Quiet Solar Storm Named After International Women’s Day (Planetary Science)

Scientists from Hvar Observatory (Croatia), the University of Graz (Austria), and Skoltech (Russia) along with their colleagues from the U.S., Belgium, and China have investigated a peculiar solar storm that happened on the International Women’s Day 2019. The all-female research team unraveled how a double structure erupted from the Sun, resulting in a plethora of phenomena observed across the electromagnetic spectrum, eventually merging into a single structure that sped toward the Earth. Published in Astronomy & Astrophysics, the study contributes to accurate predictions of hostile space weather events.

Solar storms are the most violent eruptions in the Solar System, fueled by the magnetic energy of the Sun. These streams of magnetized plasma expelled from the Sun travel through the interplanetary space and may create radiation hazards for astronauts and induce currents disturbing space- and ground-based technological systems.

To forecast these dangerous events, researchers need to understand their underlying physics, as well as the nature and the effects on Earth of the associated phenomena:

  • Solar flares are bursts of solar electromagnetic radiation that can generate more energy in minutes than all the power plants on Earth combined within a year. This may heat up the Earth’s atmosphere and thus increase the drag experienced by satellites, nudging them into lower orbit.
  • Coronal mass ejections(CMEs), which often accompany solar flares, are giant plasma clouds expelled from the Sun at speeds from 100 to over 3,000 kilometers per second. Reaching our planet within one to five days, they can cause severe geomagnetic storms and pose a hazard to astronauts and technological systems.
  • Radio bursts are intense radio-frequency emissions from the Sun related to solar flares and CMEs. These extreme space weather events can interfere with radio communication and disrupt satellite-based positioning systems. Besides that, type II bursts are particularly important for characterizing CMEs.
  • Extreme ultraviolet waves accompany CMEs, which like a supersonic airplane can initiate shockwaves. CMEs and the associated shocks can accelerate hazardous high-energy particles and even shrink the Earth’s magnetic field, leaving geostationary satellites without its natural protection.
  • Coronal dimmings are traces of CMEs on the Sun. They are observed as gaps in extreme UV radiation intensity and result from the loss of matter in the solar corona — the aura of plasma surrounding the Sun.

These events tend to accompany strong solar storms and serve as proxies for their study through remote observations at various wavelengths of the electromagnetic spectrum: visible light, radio waves, UV radiation, and X-rays. 

If a major storm passes over a probe in the interplanetary space, these remote sensing data are complemented by direct measurements of the storm’s propagation speed and the orientation and strength of its magnetic field. For storms directed at our planet, their magnetic field is inferred from how it affects that of the Earth.

Combining remote and in situ observations, the study in Astronomy & Astrophysics presents a comprehensive analysis of an eruptive event of March 8, 2019, which reveals the finesse of the physics that underlies solar storms. The scientists report on a plethora of associated phenomena: a double-peak solar flare, two so-called loop ejections evolving into an Earth-directed CME, two extreme UV waves in close succession, and two-stage coronal dimmings that evolved co-temporally with the flare and type II and III radio bursts.

Video: Overview of the event on March 8, 2019. The left panel shows two episodes in the flare energy release process (imagery by NASA’s SDO/AIA), and the right panel represents two associated extreme ultraviolet waves (bright fronts) and two-stage coronal dimmings (dark areas) in processed images. Credit: from Dumbović et al., 2021

“This solar storm seemed peculiar from the very first moment. It had many accompanying phenomena that could be observed at the Sun, something that is usual for very strong solar storms. The only trouble was — the storm was not strong at all!” says Dr. Mateja Dumbović, the lead author of the study and a research associate at Hvar Observatory in Croatia. She further explains how the storm was named: “In solar physics it is common to name interesting solar storms according to the date when they happened. We have for instance Halloween and Bastille day events, and now also an International Women’s Day event.”

“We showed that on March 8, 2019, the Sun produced two successive eruptions of two systems of sheared and twisted magnetic fields, which merged already in the upper solar atmosphere and further evolved out as a single entity. We also demonstrated that the large-scale magnetic field significantly influences both the early and the interplanetary evolution of the structure. During the first eruption the stability of the overlying field was disrupted, which enabled the second eruption,” says Dr. Astrid Veronig, professor at the University of Graz, who co-authored the study.

“When the solar wind, a continuous flow of charged particles from the Sun, leaves the solar atmosphere, it carries away part of the solar magnetic field. As a result, the solar magnetic field permeates the entire Solar System. Since the Sun’s equator rotates faster than its poles, the magnetic field twists into an Archimedean spiral, as it extends through the Solar System, creating the largest structure in our Solar System — the heliospheric current sheet, which separates regions of the solar wind where the magnetic field points toward or away from the Sun. The current sheet circles the solar equator like a wavy skirt around a ballerina’s waist. Earth and all the planets of the Solar System exist within these wavy spiral folds. In our study we showed that the location of the heliospheric current sheet between the active region on the Sun and the Earth likely influences the propagation and the evolution of the structures erupted on March 8, 2019. And whatever storms may rage, we wish everyone a good weather in space,” says study co-author Dr. Tatiana Podladchikova, an assistant professor at the Skoltech Space Center.

The International Women’s Day study was carried out by a synergetic international team of 10 female researchers from Europe, Russia, the United States, and China at different stages in their scientific careers, from PhD students to full professors, including three awardees of the prestigious international Alexander Chizhevsky medal for space weather and space climate: Dr. Mateja Dumbović (the University of Zagreb, Croatia), Dr. Tatiana Podladchikova (Skoltech, Russia), and Dr. Julia Thalmann (University of Graz, Austria). Other institutions involved in this research include NorthWest Research Associates (USA), the Solar-Terrestrial Centre of Excellence — SIDC, the Royal Observatory of Belgium, the Centre for Mathematical Plasma Astrophysics at KU Leuven (Belgium), and the School of Earth and Space Sciences of the University of Science and Technology of China.

flare_8_march_2019
Image. Magnetic field and extreme ultraviolet emission during the extended impulsive phase of the solar flare on March 8, 2019. The panels in the two columns correspond to the two phases of the double-peak flare and two eruptions. Snapshots are shown at two time steps corresponding to the first (around 03:12 UT, left column) and the second (around 03:30 UT, right column) flare-related eruptions. Rows from top to bottom show line-of-sight magnetic field maps (data from the Helioseismic and Magnetic Imager — HMI), 1600, 304, 171, 211, and 94 angstrom filtergrams (data from the Solar Dynamics Observatory’s Atmospheric Imaging Assembly — AIA). The labels “K1” and “K2” in the 1600 angstrom AIA filtergrams refer to locations of flare kernels. The labels “R1” and “R2” in the 304 angstrom AIA filtergrams refer to the corresponding flare ribbons. The large white arrows in the 94 angstrom AIA filtergrams point to the location of the erupting loops during stages one and two of the flare process. The small arrow in the bottom left 94 angstrom AIA filtergram points to the location of a narrow ejection to the north-east during the first stage. Credit: from Dumbović et al., 2021

Featured image Credit: Pavel Odinev / Skoltech


Provided by SKOLTECH

Does Testosterone Influence Success? Not Much, Research Suggests (Neuroscience)

With the Olympics underway, higher testosterone has often been linked to sporting success, and other kinds of success too. But beyond sport, new research has found little evidence that testosterone meaningfully influences life chances for men or women. In fact, the study suggests that despite the social myths surrounding testosterone, it could be much less important than previously thought.

It is already known that in men testosterone is linked with socioeconomic position, such as income or educational qualifications.  Researchers from the University of Bristol’s Population Health Sciences (PHS) and MRC Integrated Epidemiology Unit (IEU) wanted to find out whether this is because testosterone actually affects socioeconomic position, as opposed to socioeconomic circumstances affecting testosterone, or health affecting both.  The findings are published today [28 July] in Science Advances.

To isolate effects of testosterone itself, the research team applied an approach called Mendelian randomization in a sample of 306,248 UK adults from UK Biobank. They explored testosterone’s influence on socioeconomic position, including income, employment status, neighbourhood-level deprivation, and educational qualifications; on health, including self-rated health and BMI, and on risk-taking behaviour.  

Dr Amanda Hughes, Senior Research Associate in Epidemiology in Bristol Medical School: Population Health Sciences (PHS), said: “There’s a widespread belief that a person’s testosterone can affect where they end up in life. Our results suggest that, despite a lot of mythology surrounding testosterone, its social implications may have been over-stated.”

First, the team identified genetic variants linked to higher testosterone levels and then investigated how these variants were related to the outcomes. A person’s genetic code is determined before birth, and generally does not change during their lifetime (there are rare exceptions, such as changes that occur with cancer).  This makes it very unlikely that these variants are affected by socioeconomic circumstances, health, or other environmental factors during a person’s lifetime. Consequently, any association of an outcome with variants linked to testosterone would strongly suggest an influence of testosterone on the outcome.

Similar to previous studies the research found that men with higher testosterone had higher household income, lived in less deprived areas, and were more likely to have a university degree and a skilled job. In women, higher testosterone was linked to lower socioeconomic position, including lower household income, living in a more deprived area, and lower chance of having a university degree. Consistent with previous evidence, higher testosterone was associated with better health for men and poorer health for women, and greater risk-taking behaviour for men.

In contrast, there was little evidence that the testosterone-linked genetic variants were associated with any outcome for men or women. The research team concluded that there is little evidence that testosterone meaningfully affected socioeconomic position, health, or risk-taking in men or women. The study suggests that – despite the mythology surrounding testosterone – it might be much less important than previously claimed. 

Results for women were less precise than results for men, so the influence of testosterone in women could be studied in more detail in the future using larger samples. 

Dr Hughes added: “Higher testosterone in men has previously been linked to various kinds of social success. A study of male executives found that testosterone was higher for those who had more subordinates. A study of male financial traders found that higher testosterone correlated with greater daily profits. Other studies have reported that testosterone is higher for more highly educated men, and among self-employed men, suggesting a link with entrepreneurship.

“Such research has supported the widespread idea that testosterone can influence success by affecting behaviour. There is evidence from experiments that testosterone can make a person more assertive or more likely to take risks – traits which can be rewarded in the labour market, for instance during wage negotiations. But there are other explanations. For example, a link between higher testosterone and success might simply reflect an influence of good health on both. Alternatively, socioeconomic circumstances could affect testosterone levels. A person’s perception of their own success could influence testosterone: in studies of sports matches, testosterone has been found to rise in the winner compared to the loser.”

The research is supported by the Health Foundation as part of a project entitled ‘Social and economic consequences of health: causal inference methods and longitudinal, intergenerational data’, which is part of the Health Foundation’s Social and Economic Value of Health.

Paper

Testosterone and socioeconomic position: Mendelian Randomization in 306,248 men and women in UK Biobank‘ by Sean Harrison, Neil M. Davies, Laura D. Howe, Amanda Hughes in Science Advances


Provided by University of Bristol

Motivation Depends On How The Brain Processes Fatigue (Neuroscience)

How do we decide whether or not an activity which requires work is ‘worth the effort’? Researchers at the University of Birmingham & University of Oxford have shown that the willingness to work is not static, and depends upon the fluctuating rhythms of fatigue.

Fatigue – the feeling of exhaustion from doing effortful tasks – is something we all experience daily. It makes us lose motivation and want to take a break. Although scientists understand the mechanisms the brain uses to decide whether a given task is worth the effort, the influence of fatigue on this process is not yet well understood.

The research team conducted a study to investigate the impact of fatigue on a person’s decision to exert effort. They found that people were less likely to work and exert effort – even for a reward – if they were fatigued. The results are published in Nature Communications.

Intriguingly, the researchers found that there were two different types of fatigue that were detected in distinct parts of the brain. In the first, fatigue is experienced as a short-term feeling, which can be overcome after a short rest. Over time, however, a second, longer term feeling builds up, stops people from wanting to work, and doesn’t go away with short rests.

“We found that people’s willingness to exert effort fluctuated moment by moment, but gradually declined as they repeated a task over time,” says Tanja Müller, first author of the study, based at the University of Oxford. “Such changes in the motivation to work seem to be related to fatigue – and sometimes make us decide not to persist.”

The team tested 36 young, healthy people on a computer-based task, where they were asked to exert physical effort to obtain differing amounts of monetary rewards. The participants completed more than 200 trials and in each, they were asked if they would prefer to ‘work’ – which involved squeezing a grip force device – and gain the higher rewards offered, or to rest and only earn a small reward.

The team built a mathematical model to predict how much fatigue a person would be feeling at any point in the experiment, and how much that fatigue was influencing their decisions of whether to work or rest.

While performing the task, the participants also underwent an MRI scan, which enabled the researchers to look for activity in the brain that matched the predictions of the model.

They found areas of the brain’s frontal cortex had activity that fluctuated in line with the predictions, while an area called the ventral striatum signalled how much fatigue was influencing people’s motivation to keep working.

“This work provides new ways of studying and understanding fatigue, its effects on the brain, and on why it can change some people’s motivation more than others” says Dr Matthew Apps, senior author of the study, based at the University of Birmingham’s Centre for Human Brain Health. “This helps begin to get to grips with something that affects many patients lives, as well as people while at work, school, and even elite athletes.

The University of Birmingham’s Centre for Human Brain Health, Institute for Mental Health and School of Psychology all contributed to this research project.

This work was funded by the Biotechnology and Biological Science Research Council (part of UK Research and Innovation), The Wellcome Trust, German Academic Scholarship Foundation (Studienstiftung), the German Academic Exchange Service (DAAD) and the Funds for Women Graduates (FfWG) Foundation.


Reference: Müller… Apps (2021). ‘Neural and computational mechanisms of momentary fatigue and persistence in effort-based choice’. Nature Communications.


Provided by University of Birmingham

Researchers Found A New Way To Detect the SARS-CoV-2 Alpha Variant in Wastewater (Biology)

SMART researchers have developed an innovative method to detect and quantify the B.1.1.7 (Alpha) variant of concern via wastewater epidemiology.

Researchers from the Antimicrobial Resistance (AMR) interdisciplinary research group at the Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, alongside collaborators from Biobot Analytics, Nanyang Technological University (NTU), and MIT, have successfully developed an innovative, open-source molecular detection method that is able to detect and quantify the B.1.1.7 (Alpha) variant of SARS-CoV-2. The breakthrough paves the way for rapid, inexpensive surveillance of other SARS-CoV-2 variants in wastewater.

As the world continues to battle and contain Covid-19, the recent identification of SARS-CoV-2 variants with higher transmissibility and increased severity has made developing convenient variant tracking methods essential. Currently, identified variants include the B.1.17 (Alpha) variant first identified in the United Kingdom and the B.1.617.2 (Delta) variant first detected in India.

Wastewater surveillance has emerged as a critical public health tool to safely and efficiently track the SARS-CoV-2 pandemic in a non-intrusive manner, providing complementary information that enables health authorities to acquire actionable community-level information. Most recently, viral fragments of SARS-CoV-2 were detected in housing estates in Singapore through a proactive wastewater surveillance program. This information, alongside surveillance testing, allowed Singapore’s Ministry of Health to swiftly respond, isolate, and conduct swab tests as part of precautionary measures.

However, detecting variants through wastewater surveillance is less commonplace due to challenges in existing technology. Next-generation sequencing for wastewater surveillance is time-consuming and expensive. Tests also lack the sensitivity required to detect low variant abundances in dilute and mixed wastewater samples due to inconsistent and/or low sequencing coverage.

The method developed by the researchers is uniquely tailored to address these challenges and expands the utility of wastewater surveillance beyond testing for SARS-CoV-2, toward tracking the spread of SARS-CoV-2 variants of concern.

Wei Lin Lee, research scientist at SMART AMR and first author on the paperadds, “This is especially important in countries battling SARS-CoV-2 variants. Wastewater surveillance will help find out the true proportion and spread of the variants in the local communities. Our method is sensitive enough to detect variants in highly diluted SARS-CoV-2 concentrations typically seen in wastewater samples, and produces reliable results even for samples which contain multiple SARS-CoV-2 lineages.”

Led by Janelle Thompson, NTU associate professor, and Eric Alm, MIT professor and SMART AMR principal investigator, the team’s study, “Quantitative SARS-CoV-2 Alpha variant B.1.1.7 Tracking in Wastewater by Allele-Specific RT-qPCR” has been published in Environmental Science & Technology Letters. The research explains the innovative, open-source molecular detection method based on allele-specific RT-qPCR that detects and quantifies the B.1.1.7 (Alpha) variant. The developed assay, tested and validated in wastewater samples across 19 communities in the United States, is able to reliably detect and quantify low levels of the B.1.1.7 (Alpha) variant with low cross-reactivity, and at variant proportions down to 1 percent in a background of mixed SARS-CoV-2 viruses.

Targeting spike protein mutations that are highly predictive of the B.1.1.7 (Alpha) variant, the method can be implemented using commercially available RT-qPCR protocols. Unlike commercially available products that use proprietary primers and probes for wastewater surveillance, the paper details the open-source method and its development that can be freely used by other organizations and research institutes for their work on wastewater surveillance of SARS-CoV-2 and its variants.

The breakthrough by the research team in Singapore is currently used by Biobot Analytics, an MIT startup and global leader in wastewater epidemiology headquartered in Cambridge, Massachusetts, serving states and localities throughout the United States. Using the method, Biobot Analytics is able to accept and analyze wastewater samples for the B.1.1.7 (Alpha) variant and plans to add additional variants to its analysis as methods are developed. For example, the SMART AMR team is currently developing specific assays that will be able to detect and quantify the B.1.617.2 (Delta) variant, which has recently been identified as a variant of concern by the World Health Organization.

“Using the team’s innovative method, we have been able to monitor the B.1.1.7 (Alpha) variant in local populations in the U.S. — empowering leaders with information about Covid-19 trends in their communities and allowing them to make considered recommendations and changes to control measures,” says Mariana Matus PhD ’18, Biobot Analytics CEO and co-founder.

“This method can be rapidly adapted to detect new variants of concern beyond B.1.1.7,” adds MIT’s Alm. “Our partnership with Biobot Analytics has translated our research into real-world impact beyond the shores of Singapore and aid in the detection of Covid-19 and its variants, serving as an early warning system and guidance for policymakers as they trace infection clusters and consider suitable public health measures.”

The research is carried out by SMART and supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence And Technological Enterprise (CREATE) program.

SMART was established by MIT in partnership with the National Research Foundation of Singapore (NRF) in 2007. SMART is the first entity in CREATE developed by NRF. SMART serves as an intellectual and innovation hub for research interactions between MIT and Singapore, undertaking cutting-edge research projects in areas of interest to both Singapore and MIT. SMART currently comprises an Innovation Center and five IRGs: AMR, Critical Analytics for Manufacturing Personalized-Medicine, Disruptive and Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems.

The AMR interdisciplinary research group is a translational research and entrepreneurship program that tackles the growing threat of antimicrobial resistance. By leveraging talent and convergent technologies across Singapore and MIT, AMR aims to develop multiple innovative and disruptive approaches to identify, respond to, and treat drug-resistant microbial infections. Through strong scientific and clinical collaborations, its goal is to provide transformative, holistic solutions for Singapore and the world.

Featured image: SMART AMR researchers Wei Lin Lee (left), Xiaoqiong Gu (center), and Federica Armas evaluate a 384-well plate set up for variant detection assays. Credits: Photo courtesy of SMART.


Provided by MIT

Top Discoveries By MD Anderson Cancer Center (Medicine)

Featuring discoveries in B cell survival, epigenetics, genomic stability, COVID-19 cell therapies, pain treatment, CRISPR, aneuploidy and Hodgkin lymphoma survivorship

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include a newly discovered protein that controls B cell survival, understanding epigenetic changes in malignant peripheral nerve sheath tumors (MPNSTs) and melanoma, identifying a protein that protect genome stability, developing novel cell therapies for COVID-19, a new option for treating neuropathic pain, exosome delivery of CRISPR/Cas9 to pancreatic cancer, discovering how cancer cells tolerate aneuploidy and the role of health disparities in long-term survival of adolescent and young adult patients with Hodgkin lymphoma.

Discovery of a novel protein regulating B cell survival and malignancy

Normal signaling from the B cell-activating factor receptor (BAFFR) is critical for development and survival of B cells, but dysregulated signaling promotes autoimmune disease and certain cancers. However, it’s not clear how BAFFR works to regulate these important processes. Researchers led by Yanchuan Li, Ph.D., and Shao-Cong Sun, Ph.D., discovered a new protein, DYRK1a, and its precise role in connecting BAFFR to the downstream noncanonical NF-kB pathway to promote B cell survival. DYRK1a loss resulted in fewer mature B cells, whereas DYRK1a overexpression is found in some cases of B-cell acute lymphoblastic leukemia (B-ALL). The researchers showed that DYRK1a was important for the survival of B-ALL cells, suggesting a possible new therapeutic target. Learn more in Blood.

Epigenetic reprogramming points to therapeutic approach for MPNSTs

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare and aggressive form of soft-tissue sarcoma. These tumors frequently have mutations in SUZ12 and EED, both of which are components of a protein complex called PRC2 that makes epigenetic modifications to regulate chromosome structures. Researchers led by Veena Kochat, Ph.D., Ayush Raman, Ph.D., Kunal Rai, Ph.D., and Keila Torres, M.D., Ph.D., discovered that MPNSTs with PRC2 defects have extensive epigenetic changes, resulting in alterations to chromosome structure and unique molecular traits. As a result, enhancer regions of the genome were activated, driving increased expression of genes that contribute to MPNST survival. Drugs that blocked the enhancer activity were effective against PRC2-mutant MPNSTs in laboratory models, pointing to a possible treatment approach for patients with these tumors. Learn more in Acta Neuropathologica.

Study finds novel role for protein in safeguarding genome stability

DNA breaks can occur as a normal part of replication and transcription, and they typically are fixed by DNA repair processes such as homologous recombination. In certain cases, a form of homologous recombination called break-induced replication (BIR) is used, although this process is less accurate and results in mutations and chromosome rearrangements. Xiao Wu, Ph.D., and Bin Wang, Ph.D. discovered that a BRCA1-interacting protein called Abraxas plays an important role in limiting the use of BIR repair and in protecting genome integrity. The researchers uncovered a complex mechanism by which Abraxas minimizes the specific types of DNA breaks that are fixed by BIR. When Abraxas is missing, the downstream molecular cascade results in excessive DNA end resection, BIR-mediated repair and chromosomal alterations. Learn more in Nature Communications.

Developing adoptive cell therapies for treating COVID-19

MD Anderson researchers are working to develop an adoptive cell therapy using viral-specific, steroid-resistant T cells that recognize SARS-CoV-2. Adapting previously developed techniques for creating antiviral T cell therapies, a team led by Rafet Basar, Ph.D., E.J. Shpall, M.D., and Katy Rezvani, M.D., Ph.D., described the successful isolation and expansion of SAR-CoV-2-specific T cells from the blood of donors who previously recovered from COVID-19. Further, the team utilized CRISPR/Cas9 gene editing to render these cells resistant to corticosteroids, which may allow the treatment to be used alongside routinely administered steroids. A clinical trial to evaluate the safety and efficacy of off-the-shelf SARS-CoV-2 T-cells in treating COVID-19 is now open at MD Anderson. Learn more in Cell Reports.

New understanding of mechanism behind gabapentinoids shows promise for treating neuropathic pain

Gabapentinoids, a first-line drug treatment used to reduce neuropathic pain and epilepsy for more than three decades, work by targeting α2δ‐1, previously considered a Ca2+ channel subunit. However, the underlying molecular mechanism behind α2δ-1’s role in neuropathic pain and gabapentinoids’ actions has not been well understood. In a study led by Hui-Lin Pan, M.D., Ph.D., researchers focused on the switch from Ca 2+-impermeable to Ca2+-permeable AMPA receptors in the spinal cord, which have been shown to contribute to chronic neuropathic pain. They demonstrated that nerve injury promotes Ca 2+-permeable AMPA receptors through α2δ‐1 – altering synaptic function and amplifying pain signals as a result. α2δ‐1 directly interacts with AMPA receptor proteins and can control Ca 2+ permeability by disrupting its heteromeric subunit assembly. These findings could lead to further exploration of α2δ‐1–coupled AMPA receptors as a potential target for treating other neurological conditions, including Alzheimer’s disease, epilepsy, stroke and drug addiction. Learn more in Cell Reports.

Profiling chromatin states points to new treatment target in metastatic melanoma

Melanoma sequencing studies have identified frequent mutations in genes responsible for regulating the epigenome – reversible chemical modifications that change chromosome structures and fine-tune gene expression. To understand how epigenetic alternations contribute to melanoma progression, researchers led by Christopher Terranova, Ph.D., Ming Tang, Ph.D., Mayinuer Maitituoheti, M.D., Ph.D., and Kunal Rai, Ph.D., profiled 46 melanoma tumors and cell lines, looking specifically at chromatin – the DNA, RNA and proteins that make up chromosomes. The researchers discovered that melanomas with BRAF, NRAS or WT mutations have unique chromatin states. They demonstrated that the unique states, marked by the PRC2 protein complex, regulate expression of genes driving metastasis. Results suggest that therapeutically blocking PRC2 in combination with MEK inhibitors is a promising treatment strategy for NRAS-mutant melanomas. Learn more in Cell Reports

Exosomes can deliver targeted genome editing to suppress pancreatic cancer cells

The CRISPR/Cas9 system is a useful tool for a variety of genome-editing applications. However, reliably delivering CRISPR/Cas9 specifically to cells of interest remains a challenge for the field. Research led by Kathleen McAndrews, Ph.D., Fei Xiao, Ph.D., Antonios Chronopoulos, Ph.D., and Raghu Kalluri, M.D., Ph.D., demonstrated that exosomes – small membrane-bound vesicles that shuttle information between cells – can efficiently deliver the CRISPR/Cas9 machinery to pancreatic cancer cells via systemic delivery, achieving targeted disruption of mutant KRAS G12D, the most common gene mutation in pancreatic cancer. As proof-of-principle, the researchers demonstrated this technique could block tumor growth in pancreatic cancer models, suggesting the technique warrants further evaluation as a therapeutic tool. Learn more in Life Science Alliance.

Discovering a mechanism for cancer cells to tolerate extra chromosomes

Cancer cells often have extra chromosomes present – a condition known as aneuploidy. Having extra copies of pro-tumor genes could benefit cancer cells, but aneuploidy often affects hundreds or thousands of genes, which can overwhelm the cell. By analyzing data from more than 5,000 tumors, researchers led by Vakul Mohanty, Ph.D., and Ken Chen, Ph.D., discovered that cancer cells have a mechanism to overcome this issue. Through a complex set of regulatory changes, cancer cells can uncouple gene expression from copy number, meaning that extra gene copies do not result in increased gene expression. The team also identified proteins that could be targets to disrupt this uncoupling mechanism, suggesting possible therapeutic possibilities. Learn more in Cell Reports Medicine.

Disparities play key role in long-term survival of AYA Hodgkin lymphoma patients

Hodgkin lymphoma (HL) is one of the most common cancers among adolescent and young adults (AYA), and many factors can impact long-term survivorship among this group. A team led by Michael Roth, M.D., used the Surveillance, Epidemiology, and End Results (SEER) registry to identify more than 15,000 AYA HL survivors five years post-diagnosis to determine if socioeconomic status (SES), race/ethnicity, age of diagnosis, gender or living in rural areas impact long-term survivorship. Results demonstrated many disparities in survival persist years after initial diagnosis, and there was no evidence of disparities in long-term survival changing over time for AYA HL survivors. These findings build upon previous studies indicating race/ethnicity and SES factors impact short-term survival in AYA HL survivors, and more targeted studies are needed to identify opportunities for early and successful interventions. Learn more in Cancer Epidemiology, Biomarkers & Prevention.

Featured image: Image courtesy of Torres/Rai Laboratory.


Provided by MD Anderson Cancer Center

Probody: The Promise Of ‘Kinder’ Antibody-based Immunotherapy (Medicine)

Recently published ahead of print in Clinical Cancer Research (1), a CCR Translations article co-authored by Elena Garralda, Director of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch (Vall d’Hebron Barcelona Hospital Campus), and Honey K. Oberoi, a phase I Investigator of her team, explores the promise of Probody therapeutics by drawing on current directions, including the results of a study (2) led by Melissa Johnson, the Sarah Cannon Research Institute/Tennessee Oncology (Nashville, USA), which published in the same issue of the journal.

More specifically, they discuss how these novel, masked antibodies could advance the development of targeted therapies based on the findings from this first-in-human phase I trial of CX-2029; a new Probody drug-conjugate (PDC) targeting transferrin receptor 1 (TfR1/CD71). Notably, the results are the first to clinically validate CD71 as a novel target for antibody drug conjugates (ADCs) in patients with advanced solid tumors.

ADCs are designed to exclusively target and destroy malignant cells while sparing healthy tissues, and therefore reduce the toxicity associated with cancer treatments. Representing a potentially powerful class of therapeutic agents in oncology, the promise of ADCs lies in their design where their attack relies on a tumor targeted antibody attached to a cytotoxic payload via a linker. Upon antigen binding, the cytotoxic load is internalized into cancer cells and leads to their death.

However, as Elena Garralda and Honey K. Oberoi go on to highlight, developing these agents is a hugely complex process, necessitating the alignment of multiple actors; target antigen selection, the antibody construct, the linker stability and the payload conjugation and potency.

“Over the last decades several hundred ADCs have entered the clinic and yet, as of April this year, only 10 have since been approved by the U.S. Food and Drug Administration; five of them only during the past two years. Furthermore, only four have been approved for treating solid tumors, exclusively targeting 3 antigens”, observed Elena Garralda, Corresponding Author of this present article and Principal Investigator of VHIO’s Early Clinical Drug Development Group.

She continued, “One major limitation to-date has been antigen selection. Unlike hematological tumors, the majority of solid tumor antigens are tumor-associated as opposed to tumor-specific. The delivery of the payload to normal tissues has therefore limited the therapeutic efficacy and value of ADCs. Broadening the array of antigens for ADCs represents an unmet need in oncology”.

The advent of Probody

To respond to this need, they explore the current landscape of Probody technology as a novel approach to more effectively outsmart cancer. By exploiting the conditions of the tumor microenvironment (TME), Probody is designed to exclusively target the tumor, while limiting activity in healthy tissues, and to take advantage of elevated levels of protease activity in the TME. The targeting-binding regions of Probody therapies are masked to reduce the side effects and toxicity associated with certain monoclonal antibodies, including immune checkpoint inhibitors (ICIs) and bispecific T cell engagers (BiTEs). Once these disguised Probody ‘deliverers’ encounter active proteases near tumor tissue, their substrates are engineered to be cleaved, removing their masks, which triggers them to bind directly to their tumor targets.

“When the Probody reaches the tumor microenvironment, tumor associated proteases cleave the linker, and the unmasking allows the antibody to bind to the target antigen and deliver powerful anti-cancer blows exclusively to cancer cells. While we are only at the initial stages of developing this new approach, we are now beginning to see promising results”, observed co-author Honey Oberoi.

Illustrative of such progress, they further discuss the study published by Johnson and colleagues (2) which represents proof of concept of this technology applied to patients, and points to value of the transmembrane glycoprotein CD71 in cancer therapy. Highly expressed in normal proliferating cells across several tumor types, CD71 binds transferrin and is key in cellular iron uptake.

“Considering CD71’s crucial role in cancer cell pathology, high expression in the membrane as well as its efficient internalization, it is an attractive target for cancer therapy. Research focused on developing antibodies targeting CD71 as anti-cancer weaponry is therefore expanding”, said Honey Oberoi.

Providing a summary of this phase I, first-in-human study of the CX-2029 Probody, Elena and Honey then highlight examples of alternative strategies that are currently under investigation to generate antibody prodrugs. These include the development of antibodies with a heterodimeric coiled-coil domain that sterically occlude the complementarity-determining regions that are also unmasked upon exposure to proteases. They also mention other current approaches aimed at seeking out novel targets for ADCs beyond the targeting of antigens expressed exclusively on the surface of tumors.

“While these areas of research are now showing promise in improving and expanding target selection as well as increasing the number of antigens for ADCs, we should consider that a good target does not necessarily guarantee success. In fact, several antiHER2 ADCs have failed in the clinic”, cautioned Elena Garralda.

“That said, with continued research aimed at optimizing the various components of ADCs, we can be optimistic that they could, in the near future, represent powerful armory against cancer”, concluded Elena, who is also participating in a VHIO-led project aimed at developing Probody, headed by VHIO’s Director, Josep Tabernero.

Featured image: Dr. Elena Garralda © VHIO


References:

  1. Oberoi HK, Garralda E. Unmasking new promises: expanding the antigen landscape for antibody drug conjugates. Clin Cancer Res. 2021 Jun 16:clincanres.1353.2021. doi: 10.1158/1078-0432.CCR-21-1353. Epub ahead of print. PMID: 34135020
  2. Johnson M, El-Khoueiry A, Hafez N, Lakhani N, Mamdani H, Rodon J, Sanborn RE, Garcia-Corbacho J, Boni V, Stroh M, Hannah AL, Wang S, Castro H, Spira A. Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies. Clin Cancer Res. 2021 Jun 3. doi: 10.1158/1078-0432.CCR-21-0194. Epub ahead of print. PMID: 34083236.

Provided by VHIO

Moderate Drinking Linked to Fewer Heart Attacks in People With Heart Disease (Food)

Light to moderate drinking may be associated with a decreased risk of heart attack, stroke, angina or death among those with cardiovascular disease, finds a new study led by a UCL researcher.

The new BMC Medicine meta-analysis study suggest that drinking up to 105 grams of alcohol per week – equivalent to 13 UK units of alcohol, less than six pints of medium-strength beer or just over one bottle of wine – could potentially confer some protective benefits.

Lead author, PhD student Chengyi Ding (UCL Institute of Epidemiology & Health Care), said: “Our findings suggest that people with cardiovascular disease may not need to stop drinking in order to prevent additional heart attacks, strokes or angina, but that they may wish to consider lowering their weekly alcohol intake. As alcohol consumption is associated with an increased risk of developing other illnesses, those with cardiovascular disease who do not drink should not be encouraged to take up drinking.”

The researchers found that, among people with cardiovascular disease, those who drank up to 15 grams of alcohol per day – equivalent to less than two UK units, with one unit equal to half a pint of medium-strength beer or half a standard glass of wine – had a lower risk of recurrent heart attack, stroke, angina or death, compared to those who did not drink. They also found that those who drank more than 62 grams of alcohol per day – close to eight UK units – did not have an increased risk of recurrent heart attack, stroke, angina or death, compared to those who did not drink alcohol.

While drinking up to 15 grams of alcohol per day was associated with lower risks of heart attack, stroke, angina or death, the researchers found that those with the lowest risk drank between six and eight grams of alcohol per day – equivalent to less than one UK unit. Those who drank six grams of alcohol per day had a 50% lower risk of recurrent heart attack, angina or stroke than those who did not drink. Those who drank eight grams per day had a 27% lower risk of death due to heart attack, stroke or angina, and those who drank seven grams per day had a 21% lower risk of death due to any cause, compared to those who did not drink.

The authors estimated the risk of heart attack, stroke, angina and death for 48,423 adults with cardiovascular disease, using data obtained from the UK Biobank, the Health Survey for England, the Scottish Health Survey and from 12 previous studies. Participants reported their average alcohol consumption and data on subsequent heart attacks, strokes, angina or death, over a period of up to 20 years, were obtained from health, hospital admission and death registry records.

The authors caution that their findings may overestimate the reduced risk of recurrent heart attack, stroke, angina and death for moderate drinkers with cardiovascular disease. This is due to the under-representation of heavy drinkers and categorisation of former drinkers who may have quit drinking due to ill health as non-drinkers in some of the datasets included in their analyses.

The researchers say that for secondary prevention of CVD, current drinkers may not need to stop drinking but should be informed that the lowest risk of mortality and having another cardiovascular event is likely to be associated with lower levels of drinking, that is up to approximately 105g/week. However, they caution that non-drinking patients should not be encouraged to take up light drinking because of well-known adverse effects on other health outcomes, such as cancers.

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Provided by UCL

Combination Vaccines Exerted Stronger Immune Response Than Two Doses Of AstraZeneca Vaccine (Medicine)

Immune response stronger than after two doses of AstraZeneca vaccine

For safety reasons, the Standing Committee on Vaccination (STIKO) recommends that anyone under the age of 60 who initially received a vaccine from AstraZeneca should be given an mRNA vaccine at their second appointment. Up until now, there were no data available to indicate to what extent the human organism would react to such a combined vaccination and start to form antibodies. Researchers at Technische Universität München (TUM), Helmholtz Zentrum München, Universitätsklinikum Erlangen and Universitätsklinikum Köln have now investigated this immune response within the framework of a retrospective scientific study. Blood samples were taken from 500 people who received a second vaccination with the mRNA vaccine from BioNTech/Pfizer nine weeks after their first AstraZeneca vaccine. The result: The neutralising antibody response was much higher in these people than in those who had received two doses of the AstraZeneca vaccine. The immune response to combination vaccines has proven to be just as good as the antibody response after two vaccinations with the mRNA vaccine from BioNTech/Pfizer. The study has now been published in the journal ‘The Lancet Infectious Diseases’.

Based on the data they collected, the three principal investigators – Prof. Dr. Ulrike Protzer (TUM and Helmholtz Zentrum München), Prof. Dr. Klaus Überla (Universitätsklinikum Erlangen) and Prof. Dr. Oliver Cornely (Universitätsklinikum Köln) – have come to the conclusion that combination vaccines are a valid option. The combination is even more effective than two doses of the AstraZeneca vaccine, and might be used, for example, in individuals with allergies or if there are bottlenecks with supplies. The researchers also hope that the combination vaccine will be a further building block that can be used to improve the overall effectiveness of the Covid-19 vaccination. However, more studies are required to confirm the safety and clinical effectiveness of using this and other combination vaccines.

The study was able to be carried out so quickly thanks to assistance from several different parties: the Bavarian State Ministry of Science and the Arts as part of the CoVaKo-2021 project and the FOR-COVID consortium, the German Centre for Infection Research (DZIF) and the vaccination network VACCELERATE (funded by the EU programme Horizon 2020). The aim of CoVaKo-2021 and FOR-COVID is for scientists to monitor the introduction of Covid-19 vaccinations in Bavaria.

Bernd Sibler, Bavarian State Minister for Science and the Arts, emphasises: ‘The results of this study have a direct impact on our vaccination strategy. They help us to use vaccinations as effectively as possible and act as an important basis for political decisions regarding our vaccination strategy in the future. The work of our scientists at the Faculty of Medicine and the university hospitals is indispensable for finding a way out of the Covid-19 pandemic.’

Featured image: Bild: Michael Rabenstein/Uni-Klinikum Erlangen


Further information

https://doi.org/10.1016/S1473-3099(21)00420-5


Provided by FAU

SARS-CoV-2 Lambda Variant Is Highly Infectious, Scientists Revealed (Biology)

Highlights

  • Izumi Kimura showed that Lambda spike (S) is highly infectious and T76I and L452Q are responsible for this property.
  • Lambda S is more susceptible to an infection-enhancing antibody.
  • RSYLTPGD246-253N, L452Q and F490S confer resistance to antiviral immunity.

The SARS-CoV-2 Lambda BS variant, also known as lineage C.37, is a variant of SARS-CoV-2, the virus that causes COVID-19. It was first detected in Peru in December 2020. On 14 June 2021, the World Health Organization named it Lambda variant and designated it as a variant of interest. Although the vaccination rate in Chile is relatively high (i.e. 60% people received at least one dose), a big Covid-19 surge has occurred in Chile in Spring 2021, which suggested that the Lambda variant is proficient in escaping from the antiviral immunity elicited by vaccination. Besides, that its virological features and evolutionary trait remain unknown.

Now, Izumi Kimura and colleagues revealed the virological features and evolutionary trait of the Lambda variant by performing virological experiments and molecular phylogenetic analysis.

They demonstrated that, there are three mutations which confer resistance to the vaccine-induced antiviral immunity, those are RSYLTPGD246-253N, L452Q and F490S mutations, respectively. Additionally, the T76I and L452Q mutations contributed to enhanced viral infectivity.

“Our data suggest that there are at least two virological features on the Lambda variant: increasing viral infectivity (by the T76I and L452Q mutations) and exhibiting resistance to antiviral immunity (by the RSYLTPGD246-253N, L452Q and F490S mutations).”

— they wrote.

They also demonstrated that the RSYLTPGD246-253N mutation, a unique mutation in the NTD of the Lambda Spike protein, is responsible not only for the resistance to the vaccine-induced neutralization as well as an NTD-targeting NAb, but also for the virological phenotype of the Lambda variant that can associate with the massive infection spread mainly in South American countries.

“Because the Lambda variant is a VOI, it might be considered that this variant is not an ongoing threat compared to the pandemic VOCs. However, because the Lambda variant is relatively resistant to the vaccine-induced antisera, it might be possible that this variant is feasible to cause breakthrough infection.”

— they said.

More studies on the evolutionary traits and virological features of SARS-CoV-2 variants are required in order to explain the possibility of wider spread of epidemic and for assessing the risk of future emerging SARS-CoV-2 variants.

Featured image: Graphical abstract © authors


Reference: Izumi Kimura, Yusuke Kosugi, Jiaqi Wu, Daichi Yamasoba, Erika P Butlertanaka, Yuri L Tanaka, Yafei Liu, Kotaro Shirakawa, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Kenzo Tokunaga, Akifumi Takaori-Kondo, Hisashi Arase, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Akatsuki Saito, So Nakagawa, Kei Sato, “SARS-CoV-2 Lambda variant exhibits higher infectivity and immune resistance”, bioRxiv 2021.07.28.454085; doi: https://doi.org/10.1101/2021.07.28.454085


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