Tambjamines as Fast-Acting Multistage Antimalarials.

Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages.

Kolmogorov n-widths for multitask physics-informed machine learning (PIML) methods: Towards robust metrics.

Physics-informed machine learning (PIML) as a means of solving partial differential equations (PDEs) has garnered much attention in the Computational Science and Engineering (CS&E) world. This topic encompasses a broad array of methods and models aimed at solving a single or a collection of PDE problems, called multitask learning. PIML is characterized by the incorporation of physical laws into the training process of machine learning models in lieu of large data when solving PDE problems.

Multi-Omic Integration of Blood-Based Tumor-Associated Genomic and Lipidomic Profiles Using Machine Learning Models in Metastatic Prostate Cancer.

Purpose: To determine prognostic and predictive clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) on the basis of a combination of plasma-derived genomic alterations and lipid features in a longitudinal cohort of patients with advanced prostate cancer.

Methods: A multifeature classifier was constructed to predict clinical outcomes using plasma-based genomic alterations detected in 120 genes and 772 lipidomic species as informative features in a cohort of 71 patients with mHSPC and 144 patients with mCRPC. Outcomes of interest were collected over 11 years of follow-up.

New aryl and acylsulfonamides as state-dependent inhibitors of Na1.3 voltage-gated sodium channel.

Voltage-gated sodium channels (Nas) play an essential role in neurotransmission, and their dysfunction is often a cause of various neurological disorders. The Na1.3 isoform is found in the CNS and upregulated after injury in the periphery, but its role in human physiology has not yet been fully elucidated.

Time Is a Critical Factor When Evaluating Oligonucleotide Therapeutics in hERG Assays.

In accord with International Conference on Harmonization S7B guidelines, an human ether-a-go-go-related gene (hERG) assay is one component of an integrated risk assessment for delayed ventricular repolarization. Function of hERG could be affected by direct (acute) mechanisms, or by indirect (chronic) mechanisms. Some approved oligonucleotide therapeutics had submitted hERG data to regulatory agents, which were all collected with the same protocol used for small-molecule testing (incubation time <20 min; acute), however, oligonucleotides have unique mechanisms and time courses of action (indirect).

Development of ASIC1a ligand-gated ion channel drug screening assays across multiple automated patch clamp platforms.

Human acid-sensing ion channels (ASIC) are ligand-gated ionotropic receptors expressed widely in peripheral tissues as well as sensory and central neurons and implicated in detection of inflammation, tissue injury, and hypoxia-induced acidosis. This makes ASIC channels promising targets for drug discovery in oncology, pain and ischemia, and several modulators have progressed into clinical trials. We describe the use of hASIC1a as a case study for the development and validation of low, medium and high throughput automated patch clamp (APC) assays suitable for the screening and mechanistic profiling of new ligands for this important class of ligand-gated ion channel.

An Audit on Oncological Safety with Magseed Localised Breast Conserving Surgery.

Wire-localised wide local excision (W-WLE) has been standard of care for impalpable breast lesions. Logistics and risks of wire localisation can be challenging. Magseed-localised wide local excision (M-WLE) is an alternative to W-WLE.

Square-Net Topological Semimetals: How Spectroscopy Furthers Understanding and Control.

Square-net materials are well positioned to lead optical spectroscopic explorations into the electronic structure, photoinduced dynamics, and phase transitions in topological semimetals. Hundreds of square-net topological semimetals can be prepared that have remarkably different electronic and optical properties despite having similar structures. Here we present what has been gleaned recently from these materials with the whole gamut of optical spectroscopies, ranging from steady-state reflectance and Raman investigations into topological band structures, electronic correlations, and equilibrium phase transitions to time-resolved techniques used to decipher ultrafast relaxation dynamics and nonequilibrium photoinduced phase transitions.

Particle Merging-and-Splitting.

Robustly handling collisions between individual particles in a large particle-based simulation has been a challenging problem. We introduce particle merging-and-splitting, a simple scheme for robustly handling collisions between particles that prevents inter-penetrations of separate objects without introducing numerical instabilities. This scheme merges colliding particles at the beginning of the time-step and then splits them at the end of the time-step.

Weyl fermions, Fermi arcs, and minority-spin carriers in ferromagnetic CoS.

Magnetic Weyl semimetals are a newly discovered class of topological materials that may serve as a platform for exotic phenomena, such as axion insulators or the quantum anomalous Hall effect. Here, we use angle-resolved photoelectron spectroscopy and ab initio calculations to discover Weyl cones in CoS, a ferromagnet with pyrite structure that has been long studied as a candidate for half-metallicity, which makes it an attractive material for spintronic devices. We directly observe the topological Fermi arc surface states that link the Weyl nodes, which will influence the performance of CoS as a spin injector by modifying its spin polarization at interfaces.

Transient Drude Response Dominates Near-Infrared Pump-Probe Reflectivity in Nodal-Line Semimetals ZrSiS and ZrSiSe.

The ultrafast optical response of nodal-line semimetals ZrSiS and ZrSiSe was studied in the near-infrared using transient reflectivity. The materials exhibit similar responses, characterized by two features, well-resolved in time and energy; the first decays after hundreds of femtoseconds, and the second lasts for nanoseconds. Using Drude-Lorentz fits of the materials' equilibrium reflectance, we show that these are well-represented by a sudden change of the electronic properties (increase of screening or reduction of the plasma frequency) followed by an increase of the Drude scattering rate.

Effect of selective I inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation.

Background And Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific I inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF.

Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels.

Patient-reported Upper Limb Function After Sentinel Lymph Node Biopsy for Breast Cancer: A Prospective Observational Study.

Introduction: Sentinel lymph node biopsy (SLNB) is the standard procedure for axillary staging in breast cancer. There is a lack of consistency in studies reporting on upper limb morbidity after SLNB. We present a prospective study evaluating upper limb function after SLNB using the validated quickDASH questionnaire.

Vector Field Decompositions Using Multiscale Poisson Kernel.

Extraction of multiscale features using scale-space is one of the fundamental approaches to analyze scalar fields. However, similar techniques for vector fields are much less common, even though it is well known that, for example, turbulent flows contain cascades of nested vortices at different scales. The challenge is that the ideas related to scale-space are based upon iteratively smoothing the data to extract features at progressively larger scale, making it difficult to extract overlapping features.

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

Introduction: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed.

The Effect of Data Transformations on Scalar Field Topological Analysis of High-Order FEM Solutions.

High-order finite element methods (HO-FEM) are gaining popularity in the simulation community due to their success in solving complex flow dynamics. There is an increasing need to analyze the data produced as output by these simulations. Simultaneously, topological analysis tools are emerging as powerful methods for investigating simulation data.

A comparative analysis of axillary nodal burden in ultrasound/biopsy positive axilla vs ultrasound negative sentinel lymph node biopsy positive axilla.

Background: Axillary Ultrasound (AUS) is now performed as a protocol in every newly diagnosed breast cancer in most European countries. It is an inexpensive and sensitive tool in hands of a trained operator. All AUS negative patients undergo Sentinel Lymph Node Biopsy (SLNB), while AUS positive patients bypass SLNB and undergo axillary nodal clearance (ANC) as a standard protocol.

Visualization in Meteorology-A Survey of Techniques and Tools for Data Analysis Tasks.

This article surveys the history and current state of the art of visualization in meteorology, focusing on visualization techniques and tools used for meteorological data analysis. We examine characteristics of meteorological data and analysis tasks, describe the development of computer graphics methods for visualization in meteorology from the 1960s to today, and visit the state of the art of visualization techniques and tools in operational weather forecasting and atmospheric research. We approach the topic from both the visualization and the meteorological side, showing visualization techniques commonly used in meteorological practice, and surveying recent studies in visualization research aimed at meteorological applications.

On the Treatment of Field Quantities and Elemental Continuity in FEM Solutions.

As the finite element method (FEM) and the finite volume method (FVM), both traditional and high-order variants, continue their proliferation into various applied engineering disciplines, it is important that the visualization techniques and corresponding data analysis tools that act on the results produced by these methods faithfully represent the underlying data. To state this in another way: the interpretation of data generated by simulation needs to be consistent with the numerical schemes that underpin the specific solver technology. As the verifiable visualization literature has demonstrated: visual artifacts produced by the introduction of either explicit or implicit data transformations, such as data resampling, can sometimes distort or even obfuscate key scientific features in the data.

Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels.

We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the K1 subfamily of voltage-gated potassium channels, K1.1-K1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay.

Association of One-Step Nucleic Acid Amplification Detected Micrometastases with Tumour Biology and Adjuvant Chemotherapy.

One-step nucleic acid amplification (OSNA) is an intraoperative technique with a high sensitivity and specificity for sentinel node assessment. The aim of this study was to assess the impact of OSNA on micrometastases detection rates and use of adjuvant chemotherapy. A retrospective review of patients with sentinel node micrometastases over a five-year period was carried out and a comparison of micrometastases detection using OSNA and H&E techniques was made.

Characterization of Endogenous Sodium Channels in the ND7-23 Neuroblastoma Cell Line: Implications for Use as a Heterologous Ion Channel Expression System Suitable for Automated Patch Clamp Screening.

The rodent neuroblastoma cell line, ND7-23, is used to express voltage-dependent sodium (Nav) and other neuronal ion channels resistant to heterologous expression in Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells. Their advantage is that they provide endogenous factors and signaling pathways to promote ion channel peptide folding, expression, and function at the cell surface and are also amenable to automated patch clamping. However, ND7-23 cells exhibit endogenous tetrodotoxin (TTX)-sensitive Nav currents, and molecular profiling has revealed the presence of Nav1.

Mixed finite elements for global tide models.

We study mixed finite element methods for the linearized rotating shallow water equations with linear drag and forcing terms. By means of a strong energy estimate for an equivalent second-order formulation for the linearized momentum, we prove long-time stability of the system without energy accumulation-the geotryptic state. A priori error estimates for the linearized momentum and free surface elevation are given in [Formula: see text] as well as for the time derivative and divergence of the linearized momentum.