Using clinical data to reclassify ESUS patients to large artery atherosclerotic or cardioembolic stroke mechanisms.

Purpose: Embolic stroke of unidentified source (ESUS) represents 10-25% of all ischemic strokes. Our goal was to determine whether ESUS could be reclassified to cardioembolic (CE) or large-artery atherosclerosis (LAA) with machine learning (ML) using conventional clinical data.

Methods: We retrospectively collected conventional clinical features, including patient, imaging (MRI, CT/CTA), cardiac, and serum data from established cases of CE and LAA stroke, and factors with p < 0.

Rapid implementation of a clinical decision-support workflow during the national blood culture bottle shortage.

Background: The United States Food and Drug Administration recently announced a national blood culture (BC) bottle shortage; the exact date of restoration is still being determined.

Aim: Implement a workflow to mitigate the BC bottle shortage at our hospital.

Methods: We created the following clinical decision support workflow in electronic medical record to help mitigate BC bottle use: (a) limit to two BC in 24 hours, (b) only repeat BC if 72 hours have passed from the prior sets, (c) do not repeat BC for coagulase-negative bacteremia when considered a contaminant (i.

Neutron imaging of the deuterium-tritium tamping gas volume in an inertial confinement fusion hohlraum.

To benchmark the accuracy of the models and improve the predictive capability of future experiments, the National Ignition Facility requires measurements of the physical conditions inside inertial confinement fusion hohlraums. The ion temperature and bulk motion velocity of the gas-filled regions of the hohlraum can be obtained by replacing the helium tamping gas in the hohlraum with deuterium-tritium (DT) gas and measuring the Doppler broadening and Doppler shift of the neutron spectrum produced by nuclear reactions in the hohlraum. To understand the spatial distribution of the neutron production inside the hohlraum, we have developed a new penumbral neutron imager with a 12 mm diameter field of view using a simple tungsten alloy spindle.

Impact of mid-Z gas fill on dynamics and performance of shock-driven implosions at the OMEGA laser.

Shock-driven implosions with 100% deuterium (D_{2}) gas fill compared to implosions with 50:50 nitrogen-deuterium (N_{2}D_{2}) gas fill have been performed at the OMEGA laser facility to test the impact of the added mid-Z fill gas on implosion performance. Ion temperature (T_{ion}) as inferred from the width of measured DD-neutron spectra is seen to be 34%±6% higher for the N_{2}D_{2} implosions than for the D_{2}-only case, while the DD-neutron yield from the D_{2}-only implosion is 7.2±0.

Stereoselective C-B and C-H Bonds Functionalization of PolyBorylated Alkenes.

Alkenes are fundamental functional groups which feature in various materials and bioactive molecules; however, efficient divergent strategies for their stereodefined synthesis are difficult. In this regard, numerous synthetic methodologies have been developed to construct carbon-carbon bonds with regio- and stereoselectivity, enabling the predictable and efficient synthesis of stereodefined alkenes. In fact, an appealing alternative approach for accessing challenging stereodefined alkene molecular frameworks could involve the sequential selective activation and cross-coupling of strong bonds instead of conventional C-C bond formation.

Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors.

Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2]pyridines or 7-alkyl azaindoles in two steps from known compounds. Using halomucononitrile reagents, we can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25-93% yield) through the cyclization of transient aminomucononitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (13 examples, up to 91% yield).

Modeling of a spatially resolved ion temperature diagnostic for inertial confinement fusion.

The performance of modern laser-driven inertial confinement fusion (ICF) experiments is degraded by contamination of the deuterium-tritium (DT) fuel with high-Z material during compression. Simulations suggest that this mix can be described by the ion temperature distribution of the implosion, given that such contaminants deviate in temperature from the surrounding DT plasma. However, existing neutron time-of-flight (nTOF) diagnostics only measure the spatially integrated ion temperature.

Mechanism and Selectivity of Copper-Catalyzed Bromination of Distal C(sp)-H Bonds.

Unactivated C(sp)-H bonds are the most challenging substrate class for transition metal-catalyzed C-H halogenation. Recently, the Yu group [Liu, T.; Myers, M.

Computational Study of Base-Catalyzed Thiohemiacetal Decomposition in HMG-CoA Reductase.

Thiohemiacetals are key intermediates in the active sites of many enzymes catalyzing a variety of reactions. In the case of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), this intermediate connects the two hydride transfer steps where a thiohemiacetal is the product of the first hydride transfer and its breakdown forms the substrate of the second one, serving as the intermediate during cofactor exchange. Despite the many examples of thiohemiacetals in a variety of enzymatic reactions, there are few studies that detail their reactivity.

Instrument design for an inertial confinement fusion ion temperature imager.

A mix of contaminant mass is a known, performance-limiting factor for laser-driven inertial confinement fusion (ICF). It has also recently been shown that the contaminant mass is not necessarily in thermal equilibrium with the deuterium-tritium plasma [B. M.

Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer.

The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream.

Synergistic Brønsted/Lewis acid catalyzed aromatic alkylation with unactivated tertiary alcohols or di--butylperoxide to synthesize quaternary carbon centers.

Dual Brønsted/Lewis acid catalysis involving environmentally benign, readily accessible protic acid and iron promotes site-selective -butylation of electron-rich arenes using di--butylperoxide. This transformation inspired the development of a synergistic Brønsted/Lewis acid catalyzed aromatic alkylation that fills a gap in the Friedel-Crafts reaction literature by employing unactivated tertiary alcohols as alkylating agents, leading to new quaternary carbon centers. Corroborated by DFT calculations, the Lewis acid serves a role in enhancing the acidity of the Brønsted acid.

Automated fitting of transition state force fields for biomolecular simulations.

The generation of surrogate potential energy functions (PEF) that are orders of magnitude faster to compute but as accurate as the underlying training data from high-level electronic structure methods is one of the most promising applications of fitting procedures in chemistry. In previous work, we have shown that transition state force fields (TSFFs), fitted to the functional form of MM3* force fields using the quantum guided molecular mechanics (Q2MM) method, provide an accurate description of transition states that can be used for stereoselectivity predictions of small molecule reactions. Here, we demonstrate the applicability of the method for fit TSFFs to the well-established Amber force field, which could be used for molecular dynamics studies of enzyme reaction.

Patterns and mechanisms of sex ratio distortion in the Collaborative Cross mouse mapping population.

In species with single-locus, chromosome-based mechanisms of sex determination, the laws of segregation predict an equal ratio of females to males at birth. Here, we show that departures from this Mendelian expectation are commonplace in the 8-way recombinant inbred Collaborative Cross (CC) mouse population. More than one-third of CC strains exhibit significant sex ratio distortion (SRD) at wean, with twice as many male-biased than female-biased strains.

Light Directs Monomer Coordination in Catalyst-Free Grignard Photopolymerization.

π-Conjugated polymers can serve as active layers in flexible and lightweight electronics and are conventionally synthesized by transition-metal-mediated polycondensation at elevated temperatures. We recently reported a photopolymerization of electron-deficient heteroaryl Grignard monomers that enables the catalyst-free synthesis of n-type π-conjugated polymers. Herein, we describe an experimental and computational investigation into the mechanism of this photopolymerization.

Microsecond timescale MD simulations at the transition state of HMGR predict remote allosteric residues.

Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to reach the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale.

Use of computer vision for analysis of image datasets from high temperature plasma experiments.

Great strides have been made in improving the quality of x-ray radiographs in high energy density plasma experiments, enabled in part by innovations in engineering and manufacturing of integrated circuits and materials. As a consequence, the radiographs of today are filled with a great deal of detail, but few of these features are extracted in a systematic way. Analysis techniques familiar to plasma physicists tend toward brittle 1D lineout or Fourier transform type analyses.

Combination of EP antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells.

Prostaglandin E (PGE), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP receptor.

ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity.

ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir.

One-dimensional hydrodynamic simulations of low convergence ratio direct-drive inertial confinement fusion implosions.

Indirect drive inertial confinement fusion experiments with convergence ratios below 17 have been previously shown to be less susceptible to Rayleigh-Taylor hydrodynamic instabilities, making this regime highly interesting for fusion science. Additional limitations imposed on the implosion velocity, in-flight aspect ratio and applied laser power aim to further reduce instability growth, resulting in a new regime where performance can be well represented by one-dimensional (1D) hydrodynamic simulations. A simulation campaign was performed using the 1D radiation-hydrodynamics code HYADES to investigate the performance that could be achieved using direct-drive implosions of liquid layer capsules, over a range of relevant energies.

Preparations for a European R&D roadmap for an inertial fusion demo reactor.

A European consortium of 15 laboratories across nine nations have worked together under the EUROFusion Enabling Research grants for the past decade with three principle objectives. These are: (a) investigating obstacles to ignition on megaJoule-class laser facilities; (b) investigating novel alternative approaches to ignition, including basic studies for fast ignition (both electron and ion-driven), auxiliary heating, shock ignition, etc.; and (c) developing technologies that will be required in the future for a fusion reactor.

Tailored quinones support high-turnover Pd catalysts for oxidative C-H arylation with O.

Palladium(II)-catalyzed carbon-hydrogen (C-H) oxidation reactions could streamline the synthesis of pharmaceuticals, agrochemicals, and other complex organic molecules. Existing methods, however, commonly exhibit poor catalyst performance with high palladium (Pd) loading (e.g.