Human tRNA (uracil-5-)-methyltransferase 2 homolog A (TRMT2A) is the dedicated enzyme for the methylation of uridine 54 in transfer RNA (tRNA). Human TRMT2A has also been described as a modifier of polyglutamine (polyQ)-derived neuronal toxicity. The corresponding human polyQ pathologies include Huntington's disease and constitute a family of devastating neuro­degenerative diseases. A polyQ tract in the corresponding disease-linked protein causes neuronal death and symptoms such as impaired motor function, as well as cognitive impairment. In polyQ disease models, silencing of TRMT2A reduced polyQ-associated cell death and polyQ protein aggregation, suggesting this protein as a valid drug target against this class of disorders. In this paper, the 1.6 Å resolution crystal structure of the RNA-recognition motif (RRM) from Drosophila melanogaster, which is a homolog of human TRMT2A, is described and analysed.

Preparation of biomacromolecules for structural biology studies is a complex and time-consuming process. The goal is to produce a highly concentrated, highly pure product that is often shipped to large facilities with tools to prepare the samples for crystallization trials or for measurements at synchrotrons and cryoEM centers. The aim of this article is to provide guidance and to discuss general considerations for shipping biomacromolecular samples. Details are also provided about shipping samples for specific experiment types, including solution- and cryogenic-based techniques. These guidelines are provided with the hope that the time and energy invested in sample preparation is not lost due to shipping logistics.

Plasmodium vivax is a major cause of malaria, which poses an increased health burden on approximately one third of the world's population due to climate change. Primaquine, the preferred treatment for P. vivax malaria, is contraindicated in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic cause of hemolytic anemia, that affects ∼2.5% of the world's population and ∼8% of the population in areas of the world where P. vivax malaria is endemic. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducted a structure–function analysis of P. vivax N-myristoyltransferase (PvNMT) as part of efforts to develop alternative malaria drugs. PvNMT catalyzes the attachment of myristate to the N-terminal glycine of many proteins, and this critical post-translational modification is required for the survival of P. vivax. The first step is the formation of a PvNMT–myristoyl–CoA binary complex that can bind to peptides. Understanding how inhibitors prevent protein binding will facilitate the development of PvNMT as a viable drug target. NMTs are secreted in all life stages of malarial parasites, making them attractive targets, unlike current antimalarials that are only effective during the plasmodial erythrocytic stages. The 2.3 Å resolution crystal structure of the ternary complex of PvNMT with myristoyl-CoA and a novel inhibitor is reported. One asymmetric unit contains two monomers. The structure reveals notable differences between the PvNMT and human enzymes and similarities to other plasmodial NMTs that can be exploited to develop new antimalarials.

The crystal structure of the intracellular domain of transforming growth factor β type I receptor (TβR1) in complex with the competitive inhibitor SB505124 is presented. The study provides insights into the structure and function of TβR1 in complex with SB505124, and as such offers molecular-level understanding of the inhibition of this critical signalling pathway. The potential of SB505124 as an avenue for therapy in cancer treatment is discussed on basis of the results.

The ability to freely control the polarization of X-rays enables measurement techniques relying on circular or linear dichroism, which have become indispensable tools for characterizing the properties of chiral molecules or magnetic structures. Therefore, the demand for polarization control in X-ray free-electron lasers is increasing to enable polarization-sensitive dynamical studies on ultrafast time scales. The soft X-ray branch Athos of SwissFEL was designed with the aim of providing freely adjustable and arbitrary polarization by building its undulator solely from modules of the novel Apple X type. In this paper, the magnetic model of the linear inclined and circular Apple X polarization schemes are studied. The polarization is characterized by measuring the angular electron emission distributions of helium for various polarizations using cold target recoil ion momentum spectroscopy. The generation of fully linear polarized light of arbitrary angle, as well as elliptical polarizations of varying degree, are demonstrated.

Form factors based on aspherical models of atomic electron density have brought great improvement in the accuracies of hydrogen atom parameters derived from X-ray crystal structure refinement. Today, two main groups of such models are available, the banks of transferable atomic densities parametrized using the Hansen–Coppens multipole model which allows for rapid evaluation of atomic form factors and Hirshfeld atom refinement (HAR)-related methods which are usually more accurate but also slower. In this work, a model that combines the ideas utilized in the two approaches is tested. It uses atomic electron densities based on Hirshfeld partitions of electron densities, which are precalculated and stored in a databank. This model was also applied during the refinement of the structures of five small molecules. A comparison of the resulting hydrogen atom parameters with those derived from neutron diffraction data indicates that they are more accurate than those obtained with the Hansen–Coppens based databank, and only slightly less accurate than those obtained with a version of HAR that neglects the crystal environment. The advantage of using HAR becomes more noticeable when the effects of the environment are included. To speed up calculations, atomic densities were represented by multipole expansion with spherical harmonics up to l = 7, which used numerical radial functions (a different approach to that applied in the Hansen–Coppens model). Calculations of atomic form factors for the small protein crambin (at 0.73 Å resolution) took only 68 s using 12 CPU cores.

X-ray free-electron laser (XFEL) light sources have enabled the rapid growth of time-resolved structural experiments, which provide crucial information on the function of macromolecules and their mechanisms. Here, the aim was to commission the SwissMX fixed-target sample-delivery system at the SwissFEL Cristallina experimental station using the PSI-developed micro-structured polymer (MISP) chip for pump–probe time-resolved experiments. To characterize the system, crystals of the light-sensitive protein light–oxygen–voltage domain 1 (LOV1) from Chlamydomonas reinhardtii were used. Using different experimental settings, the accidental illumination, referred to as light contamination, of crystals mounted in wells adjacent to those illuminated by the pump laser was examined. It was crucial to control the light scattering from and through the solid supports otherwise significant contamination occurred. However, the results here show that the opaque MISP chips are suitable for defined pump–probe studies of a light-sensitive protein. The experiment also probed the sub-millisecond structural dynamics of LOV1 and indicated that at Δt = 10 µs a covalent thio­ether bond is established between reactive Cys57 and its flavin mononucleotide cofactor. This experiment validates the crystals to be suitable for in-depth follow-up studies of this still poorly understood signal-transduction mechanism. Importantly, the fixed-target delivery system also permitted a tenfold reduction in protein sample consumption compared with the more common high-viscosity extrusion-based delivery system. This development creates the prospect of an increase in XFEL project throughput for the field.

A pressure-induced triclinic-to-monoclinic phase transition has been caught `in the act' over a wider series of high-pressure synchrotron diffraction experiments conducted on a large, photoluminescent organo-gold(I) compound. Here, we describe the mechanism of this single-crystal-to-single-crystal phase transition, the onset of which occurs at ∼0.6 GPa, and we report a high-quality structure of the new monoclinic phase, refined using aspherical atomic scattering factors. Our case illustrates how conducting a fast series of diffraction experiments, enabled by modern equipment at synchrotron facilities, can lead to overestimation of the actual pressure of a phase transition due to slow transformation kinetics.

An implementation of Slater-type spherical scattering factors for X-ray and electron diffraction for elements in the range Z = 1–103 is presented within the software Olex2. Both high- and low-angle Fourier behaviour of atomic electron density and electrostatic potential can thus be addressed, in contrast to the limited flexibility of the four Gaussian plus constant descriptions which are currently the most widely used method for calculating atomic scattering factors during refinement. The implementation presented here accommodates the increasing complexity of the electronic structure of heavier elements by using complete atomic wavefunctions without any interpolation between precalculated tables or intermediate fitting functions. Atomic wavefunctions for singly charged ions are implemented and made accessible, and these show drastic changes in electron diffraction scattering factors compared with the neutral atom. A comparison between the two different spherical models of neutral atoms is presented as an example for four different kinds of X-ray and two electron diffraction structures, and comparisons of refinement results using the existing diffraction data are discussed. A systematic but slight improvement in R values and residual densities can be observed when using the new scattering factors, and this is discussed relative to effects on the atomic displacement parameters and atomic positions, which are prominent near the heavier elements in a structure.

Macromolecular crystallography contributes significantly to understanding diseases and, more importantly, how to treat them by providing atomic resolution 3D structures of proteins. This is achieved by collecting X-ray diffraction images of protein crystals from important biological pathways. Spotfinders are used to detect the presence of crystals with usable data, and the spots from such crystals are the primary data used to solve the relevant structures. Having fast and accurate spot finding is essential, but recent advances in synchrotron beamlines used to generate X-ray diffraction images have brought us to the limits of what the best existing spotfinders can do. This bottleneck must be removed so spotfinder software can keep pace with the X-ray beamline hardware improvements and be able to see the weak or diffuse spots required to solve the most challenging problems encountered when working with diffraction images. In this paper, we first present Bragg Spot Detection (BSD), a large benchmark Bragg spot image dataset that contains 304 images with more than 66 000 spots. We then discuss the open source extensible U-Net-based spotfinder Bragg Spot Finder (BSF), with image pre-processing, a U-Net segmentation backbone, and post-processing that includes artifact removal and watershed segmentation. Finally, we perform experiments on the BSD benchmark and obtain results that are (in terms of accuracy) comparable to or better than those obtained with two popular spotfinder software packages (Dozor and DIALS), demonstrating that this is an appropriate framework to support future extensions and improvements.

High-repetition-rate free-electron lasers impose stringent requirements on the thermal deformation of beamline optics. The Shanghai HIgh-repetition-rate XFEL aNd Extreme light facility (SHINE) experiences high average thermal power and demands wavefront preservation. To deeply study the thermal field of the first reflection mirror M1 at the FEL-II beamline of SHINE, thermal analysis under a photon energy of 400 eV was executed by fluid and solid heat transfer method. According to the thermal analysis results and the reference cooling water temperature of 30 °C, the temperature of the cooling water at the flow outlet is raised by 0.15 °C, and the wall temperature of the cooling tube increases by a maximum of 0.5 °C. The maximum temperature position of the footprint centerline in the meridian direction deviates away from the central position, and this asymmetrical temperature distribution will directly affect the thermal deformation of the mirror and indirectly affect the focus spot of the beam at the sample.

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Singapore-based TransferTo has partnered with the Pan-African Ecobank Group in order to expand financial access and cross-border payments across the region of Africa.

Dr. Jill Baron, Director of the Powell Center, will present a webinar on how to develop a strong proposal for Working Group on November 19th, 2024, at 11am MT/1pm ET.

Source: Dr. Douglas Loe 11/05/2024

Leede Financial Inc. analyst Dr. Douglas Loe, in a research report published on November 4, 2024, maintained a Buy rating on Profound Medical Corp. (PROF:NASDAQ; PRN:TSX) with a price target of US$18.00. The report follows Profound's announcement that its TULSA-PRO device will receive a Category One CPT code from the U.S. Centers for Medicare & Medicaid Services (CMS).

Loe highlighted the significance of the reimbursement update, stating, "We have long viewed device-specific U.S. reimbursement codes for TULSA-PRO to be integral to its broader adoption in urology/oncology markets, and today's update thus solidifies TULSA-PRO's status on that theme."

The analyst emphasized the favorable reimbursement rates, noting, "Hospitals/ASCs will be reimbursed at the Medicare average of US$12,992/US$10,728 per procedure. This is sufficient economic incentive in our view to drive TULSA-PRO installed base and procedure volume growth in F2025 and thereafter."

Regarding growth projections, Loe stated, "Our model assumes that consolidated revenue/EBITDA/EPS in F2025 of US$34.9M/(US$3.9M)/(US$0.20/shr), but then lifting substantially on all metrics to US$59.1M/US$14.7M/US$0.10/shr in F2026 and then to US$95.5M/US$38.1M/US$1.05/shr in F2027."

The report highlighted potential strategic interest, with Loe noting, "We expect urology-focused suitors to show tangible interest in Profound as the annual top-line performance approaches US$100M on a run-rate basis, which our model projects by FH227."

Leede Financial's valuation methodology combines multiple approaches. Loe explained, "Our valuation still based on NPV (20% discount rate) and multiples of our F2027 EBITDA/fd EPS forecasts (US$38.1M & US$1.05/shr, respectively), with our EV calculation incorporating FQ224 balance sheet data (cash of US$34.1M, total debt of US$6.0M) and fully-diluted S/O of 26.0M."

The analyst also noted that while F2024 is a transition year, F2025 is expected to be transformative for U.S. TULSA-PRO adoption rates.

In conclusion, Leede Financial's maintenance of its Buy rating and US$18 price target reflects confidence in Profound Medical's growth potential following the favorable reimbursement update. The share price at the time of the report of US$7.35 represents a potential return of approximately 145% to the analyst's target price, highlighting the significant upside potential as the company advances its commercialization efforts.

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Disclosures for Leede Financial Inc., Profound Medical Corp., November 4, 2024

Important Information and Legal Disclaimers Leede Financial Inc. (Leede) is a member of the Canadian Investment Regulatory Organization (CIRO) and a member of the Canadian Investor Protection Fund (CIPF). This document is not an offer to buy or sell or a solicitation of an offer to buy or sell any security or instrument or to participate in any particular investing strategy. Data from various sources were used in the preparation of these documents; the information is believed but in no way warranted to be reliable, accurate and appropriate. All information is as of the date of publication and is subject to change without notice. Any opinions or recommendations expressed herein do not necessarily reflect those of Leede. Leede cannot accept any trading instructions via e-mail as the timely receipt of e-mail messages, or their integrity over the Internet, cannot be guaranteed. Dividend yields change as stock prices change, and companies may change or cancel dividend payments in the future. All securities involve varying amounts of risk, and their values will fluctuate, and the fluctuation of foreign currency exchange rates will also impact your investment returns if measured in Canadian Dollars. Past performance does not guarantee future returns, investments may increase or decrease in value, and you may lose money. Leede employees may buy and sell shares of the companies that are recommended for their own accounts and for the accounts of other clients. Disclosure codes are used in accordance with Policy 3600 of CIRO.

Dissemination All final research reports are disseminated to existing and potential institutional clients of Leede Financial Inc. (Leede) in electronic form to intended recipients thorough e-mail and third-party aggregators. Research reports are posted to the Leede website and are accessible to customers who are entitled to the firm’s research. Reproduction of this report in whole or in part without permission is prohibited. Research Analyst Certification The Research Analyst(s) who prepare this report certify that their respective report accurately reflects his/her personal opinion and that no part of his/her compensation was, is, or will be directly or indirectly related to the specific recommendations or views as to the securities or companies. Leede Financial Inc. (Leede) compensates its research analysts from a variety of sources and research analysts may or may not receive compensation based upon Leede investment banking revenue. Canadian Disclosures This research has been approved by Leede Financial Inc. (Leede), which accepts sole responsibility for this research and its dissemination in Canada. Leede is registered and regulated by the Canadian Investment Regulatory Organization (CIRO) and is a member of the Canadian Investor Protection Fund (CIPF). Canadian clients wishing to effect transactions in any designated investment discussed should do so through a Leede Registered Representative.

U.S. Disclosures This research report was prepared by Leede Financial Inc. (Leede). Leede is registered and regulated by the Canadian Investment Regulatory Organization (CIRO) and is a member of the Canadian Investor Protection Fund (CIPF). This report does not constitute an offer to sell or the solicitation of an offer to buy any of the securities discussed herein. Leede is not registered as a broker-dealer in the United States and is not subject to U.S. rules regarding the preparation of research reports and the independence of research analysts. Any resulting transactions should be effected through a U.S. broker-dealer.

( Companies Mentioned: PROF:NASDAQ; PRN:TSX, )

The Catawba County Board of Commissioners, at its January 19, 2010 meeting, joined with other local governments across the region in approving the agreement. The main points of the agreement hinged on Concord and Kannapolis modifying their ability, contained in their IBT certificate, to withdraw 10 million gallons of water per day (MGD) from the Catawba River at all times, by significantly limiting withdrawals during times of drought. The agreement limits withdrawals to 6 MGD during times of most severe drought, or �exceptional� drought; 7 MGD during �extreme� drought; 8.5 MGD during �severe� drought; and 9 MGD during �moderate� drought. Further, the agreement restricts Concord and Kannapolis from withdrawing more than 3 MGD from the Catawba until July 1, 2015, and after they first are withdrawing 5 MGD from the Yadkin River.

Nurses roles, responsibilities, and education should change significantly to meet the increased demand for care that will be created by health care reform and to advance improvements in Americas increasingly complex health system, says a new report from the Institute of Medicine.

Every year, approximately 100 million* adult Americans experience chronic pain, a condition that costs the nation between $560 billion and $635 billion annually, says a new report from the Institute of Medicine.

Educational and business leaders want todays students both to master school subjects and to excel in areas such as problem solving, critical thinking, and communication

Americas health care system has become too complex and costly to continue business as usual, says a new report from the Institute of Medicine

The social, behavioral, and economic (SBE) sciences make significant contributions to the National Science Foundation’s mission to advance health, prosperity and welfare, national defense, and progress in science, says a new report from the National Academies of Sciences, Engineering, and Medicine.

A number of strategies used by the police to proactively prevent crimes have proved to be successful at crime reduction, at least in the short term, and most strategies do not harm communities’ attitudes toward police, finds a new report by the National Academies of Sciences, Engineering, and Medicine.

The supercritical water oxidation (SCWO) system is a secondary waste processing reactor of the Blue Grass Chemical Agent Destruction Pilot Plant (BGCAPP). It is perhaps second in importance behind the agent neutralization reactors, which perform base hydrolysis of chemical warfare agents stored at the Blue Grass Army Depot.

Chemical separations — which are used to divide chemical mixtures into their distinct elements — are critical in providing many of the foods and services needed to maintain our quality of life.

You can find a nurse navigating city streets, on her way to a home visit. Or, maybe he is recording educational videos on preventing ear infections. She might even be running for city council.

For her role in transforming a safety net hospital into a national model for high-quality, cost-efficient health care, the National Academy of Medicine today announced Patricia Gabow is the recipient of the 2019 Gustav O. Lienhard Award for Advancement of Health Care.

Sethuraman “Panch” Panchanathan, executive vice president and chief research and innovation officer at Arizona State University (ASU), and ASU’s named representative to the National Academies’ Government-University-Industry-Research Roundtable (GUIRR), has been nominated by President Trump to serve as the next director of the National Science Foundation.

A review of the New York City Watershed Protection Program, released today by the National Academies of Sciences, Engineering, and Medicine, says the program has been largely successful in maintaining and enhancing water quality for New York City’s drinking water since its inception in 1997.

Imagine if just by sitting on the toilet, you could collect actionable information about your health. Although health and fitness wearables can help do that job, people tend to lose interest after a few months. Fitbits are forgotten at home or put in a drawer when the battery dies. Even stepping on a scale or using a Bluetooth blood pressure monitor can be difficult tasks to remember, if they’re not part of your routine. This can be especially true for seniors, who are generally less likely to use wearable gadgets.

In a new NAE Perspective, Chris Hendrickson says there are opportunities in the next few decades to reshape the landscape of familiar transportation systems, with transformations emerging in vehicle propulsion, automation, and telecommunications.

Rapid advances in small satellite technology and associated launch and production capabilities have transformed the space industry. A new report recommends ways the government can partner with commercial entities to enhance national missions and make transformative science advancements.

To provide high-quality care for all nursing home residents, the U.S. must strengthen the nursing home workforce, improve emergency preparedness, and increase the transparency and accountability of nursing homes’ finances and operations, among other actions.

Ensuring that populations globally are actively engaged in society while living longer, healthier lives will require a multisector, all-of-society approach. A new NAM report provides a roadmap with recommendations for addressing the needs of older people in the next five years and other actions to improve healthy longevity by 2050.

“Earlier, there used to be the largest companies who were there to solve the customers’ problems. But now there are hundreds of startups that are coming up. We need to make sure we work together with them and build an ecosystem with them. We share with them our issues, and they come back and build the products with us together. And then we help them scale,” he said.

Recently, India's Hon’ble Prime Minister, Narendra Modi, inaugurated the 5G service, affirming that "India will lead the Industry 4.0 revolution with 5G at the helm." Commenting on this technology, certain experts predicted that by 2035, 5G will have a cumulative economic impact of US$ 1 trillion, and between 2025 and 2040, it could deliver an additional GDP of US$ 150 billion for the country. This aligns with India's vision of becoming a US$ 5 trillion economy by 2025.

“The trial, which took place in Sofia, saw the companies successfully perform an end-to-end 5G data call (Layer 3 call) utilising Nokia’s Cloud RAN solution as well as its AirFrame servers,” Nokia said in a statement.

Big data allows retailers to analyze vast sets of customer information including purchase history, demographics, browsing behaviour, and social media interactions. This enables highly targeted marketing campaigns, product recommendations, and loyalty programs.

The partnership between Union Bank of India and Zoho began in 2021 after the merger of Andhra Bank and Corporation Bank with Union Bank of India, which significantly expanded its operations.

Physicists at the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) have successfully tested a new device that will lead to a better understanding of the interactions between ultrahot plasma contained within fusion facilities and the materials inside those facilities. The measurement tool, known as the Materials Analysis Particle Probe (MAPP), was built by a consortium that includes Princeton University and the University of Illinois at Urbana-Champaign (U. of I.).

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Cisco unified communications (UC) give your teams the freedom to be productive from anywhere, on any device. Available as one of our Cisco cloud services using Hosted Collaboration Solution (HCS) or as an on-premises solution, Cisco UC lets you access presence, instant messaging, voice, video, voice messaging, desktop sharing, and conferencing.

As organizations become more complex, the necessity for collaborative leadership—where CXOs work together rather than in silos—has never been more pronounced.

Expanding access to insurance is crucial for strengthening our country’s social safety net, addressing inequality, and building a more resilient society.

Services that have been automated include issuance of health & general insurance policies, RE-KYC, nomination facility, and online bill payment.

Satisfy your customers and win in the stock market, says a new study by a team of researchers from Michigan's University Research Corridor, who found positive stock returns on customer satisfaction far out-distance competitive market measures that have been in play for more than half a century.

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It offers centralized request management, omnichannel integration, self-service capabilities, enhanced visibility for business partners, employee training and tools, powerful analytics capabilities, seamless integration with existing systems, and comprehensive service offerings.

According to a release, Infosys will work closely with Sector Alarm to migrate their disparate, on-premises Enterprise Resource Planning (ERP) platform onto Microsoft Dynamics 365 Finance and Operations (F&O), helping them modernize their financial and business operating models.

Private label grows more competitive with snacks geared toward health and wellness, clean label and gluten-free.

The American Bakers Association and Snack Food Association say the findings from a recent Institute of Medicine report add a new perspective to the national discussion of sodium’s role in the American diet.