Astronomers Presented “THOR” For Main Belt And Kuiper Belt Object Searches (Astronomy)

The number of Solar System minor planet discoveries is growing rapidly thanks to the continuation of present day surveys such as Pan-STARRS and the Catalina Sky Survey, and upcoming surveys such as the Vera C. Rubin Observatory’s Legacy Survey of Space and Time (LSST) and NEOCam, recently renamed to NEO Surveyor. In about a decade, the number of known objects will grow from the currently known 1 million to about 6 million minor planets. Such an increase in discoveries will enable a higher resolution look into the dynamical evolution of our Solar System. However, identifying minor planets in survey images and linking their detections into orbits continues to be a challenging problem. First, linking asteroid detections across multiple nights is difficult due to the sheer number of possible linkages, made even more challenging by the presence of false positives. Second, the motion of the observer makes the linking problem non-linear as minor planets will exhibit higher order motion on the topocentric sky over the course of weeks. Finally, once potential linkages have been established, they need to be confirmed as possible orbits using computationally expensive orbit determination software. For example, the Vera C. Rubin Observatory estimates it will discover nearly six million Main Belt asteroids that will be observed hundreds of times over the course of its ten year survey. Naively attempting to link hundreds of millions of asteroid detections over a ten year period is not computationally feasible.

To make the linking problem more computationally tractable, surveys which aim to discover minor planets focus on constructing “tracklets”: two dimensional sky-plane motion vectors consisting of two or more detections spaced typically 20-90 minutes apart that constrain the direction and rate of motion of potential moving objects. Tracklets are constructed to reduce the number of possible linkages that could be formed by providing information on plausible direction and skyplane angular velocity. They are then linked into inter-night linkages known as “tracks”: sky-plane paths of motion containing several tracklets spanning up to ∼ 15 nights, typically modelled with low-order polynomials. In the case of the LSST, for a moving object to be discoverable it must be observed at least twice a night on at least three unique nights within the 15 day window to go through the trackletto-track creation process. In part due to the relative motion of the observer and the rate of motion of moving objects, both tracklets and tracks can exhibit high residuals relative to the fitted low-order polynomial, requiring relaxed fitting tolerances that can in turn lead to the creation of many spurious candidate linkages. Orbit determination (OD) algorithms are therefore required to run on each candidate track so spurious linkages can be identified and be removed.

The Zwicky Transient Facility (ZTF), an optical timedomain survey scanning the entire northern hemisphere of sky at a rate of more than 3700 deg² hr−¹ , can be seen as a precursor to the LSST. ZTF uses the ZTF Moving Object Discovery Engine (ZMODE) algorithm. Instead of linking tracklets directly into tracks, ZMODE first attempts to build a “stringlet”. A stringlet forms an intermediate step between tracklets and tracks which allows for the linking of pairs of detections across nights before tracks are built. This approach was designed to accommodate ZTF’s cadence during its main survey, where the cadence is frequently too sparse to form short intra-night tracklets.

Recently, Holman and colleagues has shown promising results by shifting the reference frame for linking detections to the heliocenter. By assuming a heliocentric distance and its rate of change, cleverly fitting tracklets for the remaining unknown parameters in inertial space, then propagating the resulting “arrows” to a common epoch, arrows corresponding to the same minor planets will form clusters. These clusters can then be extracted and subsequently validated by orbit fitting. As a testament to the effectiveness of HelioLinC, some 200,000 new minor planet orbits were recovered from the Minor Planet Center’s Isolated Tracklet File (ITF).

Common in all of these approaches is the requirement to build tracklets, which in turn requires a telescope to perform multiple revisits to the same field in a night, then more revisits a few nights later, and so on. For a survey that cannot cover the entire visible sky twice per night, this leads to up to a factor of two reduction of the nightly surveyed area. For a survey such as the LSST, which aims to balance four different science drivers, requiring such a cadence decreases the overall ease by which the other science drivers can be accommodated. It is therefore prudent to investigate whether linking algorithms that are cadence independent can be constructed and whether such algorithms can perform as good or better than the current methods. An algorithm that does not demand a high revisit cadence could increase the efficiency of future surveys, as well as help multi-science missions such as the LSST.

Now, Moeyens and colleagues presented one such cadence- and observer-independent linking algorithm: “Tracklet-less Heliocentric Orbit Recovery” (THOR). Rather than shifting the origin to the heliocenter like Holman and colleagues, they choose to shift the linking frame of reference to a series of dynamically selected heliocentric “test orbits”. The main insight is that transforming detections into the frame of a test orbit linearizes the motion of all objects in a relatively thick bundle of orbits near the test orbit (in phase space), which can then be picked out with line-detection algorithms such as the Hough transform. This provides a path to scanning an otherwise voluminous 6D phase space with a finite number of test orbits and at feasible computational cost.

“By sparsely covering regions of interest in the phase space with “test orbits”, transforming nearby observations over a few nights into the co-rotating frame of the test orbit at each epoch, and then performing a generalized Hough transform on the transformed detections followed by orbit determination (OD) filtering, candidate clusters of observations belonging to the same objects can be recovered at moderate computational cost and little to no constraints on cadence.”

They validated the effectiveness of this approach by running on simulations as well as on real data from the Zwicky Transient Facility (ZTF). They have shown that, THOR can link Main Belt asteroids and more distant populations at high completeness and at moderate computational cost. On two weeks of simulated data, THOR recovered 91.3% of the 18,332 that were ideally findable, whereas a tracklet-based linking algorithm would have recovered none.

On two weeks of ZTF data, THOR linked 97.2% of the 21,542 objects with at least five detections (a factor of ∼ 2 recovery increase over MOPS and a factor of ∼ 1.5 increase over ZMODE). THOR recovered orbits for 97.4% of objects beyond 1.7 au, with 98.4% of objects recovered beyond 2.5 au.

Figure 1. In the top panel, simulated detections of real orbits on the first night of a simulated survey are plotted in grey. The survey consists of 16 ten deg² fields visited once every other night over a 14-night window. The location of the test orbit on the first night is shown as a black plus sign. The red circle outlines the cell of gathered detections which are plotted in blue. In the bottom panel, the test orbit is propagated to all possible times in the survey (the remaining six possible exposures) with a cell of observations gathered at each predicted location and epoch. The simulated detections of the subsequent six visits are plotted in grey in addition to those from the first night. The gathered detections are plotted in blue as in the top panel. The black line tracks the sky-plane motion of the test orbit, with its location on each line plotted as black plus signs. This figure was generated using plots simulations.ipynb. © Moeyens et al.

Furthermore, by comparing the 2018 sample to the catalog of orbits as presently known (April 2021), they showed that the lower limit on purity of THOR sub-missions to the MPC would be 97.7% and – assuming all candidates shown in Figure 1 above, are confirmed as real – possibly as high as 100%. This, in combination with its capability to discover objects regardless of cadence or observer, renders it immediately useful for Main Belt and Kuiper Belt Objects (KBO) searches on survey data and archival datasets.

According to authors, while THOR can be applied to running surveys, application to archival datasets – such as ZTF, CSS, or PanSTARRS – is interesting as well. The most straightforward way to do this would be to run a sliding ∼two week window over the dataset, from beginning to the end, running THOR at each window instance. For each window run, orbits could be computed for the discovered objects and projected to the past (and future) for discovery of additional observations (and improvement of orbital solutions). This is the approach they themselves plan to take with the ZTF archival data.

Assuming the 11 objects discovered here are representative of remaining undiscovered objects in ZTF, this search would likely yield on order of 1, 000 asteroids. The discovery potential with deeper archival datasets (e.g., DES data or the DECam archive) is likely to be significantly larger.

The THOR package and demo Jupyter notebooks are open source and available at this https URL.

Featured image: The observations of the 11 discovered candidates are plotted in red, with the sky-plane motion of their best-fit orbits plotted as lines. 10 of the objects show MBA-like best fit orbit solutions. The remaining object has a hyperbolic orbit solution and corresponds to recovery observations of the hyperbolic comet C/2018 U1. The “wiggles” apparent in some of the best-fit orbit lines are due to the motion of the observer (topocentric motion). This figure was generated using plots ztf.ipynb. © Moeyens et al.


For more:

Joachim Moeyens, Mario Juric, Jes Ford, Dino Bektesevic, Andrew J. Connolly, Siegfried Eggl, Željko Ivezić, R. Lynne Jones, J. Bryce Kalmbach, Hayden Smotherman, “THOR: An Algorithm for Cadence-Independent Asteroid Discovery”, Arxiv, pp. 1-22, 2021. https://arxiv.org/abs/2105.01056


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Cardiovascular Disease Could Be Diagnosed Earlier With New Glowing Probe (Medicine)

Researchers have created a probe that glows when it detects an enzyme associated with issues that can lead to blood clots and strokes.

The team of researchers, from the Department of Chemistry and the National Lung and Heart Institute at Imperial College London, demonstrated that their probe quickly and accurately detects the enzyme in modified E. Coli cells.

“This new probe will provide real-time and easily measured responses to diagnostic enzymes.”

— Professor Nicholas Long

They are now expanding this proof-of-concept study, published in the Journal of the American Chemical Society and funded by the British Heart Foundation (BHF), with the hope of creating rapid tests for cardiovascular problems and a new way to track long-term conditions.

The build-up of plaque in the arteries – known as atherosclerosis – can lead to coronary artery disease and stroke, and is one of the leading causes of death in the Western world.

As atherosclerosis progresses, intraplaque haemorrhages (IPHs) can occur when portions of the plaque break away from the artery walls. These events can lead to the formation of more vulnerable plaques and blood clots, restricting blood flow to the heart and the brain and potentially leading to chronic diseases or catastrophic events like strokes.

Quick identification of cardiovascular diseases

Detecting IPHs and their impacts would therefore provide a warning system and allow early diagnosis of vascular conditions. The research team designed a chemical probe that can detect rises in levels of an enzyme that accompanies IPHs and even plaque instabilities that precede IPHs.

“Ultimately, these probes could provide the basis for diagnostic tests at the GP, ambulances or in hospitals for quick identification of cardiovascular diseases.

— Dr Joe Boyle

Study co-lead Professor Nicholas Long, from the Department of Chemistry at Imperial, said: “Progress in the field of early cardiovascular disease has been rather limited and slow-paced but this new probe, and others that we are developing, will go a long way to addressing this by providing real-time and easily measured responses to diagnostic enzymes.”

Study co-lead Dr Joe Boyle, from the National Heart and Lung Institute, added: “Ultimately, these probes could provide the basis for diagnostic tests at the GP, ambulances or in hospitals for quick identification of cardiovascular diseases.

The probes could also provide real-time analysis of the underpinning biological processes involved in vascular disease, providing new insights and potentially new ways to track the progress of chronic disease.”

Illustration of a heart with molecules
Illustration of the probe’s molecular interactions. Credit: Angelo Frei

The team’s probe works by detecting an enzyme that is released in large quantities during IPHs, called heme oxygenase-1 (HO-1). Previous attempts to screen for HO-1 have been unreliable and cannot be used to detect real-time changes, but the new probe addresses both these issues.

The probe is made up of two components that can host fluorescent (glowing) molecules – one ‘donor’ that transfers the fluorescent molecules to the ‘acceptor’ component. When the probe comes into contact with HO-1, the bond between the two components is severed, leading to the build-up of the fluorescent molecules in the donor component.

This build-up causes an increase in the fluorescence intensity of the probe that can be detected using spectroscopy. In tests using modified E. coli cells containing human HO-1, the team detected a six-fold increase in the fluorescence of the probe.

Fast and sensitive diagnostic tests

Professor James Leiper, associate medical director at the British Heart Foundation, said: “Current methods to detect IPH rely on hospital-based imaging techniques that are both time-consuming and expensive.

“The current technology aims to produce a fast and sensitive diagnostic test that can be used at the time that a patient first presents with symptoms to allow early detection of IPH. Use of such a test would allow for more rapid treatment and improved outcomes for patients suffering from IPH.”

The team are now extending their studies to mammal and human cells. They have recently patented their probe and have received funding from the British Heart Foundation to make a new generation of probes for other cardiovascular and neurodegenerative diseases, and to carry out more in-depth biological investigations of the underlying mechanisms.

A Coumarin−Porphyrin FRET Break-Apart Probe for Heme Oxygenase-1’ by Edward R. H. Walter, Ying Ge, Justin C. Mason, Joseph J. Boyle, and Nicholas J. Long is published in Journal of the American Chemical Society.


Provided by Imperial College London

Stem Cells Create Early Human Embryo Structure in Major Advance for Fertility Research (Medicine)

Exeter scientists have discovered a simple, efficient way to recreate the early structure of the human embryo from stem cells in the laboratory. The new approach unlocks new ways of studying human fertility and reproduction.

Stem cells have the ability to turn into different types of cell. Now, in research published in Cell Stem Cell and funded by the Medical Research Council, scientists at the University of Exeter’s Living Systems Institute, working with colleagues from the University of Cambridge, have developed a method to organise lab-grown stem cells into an accurate model of the first stage of human embryo development.

The ability to create artificial early human embryos could benefit research into infertility, by furthering understanding of how embryos develop, and the conditions needed to avoid miscarriage and other complications. The embryo models can also be used to test conditions that may improve the development of embryos in assisted conception procedures such as IVF.

The new discovery comes after the team found that a human stem cell was able to generate the founding elements of a blastocyst – the very early formation of an embryo after a fertilised egg divides. Professor Austin Smith, Director of the University of Exeter’s Living Systems Institute, said: “Finding that stem cells can create all the elements of an early embryo is a revelation. The stem cells come from a fully-formed blastocyst, yet they are able to recreate exactly the same whole embryo structure. This is quite remarkable and unlocks exciting possibilities for learning about the human embryo.” 

The research has the potential to significantly advance understanding. Few human embryos are available for study, so until now, scientists have largely focussed on animal research, particularly mice, despite the fact that their reproductive systems differ significantly from humans. Around one in seven couples in the UK has difficulty conceiving.

In the research, the team arranged the stem cells into clusters and briefly introduced two molecules known to influence how cells behave in early development. They found that 80 per cent of the clusters organised themselves after 3 days into structures that look remarkably like the blastocyst stage of an embryo – a ball of around 200 cells that forms from the fertilised egg after 6 days. The team went on to show that the artificial embryos have the same active genes as the natural embryo.

The study was directed by Dr Ge Guo, of the University of Exeter’s Living Systems Institute, said: “Our new technique provides for the first time a reliable system to study early development in humans without using embryos. This shouldn’t be seen as a move towards producing babies in a laboratory, but rather as an important research tool that could benefit IVF and infertility studies”.

The next stage for the researchers is to understand how to develop the artificial embryos a few days further to study the critical period when an embryo would implant into the womb, which is when many embryos fail to develop properly. 

The paper is entitled ‘Naive stem cell blastocyst model captures human embryo lineage segregation’, and is published in Cell Stem Cell.

Featured image: The ability to create artificial early human embryos could benefit research into infertility. © University of Exeter


Provided by University of Exeter

Crohn’s Disease Patients Have Specific IgG Antibodies to Human Bacterial Flagellins (Medicine)

Last year, Charles O. Elson, M.D., demonstrated a potential preventive treatment for Crohn’s disease, a form of inflammatory bowel disease. He used a mouse model that included immune-reactive T cells from patients with Crohn’s disease in a flagellin peptide-specific immunotherapy. This study provided proof-of-principle that a flagellin-directed immunotherapy might provide similar benefits in patients. 

Now University of Alabama at Birmingham researchers have moved a step closer to possible clinical testing of this treatment, say Elson and co-first authors Katie Alexander, Ph.D., and Qing Zhao, M.D., Ph.D. Their study, published in the journal Gastroenterology, is the first to describe IgG antibodies in Crohn’s disease specific for human-derived flagellins of bacteria belonging to the Lachnospiraceae family. Knowledge of the specific flagellin epitopes that drive the pathogenic adaptive immune response in Crohn’s disease is necessary information for Elson’s potential triple-punch Crohn’s disease treatment. Goals of the treatment are removing or exhausting pathogenic T memory cells and increasing the number of immunomodulatory T regulatory cells.

Elson is a professor, Alexander an assistant professor and Zhao a postdoctoral fellow in the UAB Department of Medicine Division of Gastroenterology and Hepatology

Crohn’s disease and ulcerative colitis — another type of inflammatory bowel disease — are characterized by dysregulated adaptive immune responses to the microbiota in genetically susceptible individuals, but the human specificity of these responses had so far been largely undefined. Mouse microbiota flagellins have previously been defined as immunodominant antigens in Crohn’s disease. 

Flagellins are building blocks of the hairlike motility flagella that extend from the bacterial cell wall. Flagellin is a potent immune activator and antigen, and it is the only known microbial protein that has three receptors for innate immunity encoded in the host genome, in addition to immunoglobulin and T cell receptors. 

The UAB researchers individually probed blood sera from 87 healthy volunteers, 152 patients with Crohn’s disease and 170 patients with ulcerative colitis. They used protein arrays of microbiota bacterial flagellins of both mouse and human origin, and they analyzed sera for IgG and IgA antibody responses.

They found selective patterns of antibody reactivity to microbiota flagellins among the inflammatory bowel disease patients.

The Crohn’s disease patients — but not the ulcerative colitis patients — had augmented serum IgG antibodies to Lachnospiraceae flagellins from various species of Roseburia and one species of Eubacterium. These bacteria are normal residents in the human ileum, the third segment of the small intestine. A subset of the Crohn’s disease patients had very high responses, with antibodies against more than 10 different flagellins. 

crohns.5
Katie Alexander, Ph.D., and Charles O. Elson, M.D. © UAB

For that subset of Crohn’s disease patients, the multiflagellin hyper-reactivity was associated with indications of severe dysregulated immune response. Patients in the subset had: 1) elevated flagellin-specific T memory cells; 2) a reduced ratio of flagellin-reactive T regulatory to T effector cells; and 3) a high frequency of disease complications. 

“Thus,” Elson said, “Crohn’s disease patients displayed a strong adaptive immune response to human-derived Lachnospiraceae flagellins, which may be targeted for prognosis and future personalized therapies.”

Co-authors with Alexander, Zhao and Elson in the study, “Human microbiota flagellins drive adaptive immune responses in Crohn’s disease,” are Meagan Reif, Peter J. Mannon and Lennard Wayne Duck, UAB Department of Medicine; and Alexander F. Rosenberg, UAB Department of Microbiology

Support came from Litwin IBD Pioneers grant 32655, Crohn’s and Colitis Foundation of America; Department of Veterans Affairs grant CX0001530; National Institutes of Health grant AI007051; and a Synergy Award from the Rainin Foundation.

At UAB, Elson holds the Basil I. Hirschowitz Endowed Chair in Gastroenterology.

Featured image: Knowledge of the specific flagellins that drive the pathogenic immune response in Crohn’s disease is a step toward a potential preventive treatment. © UAB


Reference: Alexander KL, Zhao Q, Reif M, Rosenberg AF, Mannon PJ, Duck LW, Elson CO. Human microbiota flagellins drive adaptive immune responses in Crohn’s disease. Gastroenterology. 2021 Apr 9:S0016-5085(21)00633-8. doi: https://www.gastrojournal.org/article/S0016-5085(21)00633-8/abstract


Provided by University of Alabama at Birmingham

Intestinal Polyps in Close Relatives Can Increase Risk of Colorectal Cancer (Medicine)

Cancer of the colon and rectum is one of the deadliest forms of cancer, and has in recent years affected growing numbers of young people. In the largest registry study to date, researchers at Karolinska Institutet and Harvard University in the USA demonstrate a possible connection between colorectal polyps in close relatives and the risk of developing colorectal cancer. The study, which is published in The British Medical Journal, is of potential consequence for screening procedures.

Colorectal cancer is the second deadliest form of cancer in the world, according to the World Health Organisation (WHO). While lifestyle factors, such as overweight and sedentariness, increase the disease risk, there is also a known hereditary factor.

Most people diagnosed with the disease are over 65, but in a growing number of countries the proportion of young people affected is increasing.

Local colorectal cancer can be treated with a good prognosis; prospects are much worse, however, for patients with metastases. In Sweden, people over 65 are offered colonoscopy screening, but more knowledge is needed about which individuals should be offered this prophylactic examination. 

Patient data from ESPRESSO

The disease is preceded by polyps in the mucosa of the colon. Researchers at Karolinska Institutet and Harvard University have now conducted the largest registry study to date on the relationship between colorectal cancer, and having a first-degree relative (i.e. parents and siblings) with a  colorectal polyp. 

The study included 68,060 patients with colorectal cancer and 333,753 healthy controls matched for parameters such as age and sex. Data on colorectal cancer and polyps were sourced from the ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden) cohort.

All other patient data were drawn from Swedish healthcare registries. The researchers also took the hereditariness of colorectal cancer into account. They found that approximately 8.4 per cent of the participants with colorectal cancer had a sibling or parent with colorectal polyps, as opposed to 5.7 per cent of the control group.

Several hereditary risk relationships

The results show that heredity for colorectal polyps had a 40 per cent increased risk of colorectal cancer. The researchers found what appear to be several hereditary risk relationships.

Mingyang Song. Photo: Harvard University.

“The risk was double in people with at least two first-degree relatives with polyps or a first-degree relative who had a colorectal polyp diagnosed before the age of 60.” says the study’s first author Mingyang Song, researcher at Harvard University.

A weakness of the study is the lack of information on other risk factors of colorectal cancer, such as lifestyle factors as well as the size and spread of the polyps. More research is now needed to corroborate the results.

Jonas F. Ludvigsson. Photo: Ulf Sirborn

“If additional studies reveal a link between a family history of polyps and the risk of colorectal cancer, it is something to take into account in the screening recommendations, especially for younger adults,” says Jonas F. Ludvigsson, paediatrician at Örebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “I really hope that this study can help doctors in Sweden and elsewhere identify patients at a higher risk of colorectal cancer.”

The study was financed by the National Institutes of Health and the American Cancer Society. Jonas F. Ludvigsson heads an unrelated study commissioned by the Swedish IBD Quality Registry (SWIBREG) financed by Janssen. There are no other reported conflicts of interest.

Featured image: Illustration of intestinal polyps that can cause colorectal cancer. Illustration: Getty Images.


Publication

“Risk of colorectal cancer in first degree relatives of patients with colorectal polyps: nationwide case-control study in Sweden”. Mingyang Song, Louise Emilsson, Bjorn Roelstraete, Jonas F. Ludvigsson, British Medical Journal, May 4 2021, doi: 10.1136/bmj.n877.


Provided by Karolinska Institute

New Marker Predicts Benefit Of Radiotherapy For Early-stage Breast Cancer (Medicine)

A study involving researchers at Karolinska Institutet and Gothenburg University has found that low levels of a protein called PDGFRb are associated with particularly good results of radiotherapy in women with early-stage breast cancer. The study, which is published in the journal Clinical Cancer Research, also suggests that the efficacy of radiotherapy can be improved with drugs that block this protein.

Fredrik Wärnberg
Fredrik Wärnberg, professor at Sahlgrenska Academy, Gothenburg University. Photo: Lennart Wiman

Some 900 women in Sweden are diagnosed with DCIS (ductalcarcinoma in situ), the earliest possible form of invasive breast cancer. Standard treatment is surgery and subsequent radiotherapy. Although the prognosis is generally good, some ten per cent of patients suffer a recurrence within ten years of diagnosis.

“It is well-known that the benefits of radiotherapy are individual, so we need to find predictive markers that can be used to avoid unnecessary or ineffective radiotherapy,” says the study’s co-last author Fredrik Wärnberg, professor at the Department of Clinical Sciences at Gothenburg University’s Sahlgrenska Academy.

Supporting tissue can influence therapeutic effect

Arne Östman
Arne Östman, professor at Karolinska Institutet. Photo: private

While previous studies have focused mainly on markers in the tumour cells themselves, recent findings show that supporting tissue around the tumour cells can affect the therapeutic effect of DCIS. Studies in cell and animal models have demonstrated that the efficacy of radiotherapy can be influenced by fibroblasts, which are a type of supporting cell in the breast cancer tissue.

Arne Östman’s research group at Karolinska Institutet and Professor Wärnberg’s group have now analysed a large tissue collection from a randomised radiotherapy study (SweDCIS). Their analyses showed that low levels of a particular fibroblast protein, PDGFRb, are associated with especially high radiotherapeutic efficacy for women with DCIS.

Several projects underway

Several new studies have been launched, one a collaboration with the US company PreludeDx on breast cancer diagnostics.

Carina Strell
Carina Strell, researcher at Uppsala University and Karolinska Institutet. Photo: private

“The treatment guidelines of DCIS might need to be changed if these studies confirm our original findings,” says the study’s first author Carina Strell, researcher at the Department of Immunology, Genetics and Pathology, Uppsala University, and the Department of Oncology-Pathology, Karolinska Institutet.

The results of this newly published study also indicate that the efficacy of radiotherapy can be improved if combined with the blocking of PDGFRb. The researchers now plan to interrogate this further in experimental cell and animal models before any studies on patients can begin.

The study was financed by the Swedish Cancer Society, BRECT, the Swedish Research Council, STARGET the Linné grant scheme, the Cancer Research Funds of Radiumhemmet, the EU Caffein ITN network, BRECT at Karolinska Institutet, Region Stockholm and the Research Council of Norway.

Arne Östman receives research grants from Eli Lilly and IPSEN. Co-authors Erik Holmberg and Per Karlsson have a research contract with PFS Genomics. Jonas Bergh receives research grants from Amgen, AstraZeneca, Bayer, Merck, Roche, Pfizer and Sanofi Aventis, all with Karolinska Institutet and/or Karolinska University Hospital as recipient. Fredrik Wärnberg has received financing from PreludeDx for tumour collection with Uppsala University Hospital (Akademiska sjukhuset) as recipient. Troy Bremer is employed and has proprietary interests (including patents) in PreludeDx, receives commercial research grants on behalf of the company from the National Cancer Institute, and is the co-inventor of one or more patents/patent applications licensed to or owned by PreludeDx.

Featured image: Illustration of the DCIS © Illustration: Getty Images


Publication

“High PDGFRb expression predicts resistance to radiotherapy in DCIS within the SweDCIS randomized trial”. Carina Strell, Dick Folkvaljon, Erik Holmberg, Aglaia Schiza, Viktoria Thurfjell, Per Karlsson, Jonas Bergh, Troy Bremer, Lars A. Akslen, Fredrik Wärnberg, Arne Östman. Clinical Cancer Research, online 5 May 2021, doi: 10.1158/1078-0432.CCR-20-4300.


Provided by Karolinska Institute

Unsolved Mysteries: Stevens Senior Investigates Unanswered Questions in Pure Math (Maths)

Jonathan Cerqueira’s senior research project aims to shed new light on the 50-year-old Gottschalk surjunctivity conjecture in the study of cellular automata

Everybody loves a good mystery – playing detective to solve a theft, a murder, a kidnapping, whether a cellular automaton defined on the Cayley graph of a group can be injective but not surjective…

What? You haven’t heard of that last one? Then you haven’t talked with Jonathan Cerqueira ’21, whose Stevens Institute of Technology senior research project is focused on deepening our understanding of the Gottschalk surjunctivity conjecture, an abstract mathematical concept first proposed in 1973.

“The surjunctivity conjecture is a major open problem at the intersection of abstract algebra, dynamical systems, and graph theory,” explained Jan Cannizzo, teaching assistant professor in the Department of Mathematical Sciences, and Cerqueira’s project advisor. “Jonathan’s work does not directly tackle this conjecture, but by changing the context of the problem, he’s allowing us to think about it in different ways.”

To infinite graphs, and beyond!

Cayley graph
This portion of a Cayley graph shows colors that will eventually evolve into new patterns that form the basis of the mystery Cerqueira’s research aims to help understand. © SIT

Cerqueira is studying cellular automata in a very general setting. These are discrete dynamical systems that can exhibit surprisingly complex behavior. Suppose you take an infinite, highly symmetric network of vertices and edges, assign every vertex one of a handful of colors, and then create a rule for changing the color of each vertex based on the colors of its neighbors. Now apply your rule over and over again. How will the initial coloring evolve?

“Imagine that you have two different colorings of a specific kind of graph known as a Cayley graph,” Cannizzo explained. “Over time, those two colorings evolve. If they always evolve to two distinct colorings and never merge into the same state, the system is injective. If there’s a particular coloring that can serve as the initial state but that never appears as a future state, the system is surjective. And there’s this big open question that asks whether it can be injective, but not surjective. In other words, can the dynamical system defined by such an automaton contain a copy of itself?”

“The answer is ‘yes,’ if we convert the Cayley graph in a particular way,” Cerqueira said. This involves thinking about the underlying graph not as the Cayley graph of a group, but as the so-called Schreier graph of a monoid. “Several infinite families of examples demonstrate this property and, given some assumptions, it can be shown such automata are abundant. Now I’m working on generalizing this idea.”

Photo of Jonathan Cerqueira
Jonathan Cerqueira ’21 is bringing new light to a half-century old abstract mathematical problem that involves infinite, highly symmetric graphs as might be seen in the edges of this colorful background image. © SIT

“Jonathan is modest, but I think he’s discovered a new, large family of automata that exhibits this phenomenon of injectivity but not surjectivity,” Cannizzo added. “It puts the surjunctivity conjecture in context allows us to think about it differently, and he’s trying to understand how large this class of examples that he’s been able to study actually is.”

‘It’s satisfying to come up with original ideas’

To address this complex problem, Cerqueira relied on a surprisingly simple tool.

“I did a lot of staring at whiteboards,” he said with a laugh. “You stare at the whiteboard for two hours trying to understand the problem. You don’t get anywhere. You walk away from it, and 20 minutes later, you get an idea, and then come back to work on it a bit more. And it’s typical to have what seems like a million ideas, and then most of them fall flat, and you have to try again. I think it’s how a lot of mathematical research works!”

Clearly, the rewards outweigh the challenges.

“It’s satisfying to come up with original ideas,” Cerqueira said. “It’s our hope to get these findings published in a journal. That would be exciting.”

That element of problem-solving is what initially drew Cerqueira to the field of mathematics.

“Math sparked my curiosity and made me want to seek answers,” he recalled. “I’d mess around on Desmos graphing calculators or try to teach myself some calculus. In high school I started to see math as something truly amazing when I discovered Numberphile and other math-related YouTube channels. That’s also when I found out about mathematicians, and the idea that math is an ongoing, evolving field that could be a career path for me.”

Cerqueira soon became attracted to the universality of math, as well as its relatively lower burden to deliver immediate research results.

graph of cellular automaton
A Schreier graph © Stevens Institute of Technology

“If some alien beings dropped down to Earth from a different universe, they might have a different sense of aesthetics, a different language, and a different set of scientific laws,” he explained. “Despite that, they might still have studied the math we have, or they’d be able to borrow from our mathematical works far more quickly than our scientific or cultural ones. I also love the lax nature of math studies. With science, medicine, or engineering, you face a fair amount of pressure to demonstrate immediate value for your research direction. With math, people often decide their research directions based on their interests or open questions they want to take a crack at. With pure math, people understand that over the span of a few hundred years, something can go from recreational math, to something studied for its own sake, to something with broad applications, as happened with topology, number theory, and, to a lesser degree, cellular automata.”

Stevens offered Cerqueira the opportunity to immerse himself in that supportive environment while also experiencing the broader range of scientific disciplines.

Cayley graph
The famous novel suggests that A Tree Grows in Brooklyn, but Cerqueira grew this mathematical tree – connected graphs that, like trees, never cycle back to their beginnings – in Hoboken, at Stevens Institute of Technology.

“I chose Stevens for its slightly smaller campus, as well as the atmosphere that comes along with an engineering school,” he said. “Everyone’s always doing something, working on a project, or involving themselves in some organization. I’ve been involved in seven clubs and organizations, and I’ve met so many people. I enjoy the liveliness, Hoboken, the history of the school, and most of all, I love the pace of it. The classes, clubs, and everything move fast. It feels like I was a freshman only yesterday.”

For now, Cerqueira’s research continues – both into surjunctivity, and also into which doctoral program he’ll attend this fall.

“Jonathan has made our department very proud, especially because he’s going to go on to pursue his Ph.D. in mathematics right out of his pure and applied mathematics bachelor’s degree, which he’s finishing in only three years,” Cannizzo said. “He was my student in a class I taught on mathematical proofs, and I was impressed with his mathematical skills. When he asked me about doing some research together the following summer, I was happy to agree, and it’s been a great pleasure working with him. By changing the context of the Gottschalk surjunctivity conjecture and pursuing this related, parallel question, he has helped put the conjecture into perspective.”


Provided by Stevens Institute of Technology

Long-acting Injectable Medicine as Potential Route To COVID-19 Therapy (Medicine)

Researchers from the University of Liverpool have shown the potential of repurposing an existing and cheap drug into a long-acting injectable therapy that could be used to treat Covid-19.

In a paper published in the journal Nanoscale, researchers from the University’s Centre of Excellence for Long-acting Therapeutics (CELT) demonstrate the nanoparticle formulation of niclosamide, a highly insoluble drug compound, as a scalable long-acting injectable antiviral candidate.

The team started repurposing and reformulating identified drug compounds with the potential for COVID-19 therapy candidates within weeks of the first lockdown. Niclosamide is just one of the drug compounds identified and has been shown to be highly effective against SARS-CoV-2 in a number of laboratory studies.

Using their expertise in the fields of materials chemistry, long-acting drug delivery and pharmacology, CELT scientists used nanoprecipitation to form redispersible solid drug nanoparticle formulations of niclosamide that can be stored as solids, reconstituted with water and utilised as long acting injectables. Their research has demonstrated sustained circulating drug concentrations may be maintained for the duration of early infection after a single injection.

CELT is co-directed by pharmacologist Professor Andrew Owen and materials chemist Professor Steve Rannard at the University of Liverpool.

Professor Steve Rannard said: “Repurposing drug compounds is much more than using existing medicines for a new disease. The existing active drug compound needs to be shown to be active at a significant level, then reformulated to address new challenges. The conventional route of administration may also not be relevant and modifying the way the patient receives the drug compound is highly critical to efficacy. Niclosamide is an ideal candidate to be taken forward as a potential long acting injectable therapeutic to treat Covid-19.

“This is still in early-stage development but the CELT team are currently working with a contract manufacturing organisation to take this forward towards scale up and clinical manufacture. This work is progressing well and if successful, human trials would be next. We envisage a future `Test-and-Treat’ scenario where infected people are treated at the point of diagnosis with the full course of therapy in one injection.”

Professor Andrew Owen said: “Repurposing of medicines for SARS-CoV-2 has yielded mixed results, with some clear successes for immunomodulatory drugs such as dexamethasone, and work underway to repurpose drugs like favipiravir and molnupiravir that were designed for other viruses.

“The ultimate utility of our long-acting injectable can only be determined in adequately powered and well controlled randomised clinical trials but unlike other drugs that have been explored for repurposing niclosamide target concentrations may be achievable in humans. The formulation has shown great promise in preclinical studies at a time when it is increasingly evident that drugs are urgently required to compliment the vaccines.

“A global pandemic requires a global solution, and it is critical that interventions are available to everyone and not to the privileged few. Accordingly, we are currently working to remove obstacles to availability in low- and middle-income countries to ensure equitable access if clinical success is ultimately demonstrated.”

This research paper builds on previous reports released from the team in April 2020 and published in Clinical Pharmacology and Therapeutics. The CELT team have strongly advocated in further publications in the British Journal of Clinical Pharmacology, that repurposing of drugs requires new strategies that encompass reformulation and specific dose optimisation that addresses the needs of SARS-CoV-2 treatment.

CELT is focused on repurposing existing medicines into slow-release formulations where drug effectiveness can be sustained over several months. This `long-acting’ technology has already been successfully implemented in the fields of contraception and schizophrenia. It also has the potential to bolster global efforts to tackle – and even eliminate – major diseases affecting low- and middle-income countries, including HIV/AIDS.

The long-acting therapy development from the team was initiated and supported by funds from the EPSRC and the progression to scale-up and manufacture has received support from Unitaid. The team are actively seeking partners for the next steps of product development and translation.

Established as part of a £30.5 million ($40m) international research consortium, primarily funded by Unitaid, CELT is the first of its kind in the world. For further information, please visit the CELT website. You can also follow the centre on Twitter.

The paper `Scalable nanoprecipitation of niclosamide and in vivo demonstration of long-acting delivery after intramuscular injection’ (doi:10.1039/D1NR00309G) is published in Nanoscale.


Provided by University of Liverpool

Fundamental Regulation Mechanism of Proteins Discovered (Biology)

A research team led by Göttingen University find novel switch in proteins with wide-ranging implications for medical treatments

Proteins perform a vast array of functions in the cell of every living organism with critical roles in almost every biological process. Not only do they run our metabolism, manage cellular signaling and are in charge of energy production, as antibodies they are also the frontline workers of our immune system fighting human pathogens like the coronavirus. In view of these important duties, it is not surprising that the activity of proteins is tightly controlled. There are numerous chemical switches that control the structure and, therefore, the function of proteins in response to changing environmental conditions and stress. The biochemical structures and modes of operation of these switches were thought to be well understood. So a team of researchers at the University of Göttingen were surprised to discover a completely novel, but until now overlooked, on/off switch that seems to be a ubiquitous regulatory element in proteins in all domains of life. The results were published in Nature.

Professor Kai Tittmann © Kamala Elisa Tittmann

The researchers investigated a protein from the human pathogen Neisseria gonorrhoeae that causes gonorrhea, a bacterial infection with over 100 million cases worldwide. This disease is typically treated with antibiotics but increasing rates of antibiotic resistance pose a serious threat. In order to identify new treatments, they studied the structure and mechanism of a protein that is a key player in carbon metabolism of the pathogen. Surprisingly, the protein can be switched on and off by oxidation and reduction (known as a “redox switch). The scientists suspected this was caused by a common and well-established “disulfide switch” formed between two cysteine amino acids. When they deciphered the X-ray structures of the protein in the “on” and “off” state at the DESY particle accelerator in Hamburg, Germany, they were hit by an even bigger surprise. The chemical nature of the switch was completely unknown: it is formed between a lysine and a cysteine amino acid with a bridging oxygen atom.

“I couldn’t believe my eyes,” says Professor Kai Tittmann, who led the study, when he remembers seeing the structure of the novel switch for the first time. “We thought initially that this must have formed artificially as a by-product of the experimental process as this chemical entity was unknown.” However, numerous repetitions of the experiments always gave the same result and an analysis of the protein structure database further disclosed that there are many other proteins that very likely possess this switch, which apparently escaped earlier detection as the resolution of the protein structure analysis was insufficient to detect it for certain. The researchers admit that good fortune was on their side because the crystals they measured allowed the protein structure to be determined at extremely high resolution, meaning the novel switch couldn’t be missed. “The extensive screening for high-quality protein crystals has really paid off, I couldn’t be happier,” says Marie Wensien, first author of the paper.

The researchers believe the discovery of the novel protein switch will impact the life sciences in numerous ways, for instance in the field of protein design. It will also open new avenues in medical applications and drug design. Many human proteins with established roles in severe diseases are known to be redox-controlled and the newly discovered switch is likely to play a central role in regulating their biological function as well.

Researchers from the Göttingen Center for Molecular Biosciences (GZMB), the Faculty of Chemistry of the University of Göttingen, the Max Planck Institute for Biophysical Chemistry and the Hannover Medical School contributed to the study.

Featured image: Protein structure with the newly identified switch between a cysteine and lysine residue showing its structure and electron density. This discovery has wide-reaching implications for understanding and treating diseases. © K. Tittmann


Original publication: Marie Wensien et al. A lysine-cysteine redox switch with an NOS bridge regulates enzyme function. Nature 2021. DoI: 10.1038/s41586-021-03513-3


Provided by University of Göttingen