

Cancer cell killers can become friends of the enemy

When metastatic cells enter the liver, innate immune cells are recruited, some from the bone marrow. These cells have the ability to kill cancer cells, but once in the tumour environment, they can also acquire immunosuppressive and tumour promoting functions.

MDSCs, for instance, do not directly affect cancer cell growth, but can do so by changing the microenvironment around the tumour in the liver.

"MDSCs can impede the activity of T lymphocytes, whose role is to kill the cancer cells. In this way, they act to promote--rather than curtail--the growth of metastases," explains Dr. Brodt, who is also Professor in the Departments of Surgery, Oncology and Medicine at McGill University.

The team observed that estrogen induces an immune tolerant environment that helps the tumour cells grow, and that the removal of estrogen reduces the accumulation and activity of MDSCs that, in some way, become "friends" of the enemy.

"The realization that cancer is a community of cells, not just the cancer cells, but also the cells that surround it has become an important part of how the scientific community now views cancer and how it should be treated," says Dr. Brodt.

Towards gender-specific cancer treatment?

In this era of personalized cancer management and with the worldwide effort to develop drugs that target the tumour microenvironment, awareness of the fact that male and female patients may respond differently to such treatments is very important.

"This should now be taken into account to design better, more gender-specific treatment strategies, especially when we know that colorectal cancer incidence, for instance, is increasing in the younger population," says Dr. Brodt.

There are several approved anti-estrogen drugs currently in routine clinical use. However, their use is restricted to patients with hormone-sensitive cancers such as breast cancer.

Further investigation is warranted to determine if estrogen plays the same role in cancer patients, and if low toxicity anti-estrogen drugs such as tamoxifen could be used in conjunction with immunotherapy to neutralize the immunosuppressive environment in patients who have non-sex-specific cancers, are premenopausal and have higher levels of estrogen.

A research team at Kobe University has developed a method of artificially controlling the anchorage position of target proteins in engineered baker's yeast (Saccharomyces cerevisiae).

The group, consisting of academic researcher INOKUMA Kentaro, Professor HASUNUMA Tomohisa (both of the Engineering Biology Research Center) and Professor KONDO Akihiko et al. (of the Graduate School of Science, Technology and Innovation) demonstrated that this technique could be utilized to improve the amount of ethanol produced from hydrothermally-processed rice straw by 30%. It is expected that these results will contribute to improved yeast functionality in cell surface engineering, which is utilized in a variety of fields such as bio-production and medicine.

The journal paper for this research was published in Metabolic Engineering on November 9 2019. This study was conducted in collaboration with researchers from the University of the Western Cape and Stellenbosch University under the JSPS (Japan Society for the Promotion of Science) bilateral program with South Africa. The research was also carried out as part of Kobe University and MEXT's 'Innovative BioProduction Kobe' project, and was supported by JSPS KAKENHI grant number JP18K05554.

Research Background

Cell surface engineering is a technique with applications in a variety of industrial and biotechnological fields. This technique can create microorganisms that can degrade biomass efficiently, allowing biofuels to be produced. In medical fields, cell surface engineering can also be utilized for the screening of antibodies with high antigen-binding capacity. Baker's yeast (or Saccharomyces cerevisiae) is often used as a host microorganism for this technique because its characteristics are well understood. This yeast has a cell wall that is between 100-200 nm thick and consists of a microfibrillar array of glucan chains. The cell wall provides space to display functional proteins.

In order to immobilize a target protein to the yeast cell wall, it is necessary to fuse the target protein to the "anchoring domain", which is a part of the yeast cell wall protein. Selecting the appropriate anchoring domain is important for efficient cell-surface display. A previous study by Inokuma et al. found that the degree to which activity was improved through changing the anchoring domain varied greatly depending on the target protein displayed. From these previous results, the research group hypothesized that changing the anchoring domain affected not only the display efficiency but also the anchorage position of the target protein in the cell wall and conducted the current study to verify this hypothesis.

Research Methodology

The experiments were conducted using the two anchoring domains (the Sed1-anchor and Sag1-anchor) often utilized in Saccharomyces cerevisiae cell surface engineering. Enhanced green fluorescence protein (eGFP) was used as the target protein. Confocal fluorescence microscopic and immunoelectron-microscopic analyses were performed to investigate how the anchoring domains affected where the eGFP was localized in yeast cell. These analyses revealed that the eGFP that fused with the Sed-1 anchoring domain were mainly located on the outermost layer of the cell wall, whereas the Sag1-anchored eGFP were predominantly positioned inside the cell wall (Figure 1). This result suggested that it was possible to artificially manipulate the location of the proteins on the yeast cell wall by changing the fused anchoring domain.

Next, an experiment was carried out to demonstrate if this method could be utilized to increase the ethanol productivity from hydrothermally-processed rice straw.Saccharomyces cerevisiaecells were used in the simultaneous saccharification and fermentation of the pretreated rice straw. This process converts the cellulose contained in the rice straw into ethanol. In this experiment, β-glucosidase (BGL) and endoglucanase (EG) were displayed on the yeast cell surface. These enzymes play different roles in breaking down the cellulose. EG breaks down large cellulose molecules at random, whereas BGL dissolves the smaller sugars (oligosaccharide) into glucose. Sed1- and Sag1-anchor domains were used to reposition the enzymes- with EG on the outermost layer and BGL on the interior of the cell wall. This efficient positioning resulted in a 30% greater yield of ethanol (Figure 2).

Further Development

Discussions on how to improve cell surface engineering efficiency have often centered on anchoring a large number of target proteins to the surface. The current study revealed that controlling the location of the target proteins played an important role in cell functionality, and this could provide a new strategy for improving this technology. The ethanol fermentation experiment of pretreated rice straw demonstrated in this study indicates that it is possible to position the two enzymes (EG and BGL) in locations suitable for them in the yeast cell wall. In addition, this strategy could also be utilized in other applications; for example in medicine, placing antibodies on the outermost layer of the cell wall could improve their accessibility to large antigens. Therefore, it is expected that this new strategy will improve the functionality of cell-surface engineered yeast across a wide range of fields.

WOODS HOLE, Mass. -- How did the monstrous giant squid - reaching school-bus size, with eyes as big as dinner plates and tentacles that can snatch prey 10 yards away -- get so scarily big?

Today, important clues about the anatomy and evolution of the mysterious giant squid (Architeuthis dux) are revealed through publication of its full genome sequence by a University of Copenhagen-led team that includes scientist Caroline Albertin of the Marine Biological Laboratory (MBL), Woods Hole.

Giant squid are rarely sighted and have never been caught and kept alive, meaning their biology (even how they reproduce) is still largely a mystery. The genome sequence can provide important insight.

"In terms of their genes, we found the giant squid look a lot like other animals. This means we can study these truly bizarre animals to learn more about ourselves," says Albertin, who in 2015 led the team that sequenced the first genome of a cephalopod (the group that includes squid, octopus, cuttlefish, and nautilus).

Led by Rute da Fonseca at University of Copenhagen, the team discovered that the giant squid genome is big: with an estimated 2.7 billion DNA base pairs, it's about 90 percent the size of the human genome.

Albertin analyzed several ancient, well-known gene families in the giant squid, drawing comparisons with the four other cephalopod species that have been sequenced and with the human genome.

She found that important developmental genes in almost all animals (Hox and Wnt) were present in single copies only in the giant squid genome. That means this gigantic, invertebrate creature - long a source of sea-monster lore - did NOT get so big through whole-genome duplication, a strategy that evolution took long ago to increase the size of vertebrates.

So, knowing how this squid species got so giant awaits further probing of its genome.

"A genome is a first step for answering a lot of questions about the biology of these very weird animals," Albertin said, such as how they acquired the largest brain among the invertebrates, their sophisticated behaviors and agility, and their incredible skill at instantaneous camouflage.

"While cephalopods have many complex and elaborate features, they are thought to have evolved independently of the vertebrates. By comparing their genomes we can ask, 'Are cephalopods and vertebrates built the same way or are they built differently?'" Albertin says.

Albertin also identified more than 100 genes in the protocadherin family -- typically not found in abundance in invertebrates -- in the giant squid genome.

"Protocadherins are thought to be important in wiring up a complicated brain correctly," she says. "They were thought they were a vertebrate innovation, so we were really surprised when we found more than 100 of them in the octopus genome (in 2015). That seemed like a smoking gun to how you make a complicated brain. And we have found a similar expansion of protocadherins in the giant squid, as well."

Lastly, she analyzed a gene family that (so far) is unique to cephalopods, called reflectins. "Reflectins encode a protein that is involved in making iridescence. Color is an important part of camouflage, so we are trying to understand what this gene family is doing and how it works," Albertin says.

"Having this giant squid genome is an important node in helping us understand what makes a cephalopod a cephalopod. And it also can help us understand how new and novel genes arise in evolution and development."

Blood culture surveillance programs are critical for estimating the prevalence of typhoid and paratyphoid fevers, but cases can be missed when patients don't seek medical care, or seek medical care and don't have a blood culture test. Researchers writing in PLOS Neglected Tropical Diseases have now calculated inflation factors that can be used to adjust these incidence rates to account for under-detection.

Typhoid and paratyphoid fever are infections caused by the bacteria Salmonella enterica Typhi and S. Paratyphi. In countries with a high incidence rate of the diseases, vaccine programs are used to control typhoid fever. Surveillance programs to estimate these incidence rates, however, can miss cases, when patients don't receive blood cultures or in settings where patients self-treat with widely available antibiotics. Therefore, the true burden of disease is thought to be underestimated.

In the new work, Merryn Voysey of the University of Oxford, UK, and colleagues used data from an ongoing Typhoid Vaccine Acceleration Consortium (TyVAC) clinical trial of a typhoid vaccine in Nepal. Children aged 9 months through 16 years in the Lalitpur area of Kathmandu were eligible and local healthcare providers--including 18 community clinics and one tertiary care hospital--were instructed to collect blood samples to culture for patients who had a fever for at least two days or a current temperature of at least 38 degrees. There was also an active surveillance effort included in the trial.

During the first year of passive surveillance, data was collected on 2,393 fever presentations. Overall, 1615 (68%) of patients had blood cultures. Children were more likely to have blood taken for culture if they were older, had a longer fever, a higher temperature or clinicians suspected typhoid or a urinary tract infection. Models revealed that patients who had blood taken were 1.87 times more likely to be positive for Salmonella than those without blood cultures.

"Crude typhoid incidence estimates should be adjusted for both the proportion of cases that go undetected due to missing blood cultures as well as the lower likelihood of culture-positivity in the group with missing data," the researchers say.

LEBANON, NH - While strong immune responses are needed to help protect the host from infections, the immune system also must curb the magnitude of those responses to limit the damage it can potentially cause. Over the past 8-10 years, a team of researchers at Dartmouth's and Dartmouth Hitchcock's Norris Cotton Cancer Center, led by Randolph Noelle, PhD, have identified some of the molecules that the immune system uses to temper immunity. While these molecules are usually good, they also limit the magnitude of the immune response to cancer. The team has learned that turning off these "brakes" on immunity allows therapeutic response to cancer. VISTA (V-domain Ig suppressor of T-cell activation) is one of these tempering molecules that negatively regulates immunity.

The team describes how VISTA controls immune T-cell responses in their study, "VISTA, a checkpoint regulator of naïve T-cell quiescence and tolerance in the periphery," newly published in Science.

"We have learned that keeping your immune system quiet is a challenging and very active process," says Noelle. "VISTA mediates immune system function and its loss can result in the development of unwanted immune responses. But VISTA may also be a valuable target in regulating the immune response in cancer and autoimmunity."

VISTA keeps the immune system's T-cell compartment passive and prevents activation of the immune system to self-antigens such as developing cancer cells. "Like other negative checkpoint regulators, blocking VISTA in cancer may enhance the host's ability to make protective tumor-specific immune responses," says Noelle.

Currently, there is an antibody specific to VISTA that is going to be used in Phase I clinical trials in cancer to see if it is safe and if it can amplify the immune response to cancer in patients. If so, this antibody may be valuable in the development of drugs and vaccines to provide therapeutic response to cancer and cancer cures.

Inside a cell, tentacled vesicles shuttle cargo for sorting. DNA rearranges in the nucleus as stem cells differentiate into neurons. Neighboring neurons cling to one another through a web-like interface. And a new microscopy technique shows it all, in exquisite detail.

The technique, called cryo-SR/EM, melds images captured from electron microscopes and super-resolution light microscopes, resulting in brilliant, clear detailed views of the inside of cells - in 3-D.

For years, scientists have probed the microscopic world inside cells, developing new tools to view these basic units of life. But each tool comes with a tradeoff. Light microscopy makes it simple to identify specific cellular structures by tagging them with easy-to-see fluorescent molecules. With the development of super-resolution (SR) fluorescence microscopy, these structures can be viewed with even greater clarity. But fluorescence can reveal only a few of the more than 10,000 proteins in a cell at a given time, making it difficult to understand how these few relate to everything else. Electron microscopy (EM), on the other hand, reveals all cellular structures in high-resolution pictures - but delineating one feature from all others by EM alone can be difficult because the space inside of cells is so crowded.

Combining the two techniques gives scientists a clear picture of how specific cellular features relate to their surroundings, says Harald Hess, a senior group leader at the Howard Hughes Medical Institute's Janelia Research Campus. "This is a very powerful method."

Janelia Research Scientist David Hoffman and Senior Scientist Gleb Shtengel spearheaded the project under the leadership of Hess and Janelia senior fellow Eric Betzig, an HHMI Investigator at the University of California, Berkeley. The work is described January 16, 2020 in the journal Science.

First, the scientists freeze cells under high pressure. That halts the cells' activity quickly and prevents the formation of ice crystals that can damage cells and disrupt the structures being imaged. Next, the researchers place samples into a cryogenic chamber, where they're imaged by 3-D by super-resolution fluorescence microscopy at temperatures less than ten degrees above absolute zero. Then, they're removed, embedded in resin, and imaged in a powerful electron microscope developed by the Hess lab. This scope shoots a beam of ions at the cells' surface, milling away bit by bit while taking pictures of each newly exposed layer. A computer program then stitches the images together into a 3-D reconstruction.

Finally, researchers overlay the 3-D image data from both microscopes. The result: stunning imagery that reveals cells' inner details with incredible clarity.

Included alongside this news release are a few videos that illustrate how scientists are using the technique. “There’s already been a lot of interest,” says Hess. “There are so many more experiments to do — a whole world of cells out there to study.”

1. Chromatin organization

The nucleus of a neuron looks dramatically different before (left) and after (right) the cell begins to assume its final adult role. As the cell matures, DNA is repackaged within the nucleus to turn on a new set of genes. These changes are reflected in the different patterns of grey mottling and colored fluorescence inside the two cells. “The technique provided an amazingly detailed snapshot of the state of the nucleus before and after differentiation,” says David Solecki of St. Jude Children’s Research Hospital, who collaborated on the project.

2. Neural adhesions

Developing neurons stick together. This video shows exactly how those cells adhere to each other, revealing swiss-cheese-like linkages that help young neurons properly migrate to their final places in the nervous system. Purple-and-green super-resolution fluorescence images of adhesion proteins at these linkages correlate with electron microscopy images (orange) showing the membrane’s structure in detail.

3. Endosomes

Cells are filled with small vesicles ¬¬– membrane-bound sacks that help cells store proteins, break down cellular garbage, and carry cargo. These many varieties of vesicles are indistinguishable from each other under an electron microscope alone. But with cryo-SR/EM, their distinct features become clear. This clip zooms in on endosomes, which shuttle cargo to different regions within the cell.

World leaders are currently updating the laws for international waters that apply to most of the world's ocean environment. This provides a unique opportunity, marine scientists argue this week, to introduce new techniques that allow protected zones to shift as species move under climate change.

In an article in the Jan. 17 issue of Science, researchers make the case for the United Nations to include mobile marine protected areas in the U.N. Convention on the Law of the Sea, or UNCLOS, now being updated since its last signing in 1982.

"Animals obviously don't stay in one place -- a lot of them use very large areas of the ocean, and those areas can move in time and space," said lead author Sara Maxwell, an assistant professor at the University of Washington Bothell who studies migratory marine animals. "As climate change happens, if we make boundaries that are static in place and time, chances are that the animals we are trying to protect will be gone from those places."

Former President Barack Obama, former President George W. Bush and actor Leonardo DiCaprio are well-known proponents of protecting large regions of the ocean environment in marine protected areas, or MPAs. But even these huge swaths of protected ocean aren't enough to conserve highly mobile species, like sea turtles, whales, sharks and seabirds that can travel across entire oceans in search of food and breeding grounds.

Climate change will further complicate things, the authors argue. As species, habitats and ecological communities shift, established protected areas might no longer work.

"In the context of climate change, the way that we have been applying things in the past is not likely to work into the future," Maxwell said. "Species will increasingly need protection, and we will need to apply more dynamic and innovative tools to be effective."

Maxwell's research uses tags that transmit to satellites to track sea turtles, seabirds and other marine species' movements from space -- a new technology that is just beginning to be applied to real-time protection of marine species. Only in the past 10 to 15 years, she said, have countries started to incorporate such tools into management, combining satellite tags on animals, GPS tracking of ships and ocean modeling to create rules that adjust to the situation, a technique known as dynamic management.

"Until we could implement this type of management and show that it's feasible, people didn't quite believe that it was possible," Maxwell said. "But as we know more about where animals are going in space and time, we can use that information to better protect them."

Several nations now use dynamic management strategies within the 200 nautical miles from shore that they fish exclusively, Maxwell said. A few countries also use dynamic management strategies farther from shore, for boats registered to their countries.

The TurtleWatch program, for instance, asks U.S. fishing boats to voluntarily avoid waters north of Hawaii at the surface temperatures preferred by loggerhead and leatherback sea turtles, to reduce the unintended capture of the endangered animal. In Australia, longline fishing boats bypass fishing in international waters when and where models predict the presence of the southern bluefin tuna, a commercially valuable and endangered species that's managed through a quota system.

"New technology is making this dynamic approach to ocean conservation possible, at the same time that climate change is making it necessary," Maxwell said.

With the newly published article, the authors encourage the international community to adopt this emerging management strategy and urge its widespread use in international waters, which cover some two-thirds of the planet's oceans.

"We hope the language in the United Nations treaty could be changed to explicitly include mobile marine protected areas and dynamic management, so that those become options to protect the largest parts of the ocean going forward," Maxwell said.

A new species of prehistoric scorpion from the early Siluarian period (approximately 437.5 to 436.5 million years ago) is described in a study in Scientific Reports. The findings suggest that Parioscorpio venator is the oldest-known scorpion reported to date and may have been capable of leaving its marine habitat and venturing onto land, a behaviour similar to that of present-day horseshoe crabs.

Scorpions are among the first animals to have moved from the sea onto land but because their fossil record is limited, how and when they adapted to life on land remains unclear.

Andrew Wendruff and colleagues describe two well-preserved specimens of a previously unknown fossil scorpion species discovered in the Waukesha Biota in Wisconsin, USA, which dates from the early Silurian. This makes the fossils older than Dolichophonus loudonensis, from Scotland, which was previously accepted as the oldest known scorpion species.

P. venator shows some primitive characteristics present in other early marine organisms, such as compound eyes, as well as characteristics found in present-day scorpions, such as a tail terminating in a stinger. Both P. venator specimens show details of internal anatomy, including narrow, hourglass-shaped structures that extend along much of the middle part of the body. These structures are very similar to the circulatory and respiratory systems in present-day scorpions, as well as those of modern horseshoe crabs, according to the authors.

No lungs or gills are evident in the P. venator fossils, but their similarity to horseshoe crabs, which can breathe on land, suggests that while the oldest scorpions may not have been fully terrestrial, they may have forayed onto land for extended periods of time.

A new computational model shows how different patterns of crop rotation--planting different crops at different times in the same field--can impact long-term yield when the crops are threatened by plant pathogens. Maria Bargués-Ribera and Chaitanya Gokhale of the Max Planck Institute for Evolutionary Biology in Germany present the model in PLOS Computational Biology.

The continual evolution of plant pathogens poses a threat to agriculture worldwide. Previous research has shown that crop rotation can help improve pest control and soil quality. Other research shows that switching the environment in which a pathogen grows can limit its reproduction and change its evolution. However, these two concepts have been rarely studied together from an evolutionary point of view.

To better understand how crop rotation can protect against pests, Bargués-Ribera and Gokhale developed a computational model of the technique that integrates evolutionary theory. They used the model to investigate a scenario in which cash crops (grown for profit) and cover crops (grown to benefit soil) are alternated, but are affected by a pathogen that only attacks the cash crops.

The analysis identified which patterns of crop rotation maximize crop yield over multiple decades under the given scenario, revealing that regular rotations that switch every other year may not be optimal. The findings suggest that the long-term outcome of crop rotation depends on its ability to both maintain soil quality and diminish pathogen load during harvesting seasons.

"Our model is an example of how evolutionary theory can complement farmers' knowledge," Bargués-Ribera says. "In a world with ever increasing food demand, ecological and evolutionary principles can be leveraged to design strategies making agriculture efficient and sustainable."

Future research could apply the new model to specific species to assess crop rotation patterns for specific crops and their pests. The model could also be used to help study the combined effects of crop rotation and other pest control techniques, such as fungicides and use of crops that have been genetically modified for pest resistance.

Birds fly in a meticulous manner not yet replicable by human-made machines, though two new studies in Science Robotics and Science - by uncovering more about what gives birds this unparalleled control - pave the way to flying robots that can maneuver the air as nimbly as birds. Roboticists have tried to replicate feathery fliers for almost two decades, but these efforts have been hindered by use of rigid feather-like panels and a lack of understanding of the skeletal and muscular mechanics behind birds' highly morphable wings. In Science Robotics, Eric Chang et al. measured the kinematics of wing flexion and extension in cadavers of common pigeons. They applied their findings to a robot with wings made of 40 pigeon feathers, dubbed "PigeonBot." The pigeon feathers were connected to artificial wrists and fingers via synthetic elastic ligaments. By placing pigeon wings in a wind tunnel, the researchers determined that wrist and finger action provided fine control over feather placement, wing span, area and aspect ratio. In flight tests with the PigeonBot, asymmetric wrist and finger motion initiated stable turn maneuvers at sharp angles--some of the first evidence that birds primarily use their fingers to steer in flight.
In Science, Laura Matloff, her team members from Chang et al., and additional colleagues investigated interactions between individual feathers of various bird species and found two primary mechanics underlying wing morphing: the passive redistribution of feathers and the fastening of adjacent overlapping feathers via hook-shaped microstructures protruding from each "branch" of the feather. Acting like Velcro, these structures locked during extension and unlocked automatically during flexion. In their PigeonBot, the researchers found that without this "directional Velcro," the resulting gaps between feathers led to loss of coherent feather coordination necessary for dynamic wing morphing under different environmental conditions. Interestingly, the rather noisy detachment mechanism was not found on silent fliers like the barn owl. The finding of "directional Velcro" between flight feathers informs the evolution of modern birds and their winged ancestors, and could be explored for fashion, medical and aerospace applications, the authors say.

Previous analyses of global paleobiodiversity have been coarsely resolved to roughly 10 million years, obscuring the effects of ecological processes and events that operate at shorter timescales. Now, by combining ancient marine fossils with modern machine learning and one of the world's most powerful supercomputers, researchers have composed a new record of Paleozoic biodiversity in which the age of average fossil layers can be resolved to within 26,000 years, the authors say. The computational approach allowed Jun-xuan Fan and colleagues to generate a new Cambrian-Triassic biodiversity curve with a refined temporal resolution of 26 ± 14.9 thousand years. "This new level of dating specificity is similar to moving from a system in which all people who lived in the same century are considered to be contemporaries to one in which only people who lived during the same 6-month period are deemed to be contemporaries," writes Peter Wagner in a related Perspective. To achieve this, Fan et al. developed a novel and custom-designed machine learning procedure and used the "Tianhe-2" supercomputer to synthesize data from nearly 11,000 Paleozoic marine invertebrate species recovered from more than 3,000 stratigraphic sections across China and Europe. The greatly improved resolution of the resulting paleobiodiversity curve clarified the timing of known diversification and extinction events while revealing many new, once-hidden aspects of Paleozoic biodiversity. "Supercomputer implementation that has resulted from this project will now become more or less standard in these types of biodiversity analyses throughout Earth sciences," said co-author Norman MacLeod in an accompanying video. The results also revealed a correlation between atmospheric carbon dioxide and paleobiodiversity change; however, due to the lack of a long-term and high-resolution paleoenvironmental data, more study is required to understand any causal links, the authors say.

Researchers who analyzed well-preserved ocean drilling and global temperature records have added support to the idea that the primary cause of the Cretaceous-Paleogene (K/Pg) mass extinction was an asteroid impact, rather than extreme volcanism. Their new study evaluates the impact of greenhouse outgassing by volcanism in the Deccan Traps on global temperature. According to their results, volcanic gasses may have played an important role in shaping the rise of different species after the extinction, rather than driving the initial event. Sixty-six million years ago, two planetary-scale catastrophic events - an asteroid impact and large-scale volcanism - ravaged Earth's surface as well as most of the terrestrial lifeforms that walked upon it, bringing the long reign of the dinosaurs to a close. Disentangling the relative effects of the large amounts of lava from the Deccan traps and the asteroid impact that occurred across the Cretaceous-Paleogene (K/Pg) mass extinction has been challenging and the cause of the K/Pg extinction remains uncertain. Unlike previous studies on the role of Deccan volcanism, which largely focused on the accumulation of lava, Pincelli Hull and colleagues evaluated the more environmentally relevant aspect of the eruption - outgassing. Hull et al. investigated the timing of Deccan outgassing by modeling, in several scenarios, the effects of carbon dioxide and sulfur emissions on long-term global temperatures. They compared the results to global paleotemperature records spanning the K/Pg extinction event. The results suggest that at least 50% or more of the major Deccan outgassing occurred well before the impact, not just before it. Therefore, only the impact coincided with the mass extinction event, they say. The timing of this outgassing they propose would have led to changes in the carbon cycle that allowed the ocean to absorb vast quantities of carbon dioxide, potentially limiting global warming that would otherwise be expected from post-extinction Deccan volcanism. "Deccan volcanism might have contributed to shaping [the rise of Cenozoic species and communities] during the extinction aftermath," the authors say.

PITTSBURGH, Jan. 16, 2020 - Twice as many people as previously believed are dying of sepsis worldwide, according to an analysis published today in The Lancet and announced at the Critical Care Reviews annual meeting in Belfast. Among them are a disproportionately high number of children in poor areas.

Led by researchers at the University of Pittsburgh and University of Washington schools of medicine, the study revealed 48.9 million global cases of sepsis in 2017 and 11 million deaths, representing 1 in 5 deaths worldwide. Sepsis occurs when a person's organs cease to function properly as the result of an out-of-control immune response to infection. Even if sepsis doesn't kill its victims, it can create lifelong disabilities in survivors.

The large majority of sepsis cases -- 85% in 2017 -- occurred in low- or middle-income countries. The highest burden was found in sub-Saharan Africa, the South Pacific islands near Australia, and South, East and Southeast Asia. Sepsis incidence was higher among females than males. By age, the incidence of sepsis peaks in early childhood, with more than 40% of all cases occurring in children under 5.

"I've worked in rural Uganda, and sepsis is what we saw every single day. Watching a baby die of a disease that could have been prevented with basic public health measures really sticks with you," said lead author Kristina E. Rudd, M.D., M.P.H., assistant professor in Pitt's Department of Critical Care Medicine. "I want to contribute to solving this tragedy, so I participate in research on sepsis. However, how can we know if we're making progress if we don't even know the size of the problem? If you look at any top 10 list of deaths globally, sepsis is not listed because it hasn't been counted."

For their analysis, Rudd and colleagues leveraged the Global Burden of Disease Study, a comprehensive epidemiological analysis coordinated by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington School of Medicine. The GBD 2017 Study currently reports on 282 primary causes of death not including sepsis, which is considered an intermediate cause of death. A primary cause of death is the underlying condition (e.g. cancer), which leads to the intermediate cause (sepsis) that ultimately results in death.

Previous global estimates for sepsis were limited as they relied upon hospital databases from a select group of middle- and high-income countries. The previous estimates overlooked the substantial burden of sepsis that occurs outside of the hospital, especially in low-income countries. Today's study findings are unprecedented as they represent mortality both in and out of the hospital.

"We are alarmed to find sepsis deaths are much higher than previously estimated, especially as the condition is both preventable and treatable," said senior author Mohsen Naghavi, M.D., Ph.D., M.P.H., professor of health metrics sciences at IHME at the University of Washington School of Medicine. "We need renewed focus on sepsis prevention among newborns and on tackling antimicrobial resistance, an important driver of the condition."

The study authors analyzed annual sepsis incidence and mortality trends from 1990 through 2017 and found rates are improving. In 1990, there were an estimated 60.2 million sepsis cases and 15.7 million deaths; by 2017, incidence had dropped by 19% to 48.9 million cases and deaths by 30% to 11.0 million.

The most common underlying cause of sepsis-related death in both 1990 and 2017 was lower respiratory infection.

"So what is the solution? Well, to start with it's basic public health infrastructure. Vaccines, making sure everyone has access to a toilet and clean drinking water, adequate nutrition for children and maternal health care would address a lot of these cases," said Rudd, who also is a UPMC critical care physician. "But sepsis is still a problem here in the U.S., where it is the No. 1 killer of hospital patients. Everyone can reduce their odds of developing it by getting the flu shot, and the pneumonia vaccine when appropriate. Beyond that, we need to do a better job preventing hospital-acquired infections and chronic diseases, like diabetes, that make people more susceptible to infections.

"Finally, for people in high-income countries who want to help reduce the rates of sepsis in low-income areas, we need to support research into treatments and advocate to our elected officials for the importance of supporting sepsis prevention and control efforts in low-income communities," Rudd said.

The new study, led by scientists from the universities of Bristol and Essex and published today [16 January] in Current Biology, challenge the established view of the origin of plants on land, and reveal that compared to the origin of animals, plants are better at inventing new genes during periods of evolution.

Plants constitute one of the major lineages of life and are the basis of almost all ecosystems, being an important source of food and oxygen. During evolution, all organisms gain new genes, lose old ones, or simply recycle genes.

The research team set out to understand which changes, at the genetic level, took place during the evolutionary transition of plants by comparing over 200 genomes, one of the largest datasets ever assembled to tackle the evolution of the plant kingdom.

Using sophisticated computer techniques enabled the researchers to essentially travel back in time 470 million years ago to find out which genes were present in the first land-based plants as they evolved from living in water to land.

Dr Jordi Paps, Lecturer from Bristol's School of Biological Sciences and lead researcher, explained: "After comparing over 200 genomes of the plant kingdom, we discovered that the origin of land plants is associated with two explosions of new genes, an unprecedented level of genomic novelty. Our findings challenge previous views of this transition being more gradual at genetic level.

"The first burst predates the origin of land plants, before they left their aquatic environments, and comprises genes that explain why plants are multicellular. The second coincides with the origin of land plants, and involved genes related to adaptations to challenges found in terrestrial environments."

The team now plans to use the same approach to identify drought-resistant genes in crops.

Dr Paps added: "We now plan to use the same approach to further explore the genes involved in drought tolerance. Most crops are sensitive to drought conditions, using our methods we can find genes involved in drought resistance that we can potentially introduce in dessication-sensitive plants."

Genetically engineered mosquitoes are resistant to multiple types of dengue virus (DENV), according to a study published January 16 in the open-access journal PLOS Pathogens by Prasad Paradkar of the Australian Animal Health Laboratory, and Omar Akbari of the University of California, San Diego, and colleagues. As noted by the authors, this is the first engineered approach that targets all types of DENV, which is crucial for effective disease suppression.

Dengue is a mosquito-borne viral disease that represents a pressing global problem, and new solutions are needed to prevent its transmission. DENV is mainly transmitted by Aedes aegypti mosquitoes. Recent advances in genetic engineering technologies have made it possible to create mosquitoes with reduced vector competence, limiting their ability to acquire and transmit pathogens. In the new study, the authors describe the development of A. aegypti mosquitoes synthetically engineered to be resistant to multiple types of DENV.

These mosquitoes express a gene encoding an engineered single-chain variable fragment (scFv) derived from a broadly neutralizing DENV human monoclonal antibody. Mosquitoes expressing the anti-DENV scFv cannot be infected with or transmit any of the four types of DENV, so they should not be able to transmit the virus to humans. Taken together, these results provide a compelling route for developing effective genetic-based DENV control strategies, which could be extended to curtail related viruses. According to the authors, this strategy could be coupled with a gene-drive system to rapidly convert wild mosquito populations into genetically modified mosquitoes that would be completely resistant to DENV transmission.

Akbari adds, "The most important aspect of this study is the fact that we engineered mosquitoes to be refractory to all major serotypes of Dengue virus. This may serve as a genetic tool to control Dengue in the wild in the future."