Which Formation Mechanism Show Strong Clustering of Primordial Black Holes? (Cosmology)

Masahiro Kawasaki and colleagues investigated the clustering of primordial black holes (PBHs) formed by Affleck-Dine (AD) baryogenesis. They found that formed PBHs showed strong clustering due to stochastic dynamics of the AD field. Their study recently appeared in Arxiv.

In recent years, the LIGO-Virgo collaboration has detected gravitational waves emitted by merging binary black holes, which revealed the existence of black holes with masses ∼ 10−100 M. Interestingly, many of observed black holes have heavy masses around 30M. The origin of these massive black holes is still unknown. One fascinating candidate is the primordial origin.

We have already discussed number of possible mechanisms which give rise to primordial black holes such as, by solo-multi bumps, by first-order phase transition, by fall of inflation, by fifth force etc. One of the PBHs formation scenario we haven’t discussed yet is Affleck-Dine (AD) baryogenesis. In this scenario, the IR mode of the AD field diffuses by quantum fluctuations during inflation and has multiple vacua just after inflation. Then, while the origin of the AD field becomes the true vacuum, the false vacuum has a non-zero field value. The inhomogeneity of the field value results in the inhomogeneous baryogenesis, which forms baryon-rich bubbles. At the QCD phase transition, baryons in the bubbles form massive nucleons and generate density fluctuations. If the bubbles are large enough, the density fluctuations grow sufficiently and then collapse into PBHs at the horizon reentry. PBHs generated in this scenario can have masses larger than 10 M and are expected to explain the origin of LIGO-Virgo events.

Kawasaki and colleagues investigated the clustering of PBH’s formed by this scenario. They have studied the stochastic dynamics of the AD field during inflation and derived the PBH formation rate. They have also estimated the two-point correlation function of PBHs, which characterized the clustering of PBH’s.

They found that, formed PBHs show strong clustering due to stochastic dynamics of the AD field. They have also obtained a reduced PBH correlation function given below:

They used this reduced PBH correlation function to investigate the effect of the clustering on two phenomena related to PBHs; isocurvature fluctuations and the merger rate distribution.

First, PBHs induce isocurvature fluctuations due to their Poisson fluctuations, and the clustering also sources isocurvature fluctuations. They have estimated the power spectrum of density fluctuation of PBHs (as shown in fig. 2 below) and have put the upper bound on the PBH abundance and the significance of clustering by using the current isocurvature constraints from the Planck satellite as shown in Fig. 3 below.

Second, the clustering of PBHs can drastically change the binary formation rate of PBHs, and the resultant merger rate density. They have found that the merger rate increases with the clustering for a small PBH abundance due to the enhanced binary formation rate, while it decreases for a large PBH abundance since the three-body problem occurs more frequently for the clustered PBHs. As a result, it was found that it is difficult for their model to explain the LIGO-Virgo event rate of binary mergers when they conservatively neglect the binary merger in three-body systems.

“In future work, we will see whether our model can explain the merger rate observed by LIGO-VIRGO collaboration by correctly including PBH mergers in three-body systems.”

— concluded authors of the study

All images credit except featured: Masahiro Kawasaki et al.

Reference: Masahiro Kawasaki, Kai Murai, Hiromasa Nakatsuka, “Strong clustering of primordial black holes from Affleck-Dine mechanism”, Arxiv, pp. 1-18, 2021. e-Print: ArXiv: 2107.03580

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Scientists Develop A New Geometry For A Neutron Source Platform For NIF (Physics)

The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory (LLNL) has added a new tool to its growing list of capabilities.

A team of scientists has demonstrated a new geometry for a neutron source platform for NIF, called the inverted-corona platform, which does not rely on spherically symmetric laser irradiation.

This new tool has significantly less-stringent laser-symmetry requirements than conventional laser driven neutron sources on NIF. In this technique, laser energy is used to heat the inner surface of a millimeter-scale capsule. The wall material expands and launches a centrally stagnating shock into the gas fill to heat the gas to fusion conditions.

“This platform has relevance to applications in effects testing or forensics,” said Matthias Hohenberger, LLNL staff scientist. “We have an experiment scheduled in 2022 for exploring applications as a neutron backlighter, and as a neutron source for nuclear-cross-section measurements with sample materials attached to the outside of the capsule.”

Hohenberger said there are other potential applications in basic science, and is one-of-a-kind in its geometry flexibility. “It also represents a challenging problem to simulate because of the relatively low plasma density,” he said. “So we’re using it to test mix models in state-of-the-art simulation codes, and to train junior scientists.”

The work, highlighted in a paper in Review of Scientific Instruments, presents a novel neutron-source platform for NIF. Typically, NIF neutron platforms are based on the spherical compression of a capsule filled with deuterium and tritium (DT) fuel, thus achieving the pressures and temperatures necessary for the DT to undergo fusion reactions. This is achieved using either indirect-drive intertial confinement fusion (ICF) platforms or directly-driven exploding pushers. In these platforms, the incident laser results in a pushing action from the outside of the capsule, accelerating the capsule wall inwards — either from the X-rays generated in the hohlraum, or from the laser incident on the capsule itself. That means performance is highly sensitive to drive asymmetries, as they result in an uneven push of the wall, and eventual mixing of fuel and wall material into the hot spot, said Hohenberger, who is the lead author of the paper.

“This can, and does, affect fusion performance,” he said. “It also means that the wall composition must be controlled tightly. Even small impurities in the wall, thickness variations or even surface roughness will affect the performance and neutron yield.”

Pointing lasers onto the inside of capsule wall

Hohenberger said in this new scheme, which was tested on the OMEGA laser and the NIF, the laser beams are pointed through laser entrance holes onto the inside wall of a ~5-millimeter diameter, gas-filled (D2 or DT) capsule. This causes the wall material to ablate inwards, which then launches a converging shock wave into the gas fill. The shock stagnates on center and heats the gas fill to fusion conditions (similarly to an exploding pusher). However, because the laser beams are incident onto the inside wall, the capsule wall itself is pushed outwards and away from the center, and the fusion performance is dominated by the ablatively-driven shock.

Hohenberger said this work has two key advantages. First, it decouples the wall composition from the neutron source and significantly relaxes requirements on capsule quality such as thickness uniformity, material purity and surface roughness, because the wall does not mix with the hot spot since it is pushed out rather than inwards. Second, the performance is highly insensitive to low-mode asymmetries. That means it is possible to have laser beams incident from only one side, rather than symmetrically distributed around the target, without a reduction in neutron yield.

The platform was successfully demonstrated in experiments on both the OMEGA laser and NIF. The work was funded through LLNL’s Laboratory Directed Research and Development program.

In addition to Hohenberger, co-authors include Nathan Meezan, Bob Heeter, Rick Heredia, Nino Landen, Andrew MacKinnon and Warren Hsing from LLNL; Will Riedel and Mark Cappelli from Stanford University; Neel Kabadi and Richard Petrasso from Massachusetts Institute of Technology; Chad Forrest from the Laboratory for Energetics at the University of Rochester; Loosineh Aghaian, Mike Farrell and Claudia Shuldberg from General Atomics; and Franziska Treffert and Siegfried Glenzer from SLAC National Accelerator Laboratory.

Featured image: In the inverted-corona platform, laser beams are pointed onto the inside walls via laser entrance holes. Graphic provided by Matthias Hohenberger.

Provided by LLNL

AI Predicts Diabetes Risk By Measuring Fat Around the Heart (Medicine)

A team led by researchers from Queen Mary University of London has developed a new artificial intelligence (AI) tool that is able to automatically measure the amount of fat around the heart from MRI scan images.

Using the new tool, the team was able to show that a larger amount of fat around the heart is associated with significantly greater odds of diabetes, independent of a person’s age, sex, and body mass index.

The research is published in the journal Frontiers in Cardiovascular Medicine and is the result of funding from the CAP-AI programme, which is led by Barts Life Sciences, a research and innovation partnership between Queen Mary University of London and Barts Health NHS Trust.

The distribution of fat in the body can influence a person’s risk of developing various diseases. The commonly used measure of body mass index (BMI) mostly reflects fat accumulation under the skin, rather than around the internal organs. In particular, there are suggestions that fat accumulation around the heart may be a predictor of heart disease, and has been linked to a range of conditions, including atrial fibrillation, diabetes, and coronary artery disease.

Lead researcher Dr Zahra Raisi-Estabragh from Queen Mary’s William Harvey Research Institute said: “Unfortunately, manual measurement of the amount of fat around the heart is challenging and time-consuming. For this reason, to date, no-one has been able to investigate this thoroughly in studies of large groups of people.

“To address this problem, we’ve invented an AI tool that can be applied to standard heart MRI scans to obtain a measure of the fat around the heart automatically and quickly, in under three seconds. This tool can be used by future researchers to discover more about the links between the fat around the heart and disease risk, but also potentially in the future, as part of a patient’s standard care in hospital.”

The research team tested the AI algorithm’s ability to interpret images from heart MRI scans of more than 45,000 people, including participants in the UK Biobank, a database of health information from over half a million participants from across the UK. The team found that the AI tool was accurately able to determine the amount of fat around the heart in those images, and it was also able to calculate a patient’s risk of diabetes.

Dr Andrew Bard from Queen Mary, who led the technical development, added: “The AI tool also includes an in-built method for calculating uncertainty of its own results, so you could say it has an impressive ability to mark its own homework.”

Professor Steffen Petersen from Queen Mary’s William Harvey Research Institute, who supervised the project, said: “This novel tool has high utility for future research and, if clinical utility is demonstrated, may be applied in clinical practice to improve patient care. This work highlights the value of cross-disciplinary collaborations in medical research, particularly within cardiovascular imaging.”

CAP-AI is led by Capital Enterprise in partnership with Barts Health NHS Trust and Digital Catapult and The Alan Turing Institute and is funded by the European Regional Development Fund and Barts Charity.

Featured image: Heart MRI scan showing the area of fat detected by the AI tool © QMUL

More information

  • Research paper: ‘Automated quality-controlled cardiovascular magnetic resonance pericardial fat quantification using a convolutional neural network in the UK Biobank’. Andrew Bard, Zahra Raisi-Estabragh, Maddalena Ardissino, Aaron Lee, Francesca Pugliese, Damini Dey, Sandip Sarkar, Patricia B. Munroe, Stefan Neubauer, Nicholas C. Harvey, Steffen E. Petersen. Frontiers in Cardiovascular Medicine

Provided by Queen Mary University of London

Efficient Genetic Engineering Platform Established in Methylotrophic Yeast (Chemistry)

Pichia pastoris (syn. Komagataella phaffii), a model methylotrophic yeast, can easily achieve high density fermentation, and thus is considered as a promising chassis cell for efficient methanol biotransformation. However, inefficient gene editing and lack of synthetic biology tools hinder its metabolic engineering toward industrial application.

Recently, a research group led by Prof. ZHOU Yongjin from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences established an efficient genetic engineering platform in Pichia pastoris.

The study was published in Nucleic Acids Research on July 1.

The researchers developed novel genetic tools for precise genome editing in Pichia pastoris by enhancing homologous recombination (HR) rates and engineering the multiple intrusion-induced rearrangement (MIR) processes. The key gene RAD52, which played crucial role in HR repair in Pichia pastoris, was overexpressed for improving the efficiency of single gene editing to 90%.

Furthermore, they increased the efficiency of multi-fragment recombination at one site by 13.5 times, and identified and characterized 46 neutral sites and 18 promoters for genome integration and gene expression.

Finally, they developed a two-factorial regulation system for regulating fatty alcohol biosynthesis in Pichia pastoris from different carbon sources.

“This advanced gene editing systems can theoretically realize stable loading of more than 100 exogenous genes and precise regulating of gene expression in Pichia pastoris, which will provide convenience for the synthetic biology research of Pichia pastoris. It also provides insights for metabolic engineering of other unconventional yeast,” said Prof. ZHOU.

This study was supported by the National Natural Science Foundation of China and Dalian Science and Technology Innovation Funding.

Featured image: Establishing an efficient genetic engineering platform for metabolic engineering of Methylotrophic yeast Pichia pastoris (Image by CAI Peng)

Reference: Peng Cai, Xingpeng Duan, Xiaoyan Wu, Linhui Gao, Min Ye, Yongjin J Zhou, Recombination machinery engineering facilitates metabolic engineering of the industrial yeast Pichia pastoris, Nucleic Acids Research, 2021;, gkab535, https://doi.org/10.1093/nar/gkab535

Provided by Chinese Academy of Sciences

Researchers Reveal Robust Ethane-trapping Porous Organic Cage for Efficient Ethylene Purification Application (Chemistry)

The removal of ethane (C2H6) from its analogous ethylene (C2H4) is of great importance in the petrochemical industry, and is highly challenging due to their similar physicochemical properties. The use of emerging porous organic cage (POC) materials for C2H6/C2H4 separation is still in its infancy. 

Calix[4]resorcinarene, a kind of macrocyclic cavitand with an intrinsic cavity and eigh polar upper-rim phenolic groups, has been documented as excellent building block to construct cage compounds with tunable cavities for encapsulating various guest molecules.  

In a study published in Nature Communications, the research group led by Prof. YUAN Daqiang from Fujian Institute of Research on the Structure of Matter of the Chinese Academy of Sciences reported that a [6+12] octahedral calix[4]resorcinarene-based POC (CPOC-301) is an excellent C2H6 -selective material, and can be used as a robust absorbent to directly afford high-purity C2H4 from C2H6/C2H4 mixture. 

The researchers prepared CPOC-301 via self-assembly of tetraformylresorcin[4]arene and p-phenylenediamine under mild condition.

Single-crystal X-ray diffraction revealed that CPOC-301 has a truncated octahedron structure, with eight trigonal ports having edge length reaching about 12 Å, and a large cavity with inner diameter as well as volume that respectively reach 16.8 Å and 4270 Å3. The solid-state packing ofCPOC-301 suggested that it possesses a one-dimensional channel, with a diameter of ~7 Å, viewed from [001] direction. 

The nitrogen (N2) gas adsorption isotherm of CPOC-301 showed a typical type I curve with a small fraction of a type IV adsorption behavior. The maximum N2 adsorption is 670 cm3 g-1, and the calculated Brunauer–Emmett–Teller (BET) of CPOC-301 is up to 1962 m2 g-1. Moreover, CPOC-301 exhibited preferential adsorption of C2H6 over C2H4 at room temperature. 

The ideal adsorbed solution theory (IAST) calculation result demonstrated that C2H6/C2H4 selectivity range for CPOC-301 is from 1.3 to 1.4 at 293 K. The breakthrough curves further proved that CPOC-301 can efficiently realize the complete separation of C2H4 from C2H6/C2H4 mixtures, and its separation performance does not obviously change within seven continuous cycles. 

Molecular modelling studies suggested the exceptional C2H6 selectivity is due to the suitable resorcin[4]arene cavities in CPOC-301, which form more multiple C–H···π hydrogen bonds with C2H6 than with C2H4 guests. 

This study sheds light on the design and synthesis of POCs based on supramolecular cavitands as “porous additives” in column and membrane separation applications for industrially important gases in the future. 

Featured image: Illustration of the Research (Image by Prof. YUAN’s Group)

Reference: Su, K., Wang, W., Du, S. et al. Efficient ethylene purification by a robust ethane-trapping porous organic cage. Nat Commun 12, 3703 (2021). https://doi.org/10.1038/s41467-021-24042-7

Provided by Chinese Academy of Sciences

Aspirin Reduces Preeclampsia Risk, Affecting The Gestation Metabolic Clock (Medicine)

A joint study conducted by Baylor College of Medicine and the Chinese University of Hong Kong has discovered that the benefit of aspirin treatment in preventing preeclampsia is mediated through decelerating the metabolic clock of gestation. The researchers analyzed the blood samples collected from more than 100 high-risk pregnant women at 11 to 13 weeks and 20 to 24 weeks of their pregnancy and demonstrated that the preeclamptic or non-preeclamptic outcome in response to aspirin treatment was significantly associated with the level of internal aspirin exposure ascertained from metabolomic data.

The researchers also constructed a model of the metabolic clock of gestation and found that aspirin significantly decelerated metabolic gestational-age by 1.27 weeks in mid-gestation. One-fourth of the metabolites experienced a partial reversal of gestational age advancement, suggesting that aspirin treatment help prevent preeclampsia by slowing down the metabolic clock of gestation. The study results are published in the journal Hypertension.

Recent evidence shows aspirin treatment can reduce the rate of preterm preeclampsia by 60%

Preeclampsia is a multisystem disorder of pregnancy characterized by the onset of hypertension with significant proteinuria after 20 weeks’ gestation. This disorder affects 2% to 5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality. Globally, it is associated with 76,000 maternal and 500,000 infant mortalities every year.

Low-dose aspirin has been proven to be beneficial in the prevention of preeclampsia when it is given daily before 16 weeks of gestation. Recent evidence from a multicenter, double-blind, randomized placebo-controlled trial (ASPRE: Combined Multi-marker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention), conducted by Dr. Liona Poon, professor in the Department of Obstetrics and Gynaecology at CU Medicine, has demonstrated that aspirin prophylaxis could reduce the rates of preterm preeclampsia and all preeclampsia by 60% and 30%, respectively.

“Our work has made a major discovery on the mechanism of the prophylactic response of aspirin,” said Poon, senior author of the study. “Previously, we have hypothesised that aspirin prevents preeclampsia by delaying the gestational age at delivery. This work has lent further support to our hypothesis that the benefit of aspirin treatment in preventing preeclampsia is mediated through decelerating the metabolic clock of gestation. We can now explain to high-risk pregnant women that the benefit of aspirin is moderated via a delay in the onset of the disorder, thus reducing the risk of premature delivery associated with preeclampsia.”

A multivariate metabolic clock proves aspirin significantly decelerates metabolic gestational age

The aim of the joint study was to understand why a significant proportion of aspirin-treated high-risk women still develops preeclampsia. The researchers performed untargeted metabolomic profiling on plasma samples of 58 participants in the aspirin group and 58 participants in the placebo group. They found out that aspirin induced a series of metabolomic alterations and the level of internal aspirin exposure is predictive of preeclampsia.

Through comparing the profile of women with and without preeclampsia after aspirin treatment, differences in 73 metabolites were detected. Some involve regulation important in pregnancy and placental functions, including glycerophospholipids metabolism, polyunsaturated fatty acid metabolism and steroid hormone biosynthesis.

To further understand the mechanism by which aspirin prevents preeclampsia, the researchers built a multivariate metabolic clock of gestation using the metabolomic profiling of the participants’ plasma samples. In the aspirin-treated group, gestational age acceleration significantly deviated from zero in a negative direction by 1.27 week on average, suggesting that aspirin significantly delayed metabolic gestational age. Changes during advancement of gestation were also partially reversed by aspirin in one-fourth of the pregnancy-related metabolites.

“A particularly innovative aspect of the metabolomic data analysis was the construction of the metabolic clock of pregnancy and the demonstration that aspirin exposure, as reported by patients and ascertained from metabolomic data, slows down the clock,” said Dr. Aleksandar Milosavljevic, study author and Henry and Emma Meyer Professor in Molecular Genetics at Baylor.

“This international collaborative effort highlights the importance of both basic and translational studies in the assessment of therapeutic interventions,” said Dr. Sarah Elsea, study author and professor of molecular and human genetics at Baylor. “Defining the critical underlying metabolic pathways that are affected by aspirin treatment also provides mechanistic insight for the common pregnancy-related complication and opens up opportunities to further investigate these metabolic pathways as therapeutic targets.”

“This study has been made possible by a fruitful research collaboration between our Department of Molecular and Human Genetics at Baylor, the Fetal Medicine Research Institute at King’s College in London, and the Department of Obstetrics and Gynaecology at CU Medicine under the auspices of the Joint Baylor-CUHK Center of Medical Genetics,” said Dr. Fernando Scaglia, study author, professor of molecular and human genetics at Baylor and clinical director of the Joint Baylor-CUHK Center of Medical Genetics in Hong Kong. “These relevant findings showed that aspirin treatment resulted in a robust metabolomic signature lending support to the hypothesis that the use of aspirin may delay the onset of preeclampsia. The fruits of this research may potentially impact the clinical care provided to women in high-risk pregnancies.”

“Preeclampsia is a serious obstetric complication, a consequence of maladaptation between placenta metabolism and maternal endothelial response, but the underlying mechanism remains to be poorly understood,” said Dr. Ronald Wang, study author and professor and division head of Obstetrics and Gynaecology at CU Medicine. “This is an international, collaborative and multidisciplinary study combining maternal medicine, therapeutics, reproductive biology, metabolomics and bioinformatics. The study discovered novel and important metabolic pathways in placental ageing with great potential for disease understanding and therapeutic targets for preeclampsia.”

Provided by Baylor College of Medicine

Proton Pump Inhibitors Help Radiation Therapy Target Cancer Cells (Medicine)

The resistance of cancer cells to radiation therapy is a significant clinical problem in treating cancer. Many solid tumors are only partially responsive to radiation therapy, and increasing radiation dose can be harmful to healthy tissue. There are few safe and effective radiosensitizers that can be combined with radiation to enhance tumor control. In a new article published in Oncotarget, a team of scientists from Baylor College of Medicine discovered a new use for the FDA-approved and widely used class of drug, proton pump inhibitors (PPIs), as sensitizers of cancer cells to radiation therapy to improve tumor control.

The researchers screened a library of 130,000 small molecules to search for compounds that inhibit an enzyme overexpressed in cancer cells that are considered aggressive, highly vascularized and radioresistant.

“We were surprised to find the entire class of PPIs, such as esomeprazole and lansoprazole, directly target this enzyme,” said Dr. Yohannes Ghebre, senior author of the study, associate professor of radiation biology at Baylor and member of the Dan L Duncan Comprehensive Cancer Center. “Subsequent studies demonstrated that PPIs sensitize cancer cells to ionizing radiation, depending on the dose. This is a previously unrecognized yet important effect.”

Given the unmet medical need for the sensitization of cancer cells to radiation therapy, the Baylor team conducted preclinical studies to evaluate the radiosensitizing effect of the PPI esomeprazole when combined with radiation. This research demonstrates the efficacy of PPIs in radiosensitizing cancer cells isolated from various tissue sites, including head and neck, breast and the lungs, using cancer cell colony formation assay in vitro and in animal models, according to Ghebre. The team aims to launch clinical studies to evaluate the efficacy of PPIs as radiosensitizers in cancer patients soon.

“A significant fraction of head and neck cancer patients present with aggressive disease that demonstrates an incomplete response to radiation, resulting in rapid recurrence and cancer associated death,” said Dr. Vlad Sandulache, co-author of the study, assistant professor of otolaryngology – head and neck surgery at Baylor and member of the Dan L Duncan Comprehensive Cancer Center. “As a result, it is critically important to identify drugs that can be used to sensitize tumors to radiation. Repurposing existing, FDA-approved drugs is an excellent strategy since it largely eliminates the potential for severe unanticipated toxicities.”

“Given the major contribution of radioresistance to cancer treatment failure and lifelong complications associated with the clinical use of high radiation dose, novel therapeutic agents that can selectively sensitize tumor cells to the effects of radiation to enhance tumor kill are required,” said Dr. Andrew Sikora, study author, former faculty member in the Bobby R. Alford Department of Otolaryngology – Head and Neck Surgery at Baylor and current professor and director of research in the Department of Head and Neck Surgery at the University of Texas MD Anderson Cancer Center. “However, currently available radiosensitizers, such as chemotherapeutic agents, are non-selective and are often associated with significant side effects including ototoxicity, immune suppression, hair loss, as well as hematological and cardiovascular complications.”

Additional authors involved in the study include Kassidy Hebert, Dr. Sergio Jaramillo, Wangjie Yu, Min Wang, Dr. Ratna Veeramachaneni, Dr. Mark D. Bonnen, Dr. Ananth V. Annapragada, Dr. David Corry, Dr. Farrah Kheradmand, Raj K. Pandita, Dr. Michelle S. Ludwig, Tej K. Pandita, Dr. Shixia Huang, Dr. Cristian Coarfa, Sandra L. Grimm, Dimuthu Perera and Dr. George Miles. See the publication for a full list of funding for this work.

Featured image: A microscopic image of cancer cells © BCM

Reference: Hebert K. A., Jaramillo S., Yu W., Wang M., Veeramachaneni R., Sandulache V. C., Sikora A. G., Bonnen M. D., Annapragada A. V., Corry D., Kheradmand F., Pandita R. K., Ludwig M. S., et al Esomeprazole enhances the effect of ionizing radiation to improve tumor control. Oncotarget. 2021; 12: 1339-1353. Retrieved from https://www.oncotarget.com/article/28008/text/

Provided by BCM

What’s Behind The Common COVID-19 Vaccine Side Effects? (Medicine)

Garvan immunologist Professor Jonathan Sprent explains why you should feel good about the common COVID-19 vaccine side effects, such as headache, fatigue and muscle pain.

After receiving a COVID-19 vaccine, many experience mild yet common symptoms, such as headache, fatigue and muscle pain – side effects reported by more than 100,000 Australians to date in a national survey.

These vaccine side effects have led to hesitancy in some younger people, who may have more symptoms following a COVID-19 vaccine than during an infection with coronavirus itself, says immunologist Professor Jonathan Sprent who heads the Cellular Immunity Lab at the Garvan Institute of Medical Research.

“However, these common post-vaccine side effects, such as headache, fatigue and muscle pain, are a reassuring sign that the immune system is doing its job in responding to the vaccine. They signal type I interferon production – the body’s in-built immune stimulator that elicits a powerful immune response to eliminate the pathogen and also generates memory immune cells that protect against re-infection.”

A recent Science Immunology article, co-authored by Professor Sprent, delves into the science behind common COVID-19 vaccine side effects and explains why they should be viewed positively – a necessary prelude to an effective immune response.

Interferon – a first responder with lasting protection

During an infection with a viral pathogen, the immune system jumps into action. A crucial part of this response is the immune molecule interferon. Named for its ability to ‘interfere’ with virus replication, interferon rapidly signals cells to heighten their defences and prevent viruses from replicating in human cells.

“Interferon then begins to act on immune cells, causing B cells to expand and produce specific antibodies that enter the bloodstream to inactivate the virus. At the same time interferon stimulates T cells to destroy cells that have ingested the virus,” says Professor Sprent.

“Together the combined attack by these two types of immune cells eliminates the pathogen quite quickly. Meanwhile, interferon stimulates some of the specific T and B cells generated during the initial infection to survive and form long-lived memory cells, which provide long-term protection against a second encounter with the same pathogen.”

Although direct evidence is still lacking, it is highly likely that the side effects of COVID-19 vaccines are simply a reflection of strong interferon production, says Professor Sprent. In fact, therapeutic injection of interferon, which is currently used to treat hepatitis B and hepatitis C infections and multiple sclerosis, is known to induce the same side effects as COVID-19 vaccines.

How interferon elicits these side effects is unclear, he adds, but they are likely a manifestation of interferon’s ability to stimulate production of multiple cytokines, molecules that activate various components of the immune response.

Blocking interferon – a COVID-19 survival strategy

Some people with severe COVID-19 have autoantibodies – antibodies that attack a person’s own cells or proteins – that target interferon and effectively block its action in the body, explains Professor Sprent. In addition, certain components of the virus can physically block interferon.

“This may be one of the coronavirus’s survival strategies – by suppressing interferon production, it stops people from feeling sick while allowing virus replication. This means that people are more likely to be in the community, spreading the virus on to others.”

But COVID-19 vaccines get around this problem, he adds.

“Most COVID-19 vaccines rely on production of the spike protein of SARS-CoV-2, which doesn’t block interferon and is therefore able to elicit an effective immune response – crucial for providing protection against re-infection the next time the virus comes around.”

“This difference means that young people, who are more often asymptomatic during COVID-19 infection, may have stronger side effects to the vaccine than to the virus itself. Younger people and women naturally make more interferon, and they are also the group which has the most side effects to the COVID-19 vaccine,” says Professor Sprent.

“It should be noted however, that the side effects of vaccination will nearly always be mild and transient, and indicate merely that the vaccine is doing its job of stimulating production of interferon and providing us with crucial protection against COVID-19.”

Featured image: Professor Jonathan Sprent © GIMR

Reference: Jonathan Sprent and Cecile King, “COVID-19 vaccine side effects: The positives about feeling bad”, Science Immunology  22 Jun 2021: Vol. 6, Issue 60, eabj9256 DOI: 10.1126/sciimmunol.abj9256

Provided by Garvan Institute of Medical Research

Study Identifies Gut Microbes Associated With Toxicity To Combined Checkpoint Inhibitors in Melanoma Patients (Medicine)

Results provide potential biomarkers for toxicity and treatment response

Researchers from The University of Texas MD Anderson Cancer Center found specific intestinal microbiota signatures correlate with high-grade adverse events and response to combined CTLA-4 and PD-1 blockade treatment. The study, published today in Nature Medicine, also identified a potential new strategy to treat toxicity – while maintaining response – to combined immune checkpoint blockade through either IL-1R inhibition or manipulation of the gut microbiota.

Dual immune checkpoint therapy has contributed to progress in overall survival for many cancer types, including advanced melanoma. Combining CTLA-4 and PD-1 inhibitors produces high responses, yet is often accompanied by immune-related adverse events, such as colitis, an inflammatory bowel disease that can cause additional complications. The field is currently lacking strong biomarkers to understand which patients are most likely to respond to combined checkpoint inhibitors and which patients are most likely to develop severe toxicity to the treatment. 

“This study further highlights the importance of the gut microbiome in both response as well as in toxicity in patients being treated with combined immune checkpoint blockade,” said senior author Jennifer Wargo, M.D., professor of Genomic Medicine and Surgical Oncology. “We’re committed to understanding and addressing the significant immune-related side effects that tend to accompany this combination therapy, so that patients don’t have to compromise quality of life for effective cancer treatment.”

The study found a significantly higher abundance of Bacteroides intestinalis in the gut microbiota of patients with advanced melanoma who experienced toxicity from combined immunotherapy. In both patients and preclinical models, a high abundance of B. intestinalis in the gut microbiota was affiliated with increased mucosal IL-1β and associated inflammation. Inhibiting IL-1R with a drug approved to treat rheumatoid arthritis reduced intestinal inflammation without blunting the efficacy in pre-clinical models.

Another bacterium, Parabacteroides distansonis, was associated with response to treatment in both the patient cohort and preclinical models. Gut microbiome diversity wasn’t significantly different between responders and non-responders, contrary to previous research focusing on single-agent immune checkpoint blockade targeting PD-1.

The patient cohort was comprised of 77 adults who received combined CTLA-4 and PD-1 blockade treatment for advanced melanoma at MD Anderson. The majority had stage IV disease (84%) and had not received any previous systemic therapy (74%). Nearly all patients had an adverse event of any grade (93.5%) and about half (49%) experienced grade 3 or higher adverse events in response to treatment.

Immune and genomic biomarkers

The research team also studied genomic and immune predictors of response to combined immune checkpoint blockade and identified some associations between immune cell profiles in the blood and toxicity to treatment. Patients who experienced grade 3 or higher adverse events had a more diverse T cell repertoire and a more naïve T cell phenotype in the systemic circulation.

Whole-exome sequencing of 26 pre-treatment cutaneous melanoma tumor samples revealed higher tumor mutational burden (TMB) in responders, compared to non-responders. Non-responders had a higher level of copy number loss, primarily affecting chromosomes 5, 10 and 15. These findings further support previous studies that suggest TMB is associated with response and copy number loss is associated with resistance. Baseline tumor biopsies also revealed a higher density of CD8+ T cells in responders, compared to non-responders.

These results also support previously identified immune and genomic biomarkers for response to treatment with a single immune checkpoint blockade. 

Additional studies in larger cohorts will be required to validate the biomarkers for toxicity and response, to further understand the underlying mechanisms and to investigate IL-1R inhibition as a potential therapeutic target for inflammation.

“We’re getting closer to understanding which patients are most likely to benefit from checkpoint inhibitors and to identifying strategies to mitigate toxicity,” Wargo said. “We’re grateful to the patients who have participated in our ongoing research; they continue to motivate and inspire us as we undertake additional studies to build upon the insights from this research.”  

A full list of co-authors and disclosures can be found in the paper. The study was supported by the Melanoma Moon Shot®, part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives. Additional support was provided by Lyda Hill Philanthropies, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the AIM at Melanoma Foundation.

Provided by MD Anderson Cancer Center