J0140: An Evolved Cataclysmic Variable Turned Extremely Low Mass White Dwarf (Planetary Science)

Kareem El-Badry and colleagues, using the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST), presented the discovery of a close binary binary, LAMOST J0140355+392651 (also called J0140), containing a bloated, low-mass (0.15 M) proto-white dwarf and a massive (about M = 0.95 M) white dwarf companion. Their paper recently appeared on Journal arXiv.

Extremely low-mass white dwarfs (ELM WDs) are rare helium-core WDs with masses below 0.25 solar masses. They are degenerate and semi-degenerate helium stars that never ignited core helium burning. They are assumed to be formed in binary systems via stable or unstable mass transfer, given that the universe is too young to produce such objects by single-star evolution. Therefore, it is thought that ELM WDs are the stripped cores of stars that were initially more massive but lost most of their envelope to their companions.

Now, Kareem El-Badry and colleagues reported on the discovery of J0140 that may be a newly found ELM WD. J0140 first came to their attention when LAMOST observations of this object suggested large epoch-to-epoch radial velocity (RV) variability. Then, after that it was observed/monitored by photometric surveys, Catalina Sky Survey (in between 2005-2013), Palomar Transient Factor (PTF) and is regularly observed by All-Sky Automated Survey for Supernova (ASAS-SN), to obtain more information regarding its parameters.

Kareem et al. found that, J0140 is a close binary with orbital period of approximately 3.81 hours. It contains a bloated, proto-white dwarf with a mass of around 0.15 solar masses and WD companion about 5 percent less massive than the sun. The radius of the proto-WD is estimated to be 0.29 solar radii. The system is located approximately 5,000 light years away and its orbit is inclined 80 degrees.

They also revealed that the proto-WD is cooler (Teff=6800 K) and more puffy (log[g/(cms−²)]=4.74±0.07) than any known extremely low mass (ELM) WD, but hotter than any known cataclysmic variable (CV) donor. It either completely or very nearly fills its Roche lobe (R/RRochelobe=0.99±0.01), suggesting ongoing or recently terminated mass transfer. Hence, the properties of J0140 are transitional between that of known CVs and ELM WDs.

In addition, to investigate the formation and evolution of J0140, astronomers calculated a set of MESA binary evolution models and found that the properties of the system are well-matched by MESA binary evolution models of CVs with donors that underwent significant nuclear evolution before the onset of mass transfer. In these models, the bloated proto-WD is either still losing mass via stable Roche lobe overflow or was doing so until very recently. In either case, it is evolving toward higher temperatures at near-constant luminosity to become an ELM WD.

If the system is detached, mass transfer likely ended when the donor became too hot for magnetic braking to remain efficient.

— wrote authors of the study

Figure 1. Future evolution of J0140. Colored tracks show the MESA models. Normal CVs reach a period minimum at about 80 minutes, when they become degenerate. Systems with evolved donors are smaller when they become degenerate (due to higher mass and lower 𝑌𝑒), allowing them to reach much shorter minimum periods. These models suggest that J0140 will reach a minimum period 𝑃orb ≲ 15 minutes, when (if it avoids a merger) it will be classified as an AM CVn binary. © Kareem et al.

Moreover, evolutionary models predict that the binary will shrink to Porb ≲ 10 minutes within a few Gyr, when it will either merge or become an AM Canum Venaticorum star (AM CVn) binary. J0140 provides an observational link between the formation channels of CVs, ELM WDs, detached ultracompact WD binaries, and AM CVn systems.

“Further observations are necessary to better understand the nature of the system. In particular, higher-resolution and higher-SNR (signal-to-noise ratio) spectra will allow a deeper search for emission features associated with accretion, which will enable a more conclusive determination of whether there is ongoing mass transfer,”

— concluded authors of the study

Featured image: Light curve of J0140, showing data from several time-domain surveys. Credit: El-Badry et al., 2021.

Reference: Kareem El-Badry, Eliot Quataert, Hans-Walter Rix, Daniel R. Weisz, Thomas Kupfer, Ken Shen, Maosheng Xiang, Yong Yang, Xiaowei Liu, “LAMOST J0140355+392651: An evolved cataclysmic variable donor transitioning to become an extremely low mass white dwarf”, arXiv, pp. 1-24, 2021. https://arxiv.org/abs/2104.07033

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Average-risk Individuals May Prefer Stool-based Tests Over Colonoscopy for Colorectal Cancer Screening (Medicine)

When given a choice, most individuals with an average risk of colorectal cancer said they would prefer a stool-based screening test for colorectal cancer over colonoscopy, the method most often recommended by health care providers, according to results published in Cancer Prevention Research, a journal of the American Association for Cancer Research.

Although colorectal cancer is the second most frequent cause of cancer-related death in the United States, about one-third of eligible American adults have never completed a colorectal cancer screening test, explained lead author Xuan Zhu, PhD, senior health services analyst at the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Zhu added that colorectal cancer screening is particularly underutilized by individuals experiencing socioeconomic disadvantages, racial and ethnic minorities, and certain age groups.

The U.S. Preventive Services Task Force (USPSTF) recommends several colorectal cancer screening methods for adults ages 50 to 75 with an average risk for this disease, and the USPSTF draft guideline update released in October 2020 recommends lowering the age of screening initiation to 45. The three most common tests are an annual fecal immunochemical test or fecal occult blood test (FIT/FOBT) that detects blood in the stool; the multitarget stool DNA (mt-sDNA) test (Cologuard), completed every three years, which detects altered DNA from cancer cells, precancerous polyps, or blood in the stool; and a colonoscopy every 10 years, which involves a gastroenterologist examining the colon with a camera and removing any precancerous polyps while a patient is under sedation.

“Previous research has shown that fewer patients complete colorectal cancer screening when only colonoscopy is recommended compared to when stool-based options are also recommended,” said Zhu.

In this study, Zhu and colleagues evaluated patient preferences for colorectal cancer screening through a survey conducted in collaboration with the National Opinion Research Center at the University of Chicago. The survey included short descriptions of FIT/FOBT, mt-sDNA, and colonoscopy, and asked a nationally representative sample of adults ages 40 to 75 to choose between two options presented at a time. A total of 1,595 respondents completed the survey. The researchers focused their analysis on a subgroup of 1,062 respondents aged 45 to 75 with an average risk of colorectal cancer.

When presented with a choice, 66 percent of respondents said they preferred mt-sDNA over colonoscopy, and 61 percent said they preferred FIT/FOBT over colonoscopy. When asked to choose between the two stool-based options, 67 percent indicated a preference for mt-sDNA over FIT/FOBT.

The investigators also examined differences in patient preferences across sociodemographic characteristics, access to health care, awareness of colorectal cancer screening, and prior experience completing a test. While mt-sDNA was preferred over colonoscopy for all age groups examined, a larger proportion of older adults (ages 65 to 75 years) said they preferred colonoscopy compared to those in younger age groups (ages 45 to 54 years).

Similarly, the preference for mt-sDNA over colonoscopy was higher among non-Hispanic white individuals compared with non-Hispanic Black and Hispanic individuals. Half of Hispanic and non-Hispanic Black respondents preferred stool-based tests over colonoscopy, with a preference for mt-sDNA over FIT/FOBT. Zhu said the observed differences among age and racial/ethnic groups might have reflected variations in preferences or disparities in access to information about newer testing methods.

Respondents without insurance were 2.5 times more likely to prefer less expensive stool-based tests over colonoscopy. The overall awareness of stool-based tests was about 60 percent, compared to 90 percent for colonoscopy, indicating that there is an opportunity to improve patient education about stool-based options, Zhu noted. Study participants who were aware of stool-based tests were two times more likely to prefer mt-sDNA over FIT/FOBT, and those who had previously had a stool-based test were 2.8 times more likely to choose FIT/FOBT over colonoscopy. By contrast, those who had previously had a colonoscopy were less than half as likely to prefer a stool-based test over colonoscopy and those who had a provider recommend colonoscopy in the past 12 months were 40 percent less likely to prefer mt-sDNA over colonoscopy.

“The best colorectal cancer screening test is the one that patients are most likely to complete,” Zhu said.

The findings highlight the importance of patient education about available screening options and taking patients’ needs, preferences, and values into account in shared decision-making discussions to increase colorectal cancer screening rates, Zhu added. “Providing patients with as-needed navigation support, from initiation of screening to completion of a colonoscopy after stool-based tests show abnormal results may increase screening completion and adherence.”

Limitations of this study include the observational design, meaning that causal relationships cannot be inferred, the reliance on self-reported data rather than objective measures, and limiting the scope of the study to the three colorectal cancer screening tests most commonly recommended by health care providers.

The study was supported by funding provided by Exact Sciences Corporation and the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Zhu declares no conflicts of interest.

Reference: Xuan Zhu, Philip D. Parks, Emily Weiser, Kristin Fischer, Joan M. Griffin, Paul J. Limburg and Lila J. Finney Rutten, “National Survey of Patient Factors Associated with Colorectal Cancer Screening Preferences”, Cancer Prevention Research, 2021. DOI: 10.1158/1940-6207.CAPR-20-0524

Provided by AACR

Covid-19: Clinicians Uncover Rare Blood Clotting Syndrome (Medicine)

A team led by a UCL clinical academic has outlined the mechanism behind rare cases of blood clots and low platelets seen in patients who have had the Oxford/AstraZeneca vaccine.

The new study, published in the New England Journal of Medicine, highlights the importance of rapidly spotting this new syndrome, known as vaccine-induced thrombosis and thrombocytopenia (VITT), as it requires a very different treatment from what is typically recommended for thrombosis.

The team stressed that vaccination remains the key route out of the Covid-19 pandemic.

Professor Marie Scully (UCL Institute of Cardiovascular Science), also a consultant haematologist at UCLH, and Dr Will Lester, of the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, were the first clinicians in the UK to spot the link between the Oxford/AstraZeneca vaccine and rare cases of blood clotting with low platelet count.

They also identified the correct diagnostic test for the syndrome and recommended a treatment approach that avoids the use of the blood thinner heparin.

Having spotted the link, Professor Scully and colleagues, including Professor Marcel Levi (UCL Medicine), UCLH’s former chief executive, alerted the medical community worldwide and regulatory authorities in the UK of their discovery and suggested a treatment approach.

In the research paper, the team report on the cases of 23 patients, who all presented with thrombosis and thrombocytopenia after receiving the AstraZeneca vaccine. No patients had underlying conditions which would predispose them to blood clots.

Tests confirmed the presence of the PF4 antibody (platelet factor 4) in almost all cases (21 out of 23). These antibodies are usually triggered in rare instances by the blood-thinning drug heparin, a syndrome known as heparin-induced thrombocytopenia (HIT). But the patients reported in this study did not receive heparin, so could not have had HIT.

Professor Scully, lead author of the paper, said: “The conclusion we ultimately came to is that we were seeing a heparin-independent PF4-dependent syndrome in the setting of the AstraZeneca vaccine – something that we have not seen before as clinicians.

“And what is important is that this condition needs to be identified quickly if it is present, because the treatment needs to be very different to how we would usually treat blood clots and low platelet counts.

“Platelet transfusions may make the clots worse so they should be avoided. And while we may use blood thinners, we are not using heparin-based treatments, as they may exacerbate the syndrome we are seeing.

“The approach we recommend is a type of immune modulation – damping down the immune response to lower production of PF4 antibodies. We currently use intravenous immunoglobulin which has been urgently authorised for use by NHS England.”

Professor Scully’s work was supported by the NIHR UCLH Biomedical Research Centre (BRC).

Professor Bryan Williams (UCL Institute of Cardiovascular Science), UCLH Director of Research and Director of the UCLH Biomedical Research Centre, said: “At UCLH, we call ourselves a research hospital because research is embedded into clinical practice. Through the BRC we have set up the specialist infrastructure and employed the skilled staff needed in dedicated clinical research facilities. This means that the science happens at the patient bedside, not in some remote laboratory, by the clinical scientists who are observing the disease in patients in real time.”

Featured image: The components of a blood clot. Credit: Kevin Mackenzie, University of Aberdeen. Source: Wellcome Collection. CC BY 4.0. The image has been cropped and rotated.

Reference: Marie Scully, M.D., Deepak Singh, B.Sc., Robert Lown, M.D., Anthony Poles, M.D., et al., “Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination”, New England Journal of Medicine, April 16, 2021
DOI: 10.1056/NEJMoa2105385

Provided by University of College London

Do Preservative And Stray Proteins Cause Rare COVID-19 Vaccine Side Effect? (Medicine)

Researchers in Germany and Canada have added provocative new details to their proposal for how the COVID-19 vaccine made by AstraZeneca might be causing an unusual clotting disorder in a small number of recipients. The mechanism, involving stray human proteins and a preservative in the vaccine, remains speculative. And it is not clear whether their hypothesis explains similar reactions observed in recipients of the COVID-19 vaccine made by Johnson & Johnson (J&J).

The new data are “interesting but not a smoking gun by any means” for the group’s hypothesis, says Gowthami Arepally, a hematologist at the Duke University School of Medicine who is working as an external consultant with AstraZeneca on the issue. But figuring out what in a COVID-19 vaccine might start the sometimes fatal combination of blood clotting and low platelets is crucial for developing better treatments for the side effect and possibly for understanding who might be most at risk, says Paul Offit, a vaccine researcher at the Children’s Hospital of Philadelphia (CHOP). It could also be vital for modifying vaccines so they don’t kick-start the reaction, which researchers are calling vaccine-induced immune thrombotic thrombocytopenia (VITT).

Vaccine regulators are struggling to balance the small risk of VITT versus the clear need to immunize people against the pandemic virus SARS-CoV-2. The European Medicines Agency (EMA) declared on Tuesday that the COVID-19 protection of the J&J vaccine significantly outweighs the danger of the rare side effect and recommended its use, with an addition to the warning label that alerts doctors and recipients to the clotting problem. That advice, which matches EMA’s verdict on the AstraZeneca vaccine, cleared the way for vaccinations with the J&J shots to begin across Europe.

Both J&J and AstraZeneca use modified adenoviruses to deliver and express the spike protein gene of SARS-CoV-2. But new data posted Tuesday in a preprint on Research Square show that doses of the AstraZeneca vaccine also contain significant amounts of protein from human cells—presumably from the human cell line used to grow the virus during the manufacturing process. The preprint’s authors, some whom were among the first to identify the VITT side effect, propose that these proteins, together with another component of the vaccine called ethylenediaminetetraacetic acid (EDTA), may set off a dangerous response by the immune system in some vaccine recipients.

EDTA is used in some vaccines as a preservative, but it is also known to make blood vessels a bit leaky, says Andreas Greinacher, an expert on clotting at the University of Greifswald who led the study. He said he was suprised at the concentration the group found in the AstraZeneca vaccine samples they examined: 100 micromoles, which is much higher than amounts listed for other common vaccines.

The group showed that in a mouse model, the vaccine did increase vascular leakage. Greinacher says this may make any free proteins in a vaccine dose more likely to encounter platelets, or thrombocytes, in a recipient’s bloodstream. Platelet factor 4 (PF4), a protein secreted by these thrombocytes, could then form complexes with the residual human proteins and other components of the vaccine, thanks to its strong positive charge. Indeed, when the researchers added PF4 to the vaccine in the lab, large complexes formed. Greinacher notes that other vaccines contain human proteins, but the amount—between 70 and 80 micrograms per milliliter (mcg/mL) in the four batches they tested—was “surprisingly high,” he says. Other vaccines list amounts of 5 mcg/mL or less, although many do not specify an amount.

In a tiny minority of people, Greinacher and his colleagues speculate, the combination of PF4 complexes and the strong inflammation triggered by the vaccine may turn on a specialized set of immune cells that can make antibodies to PF4. (This also happens in a similar clotting syndrome triggered by the blood thinner heparin. In that case, heparin forms the problematic complexes with PF4.) In an even smaller minority, the researchers say, the antibodies to PF4 are strong enough to fuel additional immune reactions in the blood that deplete platelets in the blood and cause potentially deadly clots to form in the brain, abdomen, or lungs.

Those PF4 antibodies can be useful if the body is fighting off severe infection—but they can get out of control, Greinacher says. “It’s like waking a sleeping dragon,” he says. “In most cases, we really want to keep the dragon sleeping, and the vaccine is like a guy coming into a cave and throwing stones at it.” An AstraZeneca spokesperson said the company could not comment directly on the preprint, but that they “continue to work to understand the individual cases, epidemiology, and possible mechanisms that could explain these rare events.”

Greinacher has asked J&J for doses of its vaccine so he can analyze its contents and see whether it might trigger the same cascade. The vaccine had not been used yet in Germany, which he says prevented him from using it in his initial experiments.

Offit notes that other vaccines are grown in cell culture and contain cellular debris, and it isn’t clear that AstraZeneca’s contains more or different remnants. EDTA may also not be needed to trigger VITT; J&J’s COVID-19 vaccine doesn’t include it, for instance. “Adenovirus has a notorious history of being a particularly inflammatory stimulating virus,” says Mortimer Poncz, a pediatric hematologist at CHOP. “Whether the EDTA is involved, I think, is the softest part of the whole story.”

Arepally agrees. “The virus itself, which has been given in such large amounts, is probably enough to cause an inflammatory response,” she says. Arepally suggests PF4 simply binds to the adenovirus—which could, in theory, be why the J&J vaccine produces the same side effect. She speculates that a few unlucky people “simply have higher levels of PF4 for some reason and that’s why they are forming these complexes when they get the vaccine.”

Poncz, on the other hand, isn’t convinced PF4 complexes are actually behind the clotting problems. The complexes may be innocent bystanders, he says, although he applauds Greinacher “for leading the field and providing thought-provoking and experiment-provoking questions.”

Rolf Marschalek, a molecular biologist at Goethe University Frankfurt, suspects that additional spike-related mechanisms may play a role once a vaccinated person’s cells start to make the viral protein, which happens in the same time frame as the clotting disorders appear, generally between 4 to 20 days following vaccination. These might then add to the PF4 antibody cascade which the Greifswald group describes, he says.

Even as the spotlight shines on the J&J and AstraZeneca vaccines, scrutiny is widening to two other COVID-19 vaccines that rely on adenovirus vectors: Sputnik V, developed by the Russian Gamaleya National Research Institute of Epidemiology and Microbiology, and another made by the Chinese company CanSino Biologics. CanSino CEO Yu Xuefeng told journalists the company is monitoring recipients more carefully after the clotting reports emerged. The Gamaleya Institute said in a press release there had been no reports of clotting disorders following its vaccine rollout it many countries, although it’s not clear how many people have received it so far.

Hungary is already using Sputnik V, and several other European countries are considering purchases, but EMA has not yet approved it for use. EMA Director Emer Cooke says the agency’s review of safety data for the vaccine “is at an early stage,” and it has not yet looked carefully at data regarding possible side effects. “But now that we are aware of [VITT], will make sure it’s part of the company’s responsibility to report any of these events.”

Featured image: The European Medicines Agency paved the way this week for Europe’s use of a COVID-19 vaccine made by Johnson & Johnson, but questions persist about a rare clotting side effect linked to it and a similar vaccine made by AstraZeneca. ROB ENGELAAR/ANP/NEWSCOM

Provided by AAAS

First Description of A New Octopus Species Without Using a Scalpel (Biology)

Biologists at the University of Bonn use state-of-the-art non-destructive methods to study an octopus from the deep sea

An evolutionary biologist from the University of Bonn brought a new octopus species to light from depths of more than 4,000 meters in the North Pacific Ocean. The sensational discovery made waves in the media a few years ago. Researchers in Bonn have now published the species description and named the animal “Emperor dumbo” (Grimpoteuthis imperator). Just as unusual as the organism is the researchers’ approach: in order to describe the new species, they did not dissect the rare creature, but instead used non-destructive imaging techniques. The results have now been published in the prestigious journal “BMC Biology”.

In the summer of 2016, Dr. Alexander Ziegler from the Institute of Evolutionary Biology and Ecology at the University of Bonn spent several months in the North Pacific aboard the research vessel SONNE. The crew lowered the steel basket to the seabed around 150 times in order to retrieve rocks, sediments, and living creatures. One organism in particular caused a media stir: a dumbo octopus. The animal, about 30 centimeters in size, was found in waters more than 4,000 meters deep. However, the octopus could not be recovered alive: “The deep-sea organism is not adapted to the environmental conditions of the ocean surface,” Ziegler explains.

The Emperor dumbo (Grimpoteuthis imperator) is about 30 centimeters long. Evolutionary biologist Dr. Alexander Ziegler recovered it from depths of more than 4,000 meters in the North Pacific. © Alexander Ziegler

Dumbo octopuses are a group of deep-sea-dwelling octopuses that includes 45 species. The name is based on the flying elephant from the Walt Disney movie of the same name, who is made fun of because of his unusually large ears – the fins of the dumbo octopuses, which are on the sides of the head resemble these elephant ears. However, the dumbo on the research vessel SONNE differed significantly from the known octopus species. “It was clear to me straight away that we had caught something very special,” the biologist reports. So Ziegler immediately photographed the unusual animal, took a small tissue sample for DNA analysis, and then preserved the octopus in formalin.

Together with his former master’s student Christina Sagorny, Ziegler has now published a description of the previously unknown species. Just as unusual as the octopus was the methodology used. The animals are usually dissected by zoologists, as the internal organs are also important for the description of a new species. “However, as this octopus is very valuable, we were looking for a non-destructive method,” explains the researcher.

High-field MRI instead of scalpel

The eight-armed cephalopod therefore did not end up under the scalpel, but in the high-field magnetic resonance imaging system of the German Center for Neurodegenerative Diseases (DZNE) in Bonn. This device is routinely used to image test persons’ brains. Thankfully, Dr. Eberhard D. Pracht from the DZNE agreed to conduct a high-resolution scan of the dumbo octopus in 3D. As part of her master’s thesis, Christina Sagorny then investigated whether high-field MRI can be used to study internal organs and other soft tissues just as well as through conventional dissection. “The quality is actually even better,” Ziegler says.

The researchers used state-of-the-art methods to examine the Emperor dumbo (Grimpoteuthis imperator). The description of the new species also includes the internal organs, which are shown here in color in the form of an interactive 3D model. © Alexander Ziegler

One of the few exceptions: the beak and rasping tongue (radula) of the cephalopod are made of hard chitin that does not image well using MRI. The biologists therefore also consulted the micro-computed tomography system of the paleontologists at the University of Bonn. This technique showed the beak and radula razor-sharp and in 3D. “These hard part structures are an integral part of the species description of octopuses,” Ziegler explains. The researchers also decoded the animal’s genetic material to reconstruct the family relationships. Ziegler: “The DNA showed beyond a doubt that we were looking at a species of the genus Grimpoteuthis.”

Examination of the reproductive organs revealed the dumbo octopus to be an adult male. Compared to other species of this genus, it displays several special characteristics. For example, an average of 71 suckers were detected on each arm, which the animal needs to catch prey and which reflect body size. The length of the cirri, which are small appendages on the arms that the deep-sea animals presumably use to sense their prey, also differs from species already known.

The web that stretches between the arms, with which the dumbo slowly floats down in the water column, catching worms and crustaceans as if in a bell, also only reaches just over halfway from the mouth down the arms. “The web is much longer in dumbo octopus species that mainly float freely in the water column,” Ziegler says. This would indicate that the new species lives close to the seafloor, because otherwise the web would be a hindrance to movements on the bottom.

As the species-describing researchers, Sagorny and Ziegler had the privilege of naming the new species: they decided on Grimpoteuthis imperator – in English “Emperor dumbo”. Background: the animal was discovered not far from Japan in an underwater mountain range whose peaks are named after Japanese emperors.

Digital copy of the organism

The combination of non-destructive methods produced a crisp digital copy of the animal. Anybody interested can download it from the online database “MorphoBank” for further research and learning purposes. The preserved octopus itself is kept in the archives of the Museum für Naturkunde in Berlin, Germany. “There, it can then still be analyzed 100 years from now, for example when more modern investigation methods or new questions arise,” Ziegler explains. “Our non-destructive approach could set a precedent, especially for rare and valuable animals,” said the Bonn-based evolutionary biologist.


No third-party funds were used to conduct the study.

Featured image: The bell-shaped umbrella of the Emperor dumbo (Grimpoteuthis imperator) extends just over halfway down the arms. This suggests a habitat close to the seafloor. © Alexander Ziegler

Publication: Alexander Ziegler, Christina Sagorny: Holistic description of new deep sea megafauna (Cephalopoda: Cirrata) using a minimally invasive approach, BMC Biology, DOI:  https://doi.org/10.1186/s12915-021-01000-9

Video of the recovery of the emperor dumbo:  https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-01000-9

Provided by University of Bonn

Successful Cancer Therapy Using Artificial Metalloenzymes to Deliver Drugs (Medicine)

Researchers led by Katsunori Tanaka and Kenward Vong at the RIKEN Cluster for Pioneering Research (CPR) in Japan have demonstrated that tumor growth can be reduced by therapy that tags cancer cells with different therapeutic molecules. In one case, the group was able to prevent tumors from forming in mice by targeting cancer cells with a compound that makes it difficult for the cells to clump together and form tumors. For tumors that already existed, they targeted cancer cells with toxic compounds that destroyed them. This study was published on April 23 in Science Advances.

One of the major problems with current cancer treatments is that their effects are not limited to cancerous cells in the body. The side effects of chemotherapy are well known–hair loss, nausea, exhaustion, compromised immune system, and nerve damage. Being able to specifically target cancer cells–and only cancer cells–with therapeutic compounds is a dream that is slowly becoming a reality, and the new study by Tanaka’s group at RIKEN CPR is the proof-of-concept. As Tanaka says, “We have succeeded for the first time in treating cancer using metal-catalyzed chemistry in mice.”

The process builds on the group’s previous work that uses artificial gold-based enzymes–generally called metalloenzymes–to tag proteins inside the body. The tagging agent and the metalloenzyme are both injected into the body, but separately. The metalloenzyme itself is designed to be glycosylated, meaning it has sugar chains called glycans attached to its surface. Specific glycans are chosen so that they can bind to the target cells in the body. For instance, different cancer cells can be identified by the unique types of lectins–glycan-binding proteins–that are embedded in their outer membranes. For this experiment, the researchers built a glycosylated metalloenzyme that would be able to attach itself to the specific lectins that are on the outside of HeLa cancer cells, thus targeting them. After the tagging agent reacts with the metalloenzyme, it can perform the desired function and tag the protein of interest on the cancer cell. In this way, only cancer cells targeted by the glycosylated metalloenzyme can be tagged.

The team performed two major targeted drug-delivery tests. The first test used a form of RGD that became functional after reacting with the artificial enzyme bound to the target cancer cell. RGD was chosen because prior testing indicated that it interferes with the ability of cancer cells to clump together and form tumors. They injected mice with HeLa cancer cells, and then injected them with both the glycosylated metalloenzyme and RGD. Control mice were injected with the artificial enzyme alone, RGD alone, or saline. The mice were monitored for 81 days. While all the controls developed tumors and died well before 81 days had been reached, the mice treated with the selective cell therapy with RGD tagging had a survival rate of 40%. Imaging analysis indicated that tumor onset and progression were disrupted by the treatment.

The second test was designed to attack tumors that had already formed. For this, the team used the same glycosylated metalloenzyme, but with a form of non-toxic doxorubicin that became functional after reacting with the metalloenzyme. Prior testing showed that the agent was harmless until it interacted with the metalloenzyme, at which time it released toxic doxorubicin. In this way, only targeted cancer cells were affected by the drug. Testing in mice was similar to testing with RGD, except that tumors were allowed to develop for a week before injecting the artificial enzyme and tagging agent. Mice receiving the real treatment showed reduced tumor growth and a higher survival rate over the course of 77 days.

“We were able to use our system to carry metalloenzymes to cancer cells in living mice, which reacted with tagging agents to deliver targeted drug therapies that reduced tumor onset and growth,” says Tanaka. “The next step is certainly clinical application in humans.”

Featured image: Imaging results showing a representative set of mice from each group three weeks after treatment. Top left, saline. control. Top right, artificial enzyme alone control. Bottom left, tagging agent alone. Bottom right, acctual treatment — reactively functional RGD with the glycosylated metalloenzyme. Imaging shows much less tumor growth in the mice treated with the real therapy. © Riken

Reference: Vong et al. (2021) Disrupting tumor onset and growth via selective cell tagging (SeCT) therapy. Sci Adv. doi: 10.1126/sciadv.abg4038.

Provided by Riken

Significant Reductions in COVID-19 Infections Found After Single Dose of Oxford-AstraZeneca & Pfizer-BioNTech Vaccine (Medicine)

COVID-19 infections fell significantly – by 65% percent – after a first dose of the Oxford-AstraZeneca or Pfizer-BioNTech vaccines in this large community surveillance study.

Data from the COVID-19 Infection Survey, a partnership between the University of Oxford, the Office of National Statistics (ONS) and the Department for Health and Social Care (DHSC), is the first to show the impact of vaccination on antibody responses and new infections in a large group of adults from the general population aged 16 years and older.

Two studies, released today as pre-prints, focused on the protection from infection provided by COVID-19 vaccines. Researchers analysed 1,610,562 test results from nose and throat swabs taken from 373,402 study participants between 1 December 2020 and 3 April 2021. 21 days after a single dose of either Oxford-AstraZeneca or Pfizer-BioNTech vaccines (with no second dose), the rates of all new COVID-19 infections had dropped by 65%, symptomatic infections by 72% and infections without reported symptoms by 57%.

Reductions in infections and symptomatic infections were even greater after a second dose (70% and 90% respectively), and were similar to effects in those who had previously been infected with COVID-19 naturally. Vaccines were effective against variants compatible with the Kent strain (B.1.1.7). Benefits from vaccines in reducing new infections were similar in older individuals over 75 years and under 75 years, and in those reporting long-term health conditions and not reporting them.

Dr Koen Pouwels, senior researcher in Oxford University’s Nuffield Department of Population Health, says, ‘The protection from new infections gained from a single dose supports the decision to extend the time between first and second doses to 12 weeks to maximise initial vaccination coverage and reduce hospitalisations and deaths.

‘However, the fact that we saw smaller reductions in asymptomatic infections than infections with symptoms highlights the potential for vaccinated individuals to get COVID-19 again, and for limited ongoing transmission from vaccinated individuals, even if this is at a lower rate. This emphasises the need for everyone to continue to follow guidelines to reduce transmission risk, for example through social distancing and masks.’

The second study compared how antibody levels changed after a single dose of either Oxford-AstraZeneca or Pfizer-BioNTech vaccines, or two doses of the Pfizer-BioNTech vaccine (generally given 21-42 days apart). In individuals who had not had COVID-19 before, antibody responses to a single dose of either vaccine were lower in older individuals, especially over 60 years. Antibody responses to two Pfizer-BioNTech doses were high across all ages, particularly increasing responses in older people to reach similar levels to those receiving a single dose after prior infection.

Antibody levels rose more slowly and to a lower level with a single dose of Oxford-AstraZeneca vs Pfizer-BioNTech, but then dropped more quickly with a single Pfizer-BioNTech dose to similar levels as a single dose of Oxford-AstraZeneca, particularly at older ages. However, although the size of the immune response differed, there was no group of individuals who didn’t respond at all to either vaccine.

David Eyre, Associate Professor at the Big Data Institute at the University of Oxford, says, ‘In older individuals, two vaccine doses are as effective as prior natural infection at generating antibodies to the SARS-CoV-2 virus that causes COVID-19 – in younger individuals a single dose achieves the same level of response. Our findings highlight the importance of individuals getting the second vaccine dose for increased protection.’

Sarah Walker, Professor of Medical Statistics and Epidemiology at the University of Oxford and Chief Investigator and Academic Lead for the COVID-19 Infection Survey, says, ‘Without large community surveys such as ours, it is impossible to estimate the impact of vaccination on infections without symptoms – these have the potential to keep the epidemic going, particularly if people who have been vaccinated mistakenly think they cannot catch COVID-19. However, these studies show that vaccination and previous infection both protect against getting infected again.

‘We don’t yet know exactly how much of an antibody response, and for how long, is needed to protect people against getting COVID-19 in the long-term – but over the next year, information from the survey should help us to answer these questions. We are very grateful to all our participants for giving up their time to help us.’

Health Secretary Matt Hancock says, ‘Vaccines work and today’s findings from the ONS and Oxford University provide further evidence that both the Pfizer and AstraZeneca vaccines are having a significant impact on reducing infections across the UK.

‘With over 33 million first jabs already in arms, saving lives and cutting the risk of infection, it’s vital everyone gets their second dose when invited, to protect you and your loved ones against this disease. The vaccine programme has shown what our country can achieve when working as one, it is our way out of the pandemic. When you get the call, get the jab.’

Health Minister Lord Bethell says, ‘Studies like the ONS COVID-19 Infection Survey are critical to helping us build a picture of COVID-19 infections across the UK and I thank all those who took part and conducted this vital research.

‘These real-world findings are extremely promising and show our historic vaccination programme is having a significant impact across the UK by reducing infections among people of all ages, including those with underlying health conditions.

‘I urge everyone to take-up the offer of a free vaccine when invited and to make sure they get their second dose to gain maximum protection. It remains essential everyone continues to follow COVID-19 restrictions whether they have had the vaccine or not.’

The study will continue monitoring the pandemic in the UK on a weekly basis to look for early warning signs of rising infection rates in different regions, sub-regions, and demographic groups, and to continue to compare the effectiveness of different vaccines and to monitor the impact of immunity on protection against COVID-19.

Featured image: COVID-19 Infections Survey reveals similar, significant reductions in COVID-19 infections with single dose of Oxford-AstraZeneca and Pfizer-BioNTech vaccine. Image credit: Shutterstock

Provided by University of Oxford

Young Male Fruit Flies Make Females Fight Each Other More (Ecology)

Mating changes female behaviour across a wide range of animals, with these changes induced by components of the male ejaculate, such as sperm and seminal fluid proteins. However, males can vary significantly in their ejaculates, due to factors such as age, mating history, or feeding status. This male variation may therefore lead to variation in the strength of responses males can stimulate in females.

Using the fruit fly, Drosophila melanogaster, we tested whether age, mating history, and feeding status shape an important, but understudied, post-mating response – increased female-female aggression.

Image 1: Two female fruit flies are standing on a food cap (which contains food that they eat and lay eggs in). This is where the majority of fighting happens – you can see the flies have their legs touching, so they are probably fencing in this image. Each fly is marked with a different colour of paint to aid identification. © University of Oxford

We found that females mated to old males fought less than females mated to young males. Females mated to old, sexually active males fought even less than those mated to males who were merely old, but there was no effect of male starvation status on mating-induced female aggression.

Male condition can therefore influence how females interact with each other – who you mate with changes your interactions with members of the same sex! 

Image 2: This figure shows the setup we used for contests between females, which consisted of a circular arena with a food cap set into the middle. This food cap contained regular fly food medium, with a drop of yeast paste in the middle to act as a valuable, restricted resource. © University of Oxford

Could this happen in other species?

We know that other species (including humans!) have proteins in the seminal fluid that males transfer to females during sex. Various of these proteins have effects on female physiology and behaviour, but no one knows if these affect aggression (in humans or any other species).

We also know that male age (in flies and humans) results in reduced fertility and can have serious effects on their offspring. Although it is a long leap from flies to humans, could who you mate with influence your interactions with other females?

Many reproductive molecules and important bodily functions are conserved across the animal kingdom from flies to humans, so it is possible that what we found in flies here might be hinting to a common phenomenon across the tree of life. We need more studies to understand if this is the case!

Read the full paper, ‘Male condition influences female post mating aggression and feeding in Drosophila‘ in Functional Ecology.

Provided by University of Oxford

Accumulation of Infected Red Blood Cells Key To Development of Cerebral Malaria (Medicine)

White adipose tissue (WAT), or white fat, plays a fundamental role in the development of cerebral malaria in mouse models and humans, according to a new study led by Harvard T.H. Chan School of Public Health scientists in collaboration with the University of Glasgow and an international team of researchers.

The study details the process by which red blood cells infected with malaria-causing Plasmodium parasites are sequestered in small blood vessels throughout WAT, where they stimulate the production of the hormone leptin via a well-studied nutrient-sensing pathway known as mTORC1.

The study was published in Science Advances on March 24, 2021. Among the scientists who contributed to the study was Harvard Chan School’s James Mitchell, who passed away in November 2020, before the study was published.

The findings build on previous research from the group in 2015 that showed leptin production is critical in driving cerebral malaria development and suggested the possibility that mTORC1 inhibitors such as the FDA-approved drug rapamycin could be a viable treatment option. The new findings underscore the potential of rapamycin and similar drugs, and the study may also aid in identifying other treatments as well as in the development of tools to diagnose cerebral malaria and determine the severity of infection.

“It is intriguing that in addition to the brain, infected red blood cells accumulate preferentially in subcutaneous adipose tissue of patients with cerebral malaria. Our study implicates this mechanism in the development of severe disease and opens new therapeutic avenues,” said co-corresponding author Pedro Mejia, who contributed to the research as a Yerby Postdoctoral Research Fellow in Mitchell’s lab at Harvard Chan School. “Professor Mitchell envisioned detecting parasites in this tissue with minimally invasive tools to help discriminate between cerebral and non-cerebral malaria patients and guide medical care in endemic areas. We will keep working on his vision.”

While the group had previously identified that the production of leptin, which is secreted by WAT, drove the development of cerebral malaria in mice, the process was not well understood. To determine whether the sequestration of infected red blood cells into the adipose tissue was essential for disease development, the research team ran studies on several mouse models using several strains of P. berghei parasites that had different capacities for sequestering in adipose tissue.

When they used parasite strains known to sequester in adipose tissue, the researchers found higher leptin levels and a higher lethality in mice. When they used parasite strains that did not sequester in adipose tissue, leptin production was lower and the mice did not develop cerebral malaria. The researchers determined that leptin production in white fat cells was regulated by mTORC1.

To further understand the possible implications of the findings for human health, the researchers analyzed tissue samples from pediatric patients who died from cerebral malaria. They found that the sequestration of infected red blood cells specifically in subcutaneous fat, tissue leptin production, and mTORC1 activity were present and positively correlated with cerebral malaria. The researchers did note, however, that the human serum tissue samples did not indicate that P. falciparum increased systemic leptin levels as observed in mice.

“Exploring the link between adipose sequestration and leptin production proved challenging, but Professor Mitchell was relentless and helped push us to test as many parasitic models and mice models as needed in order to conclusively prove our model. The mechanistic insights on the role of the adipose tissue in the development of cerebral malaria not only consolidate our proposed treatment strategies with mTORC1 inhibitors, but also provide novel insights into how to detect patients likely to develop this often lethal form of malaria,” said co-corresponding author José Humberto Treviño-Villarreal, who conducted the research as a research associate at Harvard Chan School and is currently a professor of endocrinology and molecular metabolism at Mexico’s Universidad Autónoma de Nuevo León.

Co-author Matthias Marti of the University of Glasgow lauded the joint effort required to complete the research. “This is an exemplary collaborative effort using both rodent malaria models and human autopsies, and it was led by my dear friend and outstanding scientist, Professor Mitchell, who is sorely missed,” he said.

Other Harvard Chan School researchers who contributed to this study include Mariana De Niz, Elamaran Meibalan, Alban Longchamp, Justin Reynolds, and Danny Milner. Other institutions affiliated with this research include the University of Glasgow, the University of Bern, Brigham and Women’s Hospital, Harvard Medical School, University of Lausanne, Indiana University School of Medicine, Makerere University, the Pasteur Institute, the Bernhard Nocht Institute for Tropical Medicine, and Michigan State University.

Funding for parts of this study came from NIH grant R01 NS055349, NIH grant R01AI034969, and the European Research Council.

“Adipose tissue parasite sequestration drives leptin production in mice and correlates with human cerebral malaria,” Pedro Mejia, J. Humberto Treviño-Villarreal, Mariana De Niz, Elamaran Meibalan, Alban Longchamp, Justin S. Reynolds, Lindsey B. Turnbull, Robert O. Opoka, Christian Roussilhon, Tobias Spielmann, C. Keith Ozaki, Volker T. Heussler, Karl B. Seydel, Terrie E. Taylor, Chandy C. John, Danny A. Milner, Matthias Marti, James R. Mitchell, Science Advances.

Provided by University of Glasgow