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Targeting a pathway that is essential for the survival of certain types of acute myeloid leukaemia could provide a new therapy avenue for patients, the latest research has found.

Researchers from the Wellcome Sanger Institute found that a specific genetic mutation, which is linked with poor prognosis in blood cancer, is involved in the development of the disease when combined with other mutations in mice and human cell lines.

The study, published today (30th April) in Nature Communications, provides a greater understanding of how the loss-of-function mutation in the CUX1 gene leads to the development and survival of acute myeloid leukaemia. The findings suggest that targeting a pathway that is essential for these cancer cells to continue growing could lead to new targeted therapies for some patients.

Acute myeloid leukaemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy and prolonged hospital admissions. It typically develops in cells within the bone marrow to crowd out the healthy cells, in turn leading to life-threatening infections and bleeding. Mainstream AML treatments have remained unchanged for decades and fewer than one in three people survive the cancer*.

Previously through large-scale DNA sequencing analysis, researchers at the Wellcome Sanger Institute found that loss-of-function mutations in the CUX1 gene on chromosome 7q were seen in several types of cancer, including AML, where it is associated with poor prognosis**. However, the role of this gene in AML development is unclear.

In this new study, the team used CRISPR/Cas9 gene-editing technology to show that lack of functioning CUX1 leads to expansion of certain types of blood stem cells, which are defective in a type of regulated cell death known as apoptosis. They found that the loss of CUX1 causes increased expression of the CFLAR gene -- which encodes a protein that restrains apoptosis -- potentially providing a means for mutated cancer cells to evade cell death and propagate. The researchers showed that targeting CFLAR, or apoptosis evasion pathways in general, could be a possible treatment for those living with this type of AML that is linked to poor prognosis. Currently, there are no clinically approved drugs that target CFLAR.

Dr Saskia Rudat, co-first author and Postdoctoral Fellow at the Wellcome Sanger Institute, said: "By investigating the role of CUX1 further, we now have new insight into how this gene, and the lack of it when mutated, plays a key role in the survival of blood cancer cells. While this mutation doesn't seem to cause the development of malignant disease on its own, focusing on the pathways involved with CUX1 is a good target for further research."

Dr Emmanuelle Supper, co-first author and Postdoctoral Fellow at the Wellcome Sanger Institute, said: "By building on our previous analysis, this research has allowed us to gain crucial information about the development of this disease, and would not have been possible without the new and exciting CRISPR/Cas9 and genome sequencing technologies that enable us to investigate genetic weaknesses in cancer. Understanding more about the genetic basis of disease, and how multiple mutations come together to cause blood cancer is vital if we hope to save lives in the future."

Dr Chi Wong, senior author and Wellcome Clinical Fellow at the Wellcome Sanger Institute and Honorary Consultant Haematologist at Addenbrooke's Hospital, said: "Acute myeloid leukaemia is a devastating disease, which is currently difficult to treat, especially in cases characterised by genetic lesions such as loss of CUX1 and chromosome 7q deletions. This new study provides evidence that could be used to help develop new targeted treatment for some people living with acute myeloid leukaemia, offering hope for this group of patients who unfortunately are more likely to have a poor prognosis."

The future of particle acceleration has begun. Awake is a promising concept for a completely new method with which particles can be accelerated even over short distances. The basis for this is a plasma wave that accelerates electrons and thus brings them to high energies. A team led by the Max Planck Institute for Physics now reports a breakthrough in this context. For the first time, they were able to precisely time the production of the proton microbunches that drive the wave in the plasma. This fulfills an important prerequisite for using the Awake technology for collision experiments.

How do you create a wave for electrons? The carrier substance for this is a plasma (i.e., an ionized gas in which positive and negative charges are separated). Directing a proton beam through the plasma creates a wave on which electrons ride and are accelerated to high energies.

The proton source of Awake is the SPS ring at Cern, a pre-accelerator for the 27-kilometer circumference ring of the Large Hadron Collider (LHC). It produces proton bunches about 10-cm long. "However, in order to generate a large amplitude plasma wave, the proton bunch length must be much shorter - in the millimeter range," explains Fabian Batsch, PhD student at the Max Planck Institute for Physics.

The scientists take advantage of self-modulation, a "natural" interaction between the bunch and plasma. "In the process, the longer proton bunch is split into high-energy proton microbunches of only a few millimeters in length, building the train beam," says Batsch. "This process forms a plasma wave, which propagates with the train travelling through the plasma field."

Precise timing allows ideal electron acceleration

However, a stable and reproducible field is required to accelerate electrons and bring them to collision. This is exactly what the team has found a solution for now. "If a sufficiently large electric field is applied when the long proton bunch is injected and the self-modulation is thus immediately set in motion."

"Since the plasma is formed right away, we can exactly time the phase of the short proton microbunches," says Patric Muggli, head of the Awake working group at the Max Planck Insstitute for Physics. "This allows us to set the pace for the train. Thus, the electrons are caught and accelerated by the wave at the ideal moment."

First research projects in sight

The Awake technology is still in the early stages of development. However, with each step toward success, the chances of this accelerator technology actually being used in the coming decades increase. The first proposals for smaller accelerator projects (e.g., for example to study the fine structure of protons) are to be made as early as 2024.

According to Muggli, the advantages of the novel accelerator technology - plasma wakefield acceleration - are obvious: "With this technology, we can reduce the distance needed to accelerate electrons to peak energy by a factor of 20. The accelerators of the future could therefore be much smaller. This means: Less space, less effort, and therefore lower costs."

Boston, MA (April 30, 2021) - A new study, presented today at the AATS 101st Annual Meeting, shows significant reduction in post-operative use of Schedule II opioids for pain management following robotic surgery. To address the on-going issues of opioid overuse and abuse, the study aimed to examine the use of painkillers in Enhanced Recovery After Thoracic Surgery (ERATS) protocols and determine the impact of alternative pain management approaches on clinical outcomes.

An Institutional Review Board-approved retrospective analysis of a prospectively maintained thoracic surgery database was performed on all patients undergoing elective robotic thoracic procedures from 7/1/2019 to 9/14/2020. The main pain management component of ERATS included opioid-sparing analgesics, infiltration of liposomal bupivacaine (a long-acting local anesthetic) 1:1 v/v dilution with normal saline to 9 intercostal spaces as intercostal nerve blocks and to surgical wounds as local and regional analgesia, as-needed potent opioids (schedule II narcotics like oxycodone), scheduled administration of tramadol (weak schedule IV opioid) and tailoring post-discharge opioid dispenses based on type and amount of opioid consumed inpatient. Protocol optimization included replacing saline diluent with 0.25% bupivacaine (a short-acting local anesthetic) and switching round-the-clock administration of tramadol to as-needed scheduling.

324 patients met the inclusion criteria (159 in the original ERATS and 183 in the optimized ERATS protocol). The two cohorts were comparable with respect to demographics, types of robotic procedures, and final pathologic diagnosis. Data analysis was performed based on robotic procedure stratification. There was no difference in postoperative complications, hospital length-of-stay or re-admission. There was a significant reduction of in-hospital (due to the elimination of scheduled tramadol) and post-discharge opioid consumption (particularly schedule II opioids with addictive tendency) in the optimized ERATS cohort. The optimized ERATS patients had lower incidences of opioid prescriptions filled and refilled after discharge, an indicator of adequate initial pain control. Subjective pain levels were similar between two cohorts. Much

According to Dao M. Nguyen, M.D., Professor of Clinical Surgery and Co-Leader of the Site Disease Group Lung at University of Miami Health System/Sylvester Comprehensive Cancer Center, "An important part of ERATS is continual evaluation of clinical outcomes and implementation modifications to achieve more superior quality improvement. We are very gratified with our results showing that by implementation of simple modifications to our pre-existing, established ERATS protocol has led to drastically reduced reliance on opioids, particularly schedule II opioids such as oxycodone or hydromorphone, for pain control both in-hospital and at discharge following robotic thoracoscopic procedures. I would encourage all thoracic surgeons to consider incorporating such peri-operative care protocol to their practice."

The ERATS protocol, such as the one presented by Nguyen and colleagues from the University of Miami, represents an important platform for surgeons in general and thoracic surgeons to aim for opioid-free postoperative pain management at discharge. It was shown in this study that 42 percent of the patients in the study required some form of prescribed narcotics for at-home pain management after surgery (compared to 83 percent before protocol optimization), with only nine percent of patients receiving prescription for schedule II opioids (compared to 66 percent prior to protocol modification).

What The Study Did: Changes in the demographic characteristics and clinical outcomes of pediatric emergency department visits for mental health conditions during the COVID-19 pandemic are described in this study.

Authors: Polina Krass, M.D., of the Children's Hospital of Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.8533)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: This simulation study estimates key populations and performance indicators along the COVID exposure notification chain of the SwissCOVID digital contact tracing app last year in Zurich, Switzerland.

Authors: Viktor von Wyl, Ph.D., of the University of Zurich, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.8184)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Supporting female survivors of childhood maltreatment is critical to disrupting intergenerational abuse as new research from the University of South Australia shows a clear link between parents who have suffered abuse and the likelihood of their children suffering the same fate.

The finding amplifies an acute need for far better support for victims of child maltreatment to ensure safer and more nurturing environments for all children.

Funded by the NHMRC and the Channel 7 Children's Research Foundation, and published in The Lancet Public Health today, the study found that most child maltreatment is occurring among families caught up in intergenerational cycles of child abuse and neglect - 83 per cent of the cases of substantiated child maltreatment were the children of mothers with a history of child protection contact.

The study showed that 30 per cent of the children of mothers with substantiated maltreatment as a child were also the subject of substantiated maltreatment (by age 12). In comparison, for children of mothers with no history of child protection contact, the rate of substantiated abuse was five per cent.

The study quantified the intergenerational transmission of child maltreatment in South Australia using a large linked data set from the internationally recognised iCAN study, which included 38,556 mother-child pairs - some of whom had experienced abuse and some who had not - based on SA child protection data.

The children of mothers exposed to substantiated maltreatment and removal into out-of-home care were at greatest risk of child maltreatment, with 14 times the risk of experiencing substantiated maltreatment, and 26 times the risk of being removed, reflecting extreme child protection concerns.

Lead Investigator, UniSA's Professor Leonie Segal, says the findings highlight the urgent need to do more to help these children and families - from early in life into adulthood - not just for their own well-being, but also as an intervention opportunity to protect their unborn children and future generations.

"The results are especially concerning given the generally poor outcomes for victims of child abuse or neglect across multiple health and social domains," Prof Segal says.

"Abused children often grow into adults with poor impulse control, a heightened sense of shame, an over-alertness to threat, easily triggered, with extreme levels of distress that can result in early substance use and mental illness, compounding harms.

"When these children become parents, their capacity for compassion or trust can be impaired, they often cannot see the needs of their own children, and can find it extremely difficult to provide the nurturing parenting that they would so want to offer.

"Our results are consistent with well-described biological mechanisms for intergenerational transmission of child maltreatment, through the lasting impacts of assault or neglect, altered brain development and disturbed relational patterning, strongly suggesting the observed associations are causal, and at least partly preventable.

"Children and parents need help. Healing their trauma is an ethical imperative, but also offers large health and economic payoffs to families and the wider community.

"The increased risk of child abuse and neglect among children whose mothers have experienced maltreatment themselves as children, is extreme and too significant to ignore - and they are already known to the service system.

"If only we could disrupt the intergenerational transmission pathway, we could prevent the lion's share of child maltreatment and turn around the life trajectories of our most vulnerable children and offer protection to future generations."

WESTMINSTER, Colorado - April 30, 2021 - Palmer amaranth is a hard-to-control noxious weed that can significantly reduce crop yields. It was first introduced in Minnesota in 2016 through contaminated seed mixes used for conservation plantings.

Fortunately, Minnesota regulators were prepared. They had already declared Palmer amaranth a prohibited noxious weed in 2015, and they quickly added the weed's seed to their prohibited list by emergency order. As a result, they were able to take prompt action to identify and eradicate newly emerged infestations.

A research paper featured in the journal Weed Technology documents Minnesota's experiences, including the timeline to eradication, best practices and lessons learned.

Of the sites sown with contaminated seed mixes, Palmer amaranth was found at eight. With intensive scouting, torching, prescribed burning and herbicide application in 2016 and 2017, those infestations were eradicated. Similar results were achieved in 2018, 2019 and 2020 when populations of Palmer amaranth were discovered at new locations across the state.

The authors point to several success factors, including broad cooperation among the commissioner of agriculture, legislative committees, commodity groups and farmers. Once an aggressive protocol to address Palmer amaranth was established, critical information could be quickly disseminated across the agricultural community and to the public. One example: When officials determined that manure from livestock could contain viable Palmer amaranth seeds, they were able to quickly share the information with growers and take steps to eliminate the risk.

"Establishing the appropriate regulatory framework, providing funding, fostering collaboration among partners and actively responding to new infestations have been critical to Minnesota's success of combatting Palmer amaranth," says Eric Yu, plant health specialist with the Minnesota Department of Agriculture.

Yu cautions, though, that lasting success will depend on regional cooperation among states to manage infestations and to address the many pathways that can contribute to Palmer amaranth's spread.

The detection of the axion would mark a key episode in the history of science. This hypothetical particle could resolve two fundamental problems of Modern Physics at the same time: the problema of Charge and Parity in the strong interaction, and the mystery of dark matter. However, in spite of the high scientific interest in finding it, the search at high radio frequency -above 6 GHz- has been almost left aside for the lack of the high sensitivity technology which could be built at reasonable cost. Until now.

The Instituto de Astrofísica de Canarias (IAC) will participate in an international collaboration to develop the DALI (Dark-photons & Axion-Like particles Interferometer) experiment, an astro-particle telescope for dark matter whose scientific objective is the search for axions and paraphotons in the 6 to 60 GHz band. The prototype, proof of concept, is currently in the design and fabrication phase at the IAC. The white-paper describing the experiment has been accepted for publication in the Journal of Cosmology and Astroparticle Physics (JCAP).

Predicted by theory in the 1970's, the axion is a hypothetical low mass particle which interacts weakly with standard particles such as nucleons and electrons, as well as with photons. These proposed interactions are studied to try to detect the axion with different types of instruments. One promising technique is to study the interaction of axions with standard photons.

"Axions 'mix' with photons under the action of a strong external magnetic field, such as those produced by the superconducting magnets in particle detectors or those used for medical diagnostics by magnetic resonance, and produce a weak radio or microwave signal. This signal has been looked for in a variety of experiments since the end of the 80's, and it is just the signal that we want to detect now with DALI, although in a new almost unexplored range of parameters, which will be accessible for the first time thanks to this experiment", explains Javier De Miguel, an IAC researcher and the first author of the study.

The first axion detectors, made in the 80's and 90's, used a resonant cavity which, inside a super-magnet, amplified the weak microwave signal predicted from the axion, trying to bring it into a power range detectable by scientific instruments. Unfortunately, the size of the cavity is inversely proportional to the scanning frequency and, for the axion, the cavies were too small to be made for frequencies greater than some 6 GHz.

For this reason, the new experiment brings together the most promising techniques for scanning at high frequencies, and includes it in a practical design to which is also added the capacity of astro-particle detectors for axionic dark matter. In this way, DALI comprises a powerful superconducting magnet, an axion detector with a novel resonator to make the weak signal caused by the axions detectable, and an altazimuth mount to allow it to scan objects and regions in the sky looking for dark matter.

This way, DALI could help in the detection of the axion, a pseudo-scalar particle whose nature is similar to that of the Higgs boson, discovered in 2012 at CERN, and a promising candidate for dark matter. Dark matter is a fundamental constituent of the Universe which interacts very weakly with ordinary matter, and so is very difficult to detect directly, but whose discovery would allow us to explain the rotation curves of the spiral galaxies, and why the formation of structure in the Universe has developed in the way it has until now, among other mysteries.

Histology is the study of biological tissues at a microscopic level. Also called microscopic anatomy, histology is widely used to provide diagnosis of cancer and other diseases. For example, tissue samples obtained during surgery might help to determine whether further surgical action is needed, and further surgery may be avoided if a diagnosis can be rapidly obtained during an operation.

Traditional methods in histopathology are generally limited to thin specimens and require chemical processing of the tissue to provide sufficiently high contrast for imaging, which slows the process. A recent advance in histopathology eliminates the need for chemical staining and enables high-resolution imaging of thick tissue sections. As reported in Advanced Photonics, an international research team recently demonstrated a 3D label-free quantitative phase imaging technique that uses optical diffraction tomography to obtain volumetric imaging information. Automated stitching simplifies the image acquisition and analysis.

Optical diffraction tomography

Optical diffraction tomography is a microscopy technique for reconstructing the refractive index of a tissue sample from its scattered field images obtained with various illumination angles. It enables label-free high contrast visualization of transparent samples. The complex scattered field transmitted through the sample is first retrieved using off-axis holography, then the scattered fields obtained with various angle of illuminations are mapped in the Fourier space enabling the reconstruction of the sample refractive index.

A recognized limitation of optical diffraction tomography is due to the complex distribution of refractive indexes, which results in significant optical aberration in the imaging of thick tissue. To overcome this limitation, the team used digital refocusing and automated stitching, enabling volumetric imaging of 100-m-thick tissues over a lateral field of view of 2 mm  1.75 mm while maintaining a high resolution of 170 nm  170 nm  1400 nm. They demonstrated that simultaneous visualization of subcellular and mesoscopic structures in different tissues is enabled by high resolution combined with a wide field of view.

Fast, accurate histopathology

The researchers demonstrated the capacity of their novel method by imaging a variety of different cancer pathologies: pancreatic neuroendocrine tumor, intraepithelial neoplasia, and intraductal papillary neoplasm of bile duct. They imaged millimeter-scale, unstained, 100-μm-thick tissues at a subcellular 3D resolution, which enabled the visualization of individual cells and multicellular tissue architectures, comparable to images obtained with traditional chemically processed tissues. According to YongKuen Park, researcher at the Korea Advanced Institute of Science and Technology and senior author on the study, "The images obtained with the proposed method enabled clear visualization of different morphological features in the various tissues allowing for recognition and diagnosis of precursor lesions and pathologies."

Volumetric histopathology of unlabeled 100-μm-thick pancreas tissue sample from a patient with intraductal papillary neoplasm of bile duct in the liver. For the purpose of comparison, adjacent tissues were prepared in thin tissue slides with conventional H&E staining method. (the fifth row, 400x magnification). Image credit: Hugonnet et al., doi 10.1117/1.AP.3.2.026004.

Park notes that further research is needed, but the results suggest great potential for fast, accurate histopathology during surgery: "More research is needed on sample preparation, reconstruction speed, and mitigation of multiple scattering. We expect optical diffraction tomography to provide faster and more precise diagnostics in histopathology and intraoperative pathology consultations."

Read the open access article by Herve Hugonnet et al., "Multiscale label-free volumetric holographic histopathology of thick-tissue slides with subcellular resolution," Adv. Photon. 3(2), 026004 (2021), doi 10.1117/1.AP.3.2.026004

Journal

Advanced Photonics

DOI

10.1117/1.AP.3.2.026004

(Boston)--Doctors treating babies born with Turner syndrome need to look for heart rhythm abnormalities, in addition to the usual heart problems of high blood pressure or left-sided structural heart defects, according to Meena Bolourchi, MD, assistant professor of pediatrics at Boston University School of Medicine.

Turner syndrome occurs in one out of 2,500 live female births and is caused by the complete or partial absence of one X chromosome. Compared to the general population, females with Turner syndrome have a three times higher risk of early death from cardiovascular disease.

In the general newborn population, cardiac arrhythmias occur in approximately 24.4 per 100,000 live births and may occur with or without congenital heart disease. The most common arrhythmia is supraventricular tachycardia (SVT) (abnormally fast heart rate coming from the top chambers of the heart) with an incidence of one per 250 to one per 1,000 pediatric patients depending on the source. Atrial flutter occurs less often, with an incidence of 2.1 per 100,000 live births and typically does not reoccur after treatment. While one study of newborns with atrial flutter showed that 25 percent had a second atrial arrhythmia, none of them had an underlying genetic syndrome.

Now for the first time, researchers report on a newborn with Turner syndrome having atrial flutter followed by SVT. "This is the first case of a baby with Turner's syndrome who was found to have more than one type of arrhythmia. This case illustrates that arrhythmias from the top chambers of the heart (atrial arrhythmias) can be found in babies with Turner's syndrome," explains corresponding author Bolourchi.

To date, there had been no known associations between Turner syndrome and the development of atrial flutter with or without SVT. Bolourchi stresses that if a baby or child has been diagnosed with Turner syndrome, it would be important to look for heart rhythm abnormalities, in addition to the usual heart problems of high blood pressure or left-sided structural heart defects.

"This case illustrates that infants and children with Turner syndrome may be at risk for cardiovascular rhythm disorders, such as atrial flutter or supraventricular tachycardia. "Early and precise investigation of such cardiac abnormalities is important to reduce morbidity and mortality of these patients," adds Bolourchi, a pediatric cardiologist at Boston Medical Center.

These findings appear online in the European Heart Journal.

Immunotherapy is a type of anti-tumor treatment and has shown great clinical success against a wide variety of malignancies in recent years. Poly(I : C), a TLR3 agonist, is the most potent type I interferon (IFN) inducer. Poly(I : C) not only directly induces tumorous apoptosis, but also stimulates tumor cells to secrete immune factors. However, the immune response rate induced by Poly(I : C) remains low in several types of malignancies and higher doses are often required to achieve the desired effect. However, poly(I : C) is highly toxic and thus only a very narrow therapeutic window is available, which greatly limits clinical application of Poly(I : C)-based treatments.

Photodynamics therapy (PDT) is a promising anti-tumor treatment method, which not only directly induces the production of excessive reactive oxygen species (ROS) in tumor cells, but also promotes the release of tumor-related antigens, thereby initiating the anti-tumor immunity. The photosensitive activity of traditional photosensitizers is weakened or even completely disappeared in the state of aggregation, which is a major problem in PDT. Fortunately, the emergence of AIEgens presents a new strategy for the construction of effective photosensitizers. The AIEgens has a stronger ability to generate ROS and produces a stronger immune effect in the aggregated state. Even so, the immunity induced by photodynamic therapy is still difficult to achieve complete tumor elimination. Therefore, combining the immune adjuvant Poly(I:C) with AIE photosensitizer-mediated photodynamic therapy to enhance the anti-tumor immune response is of great clinical significance.

Recently, Shixuan Wang from Huazhong University of Science and Technology of China, Fan Xia from the China University of Geosciences and Yuning Hong the La Trobe University of Australia reported the preparation of NPs that comprise an AIE-conjugated polymer as a photosensitizer and Poly(I : C) as an immunologic adjuvant, a PLGA matrix and an red blood cell (RBC) membrane shell, which provide a novel strategy for tumor treatment.

In order to enhance the good biocompatibility and specific organ targeting of the NPs, the authors used the red blood cell membrane as the shell, simultaneously loaded the AIEgens and the immune adjuvant Poly(I:C) to construct the M@AP NPs. In vivo, M@AP NPs are mainly enriched in tumor tissues because of the ERP effect, but they also accumulate in the spleen through the homing effect of the RBC membrane. The latter activates immune cells in the spleen to strengthen anti-tumor immunity. Under white light irradiation on the tumor region, the AIE photosensitizer induces tumor cell death by generating intracellular ROS, which further promotes the release of TA and activates the immune response with a synergistic effect of Poly(I : C). Quantitative analysis revealed that M@AP NPs simultaneously kill local cancer cells directly and stimulate the immune cells to release cytokines that present cytotoxicity against tumor cells. The authors further applied the system in a lung metastasis mouse model and demonstrated the excellent anti-metastasis capability of our approach, which provides a potential treatment strategy for preventing tumor recurrence and metastasis.

Researchers in the Nanoscience Center of University of Jyvaskyla, in Finland and in the Guadalajara University in Mexico developed a method that allows for simulation and visualization of magnetic-field-induced electron currents inside gold nanoparticles. The method facilitates accurate analysis of magnetic field effects inside complex nanostructures in nuclear magnetic resonance measurements and establishes quantitative criteria for aromaticity of nanoparticles. The work was published 30.4.2021 as an Open Access article in Nature Communications.

According to the classical electromagnetism, a charged particle moving in an external magnetic field experiences a force that makes the particle's path circular. This basic law of physics is used, e.g., in designing cyclotrons that work as particle accelerators. When nanometer-size metal particles are placed in a magnetic field, the field induces a circulating electron current inside the particle. The circulating current in turn creates an internal magnetic field that opposes the external field. This physical effect is called magnetic shielding.

The strength of the shielding can be investigated by using nuclear magnetic resonance (NMR) spectroscopy. The internal magnetic shielding varies strongly in an atomic length scale even inside a nanometer-size particle. Understanding these atom-scale variations is possible only by employing quantum mechanical theory of the electronic properties of each atom making the nanoparticle.

Now, the research group of Professor Hannu Häkkinen in the University of Jyväskylä, in collaboration with University of Guadalajara in Mexico, developed a method to compute, visualize, and analyze the circulating electron currents inside complex 3D nanostructures. The method was applied to gold nanoparticles with a diameter of only about one nanometer. The calculations shed light onto unexplained experimental results from previous NMR measurements in the literature regarding how magnetic shielding inside the particle changes when one gold atom is replaced by one platinum atom.

A new quantitative measure to characterize aromaticity inside metal nanoparticles was also developed based on the total integrated strength of the shielding electron current.

"Aromaticity of molecules is one of the oldest concepts in chemistry, and it has been traditionally connected to ring-like organic molecules and to their delocalized valence electron density that can develop circulating currents in an external magnetic field. However, generally accepted quantitative criteria for the degree of aromaticity have been lacking. Our method yields now a new tool to study and analyze electron currents at the resolution of one atom inside any nanostructure, in principle. The peer reviewers of our work considered this as a significant advancement in the field", says Professor Häkkinen who coordinated the research.

Governments throughout the world have accelerated their ambitions towards effective climate change mitigation. What is clear, in this challenge of how to tackle the complex and global issue of climate change, is that there is no one technology or stakeholder that will drive the full and timely decarbonisation that the world and its citizens require.

Therefore, as part of this global energy transition, there is an unprecedent increase in decarbonisation investments accompanied with new levels of accessibility to both energy systems and markets. So, a key research question is how best to understand and optimise the value proposition for different stakeholders. Due to the need to fast track decarbonisation and to ensure that this is an inclusive energy transition with social justice and equity at its core, we need to understand the dynamics and interdependencies across people, technology and economics.

A team of researchers within the Smart Systems Group at Heriot-Watt University, have been exploring how Game-theoretic models could represent a promising approach to study strategic interactions between self-interested private energy system investors.

In this research, we design and evaluate a game-theoretic framework to study strategic interactions between profit-maximising players that invest in an electrical network, renewable generation and storage capacity. Specifically, we study the case where grid capacity is developed by a private renewable investor, but line access is shared with competing renewable and storage investors, thus enabling them to export energy and access electricity demand.

Professor David Flynn, founder of the Smart Systems Group, stated; "We model the problem of deducing how much capacity each player should build as a non-cooperative Stackelberg-Cournot game between a dominant player (leader) who builds the power line and renewable generation capacity, and local renewable and storage investors (multiple followers), who react to the installation of the line by increasing their own capacity. Using data-driven analysis and simulations, we developed an empirical search method for estimating the game equilibrium, where the payoffs capture the realistic operation and control of the energy system under study."

The results within this research use a practical demonstration of the underlying methodologies, for a real-world grid reinforcement project in the UK. The methodology provides a realistic mechanism to analyse investor decision-making and investigate feasible tariffs that encourage distributed renewable investment, with sharing of grid access.

Through T cell engineering, researchers at Virginia Commonwealth University Massey Cancer Center show that it's possible to arrest tumor growth for a variety of cancers and squash the spread of cancer to other tissues. This research will be published in tomorrow's print edition of Cancer Research.

The paper builds on decades of research by study co-senior author Paul B. Fisher, M.Ph., Ph.D., a member of Massey's Cancer Biology research program, who discovered a protein called IL-24 that attacks a variety of cancers in several different ways.

In this latest study, Fisher teamed up with his colleague Xiang-Yang (Shawn) Wang, Ph.D., who co-leads the Developmental Therapeutics research program at Massey, to deliver the gene coding for IL-24, which is called MDA-7, to solid tumors using T cells.

"I think the beauty of what we've been involved in is that it expands the scope of immunotherapy," said Fisher, professor and chair of the Department of Human and Molecular Genetics at the VCU School of Medicine, director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Endowed Chair in Oncology Research. "Our approach is less dependent on cancer cells expressing something specific to target."

After all, this isn't the first time T cells have been engineered for cancer immunotherapy. FDA-approved chimeric antigen receptor T (CAR-T) cell therapy - which is designed to destroy cancer cells expressing specific surface molecules - has shown tremendous success for treating advanced cancers of the blood and lymphatic systems.

But CAR-T has made limited progress on solid tumors, such as prostate cancer or melanoma, because the cells that make up those tumors aren't all the same, which blocks the engineered T cells from recognizing and attacking.

Wang and Fisher armed T cells with MDA-7/IL-24 to target cancer more broadly.

"Engineering T cells to produce MDA-7/IL-24 allows killing of cancer cells regardless of their expression of target molecules. This will help prevent cancer cells from escaping immune attack," said Wang, who is also a professor of human and molecular genetics at VCU, associate director of immunology in the VIMM and holds the Harry and Judy Wason Distinguished Professorship at Massey.

At the sub-cellular level, MDA-7/IL-24 binds to receptors on the surface of cells and instructs them to make and release more copies of the MDA-7/IL-24 protein. If the cell is normal, the protein is simply secreted and no damage occurs. But if the cell is cancerous, MDA-7/IL-24 causes oxidative stress damage and ultimately cell death, not only within the primary tumor but also among its distant metastases - the cause of death in 90% of patients.

As a result of this process, the immune system generates memory T cells that can theoretically kill the tumor if it ever comes back. At the whole tumor level, IL-24 also blocks blood vessel formation, starving tumors of the nutrients so badly needed to sustain their unchecked growth.

In mice with prostate cancer, melanoma or other cancer metastases, MDA-7/IL-24-expressing T cells slowed or stopped cancer progression better than unmodified T cells.

The researchers also discovered that arming T cells with MDA-7/IL-24 allowed them to survive better and multiply in the tumor microenvironment - the space right around the cancerous mass.

"The tumor site is often very hostile to immune cells," Wang said. "We discovered that MDA-7/IL-24 can help T cells to proliferate and outnumber cancer cells."

In the clinic, this approach would involve extracting the patient's own T cells from tumor samples, genetically engineering them to express MDA-7/IL-24, growing millions of copies of the cells in the lab and finally transplanting them back into the patient. With federally-mandated manufacturing standards, the procedure is generally safe and minimally invasive. CAR-T cells could also be engineered to express MDA-7/IL-24.

To be most effective, MDA-7/IL-24 T cells would likely be used in conjunction with other therapies.

Although it's never easy bringing a technology from the bench to the bedside, Fisher is optimistic that much of the groundwork has already been laid.

Clinical trials using different methods of delivering IL-24 are already underway for several cancers. A phase 1 trial using an adenovirus - similar to the common cold - to deliver MDA-7/IL24 to the tumor demonstrated about 44% efficacy against multiple forms of cancer and generally proved non-toxic.

"I think we have a head start and a running ramp that could be really accelerated," Fisher said.

Together, Wang and Fisher recently secured a grant from the National Cancer Institute to optimize their technology for the treatment of solid tumors and cancer metastases, in anticipation of future human trials.

Passed in 2018, the First Step Act sought to address re-entry challenges for inmates in the federal prison system. The legislation called for developing an assessment tool to identify inmates for release who had the lowest likelihood of recidivism. A new study assessed how the tool was developed and is used, finding that a greater proportion of inmates could reduce their risk and become eligible for early release over time if they participated in a re-entry program and did not incur infractions. This finding has implications for efforts to reduce prison populations during the COVID-19 pandemic.

The study, by researchers at the University of Nebraska at Omaha, Baylor University, the Federal Bureau of Prisons, and Washington State University, appears in Justice Quarterly, a publication of the Academy of Criminal Justice Sciences.

"This federal initiative represents a substantial opportunity to reverse the tide of a decades-long trend of growing rates of incarceration," according to Zachary Hamilton, associate professor of criminology and criminal justice at the University of Nebraska at Omaha, who led the study.

The First Step Act sought to reduce recidivism in federal prisons by giving lower-risk individuals the opportunity to earn time credits and participate in programs to improve success of re-entry into their communities. In this study, researchers determined that a tool being used by the Bureau of Prisons to identify inmates with the lowest risk of violent and nonviolent recidivism included items that did not predict recidivism.

They expanded the existing tool to create a new one, called PATTERN (the Prisoner Assessment Tool Targeting Estimated Risk and Needs). PATTERN, launched in January 2020, and was designed to be gender-responsive and customized to the Bureau of Prisons population. Among the factors measured by PATTERN are age, prior convictions, work programming, drug treatment while incarcerated, criminal history, history of escapes, and education.

Using PATTERN, roughly half the population sampled was identified as being immediately eligible for early-release time credits. A substantial portion of the other half could become eligible if they participated in re-entry programs, did not incur infractions, and exhibited positive behavior change when reassessed, the study found. In all, almost 72 percent of men and about 96 percent of women could be eligible for early-release credits during the course of their incarceration, according to the study's findings.

"If more programming to boost re-entry success were available in federal prisons and more prisoners participated in this programming, especially those in high-risk categories, the proportion of offenders eligible for early-release credits would rise," suggests Grant Duwe, non-resident scholar at Baylor University and director of research at the Minnesota Department of Corrections.

The study concluded that PATTERN demonstrates one of the highest levels of predictive performance, outpacing that of all contemporary assessments researchers reviewed. In addition, PATTERN was validated on the same population on which it was developed and tested on a large development sample, yielding more stable and reliable estimates. Finally, the tool was tailored to specific outcomes (general and violent recidivism) and groups (males and females), which improves its predictive performance. Tests for bias revealed that PATTERN further reduced race/ethnicity disproportionality.

The researchers identified limitations of the study, including constraints regarding the pool of items used to predict recidivism and tight timing due to a requirement to meet legislative schedules. They recommend that the Bureau of Prisons continue to expand the standardized set of needs-based items collected for all offenders, adding items to improve PATTERN's accuracy and potential for case management. The authors also point to the importance of creating optimized tools for correctional systems, making use of agency-specific data to create strategies that will reduce the prison population while prioritizing public safety.