A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays.

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning.

Inequality in household adaptation to schooling shocks: Covid-induced online learning engagement in real time.

We use high frequency internet search data to study in real time how US households sought out online learning resources as schools closed due to the Covid-19 pandemic. By April 2020, nationwide search intensity for both school- and parent-centered online learning resources had roughly doubled relative to pre-Covid levels. Areas of the country with higher income, better internet access and fewer rural schools saw substantially larger increases in search intensity.

Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation.

Importance: Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis.

Objective: To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation.

Cultural adaptation of a children's weight management programme for Bangladeshi and Pakistani families in the UK: a cluster-randomised feasibility study protocol.

Background: Group-based children's weight management programmes are widely available in the UK and evidence shows that these are effective in the short-term. No programmes have been specifically developed to meet the cultural requirements of UK minority ethnic communities. South Asian children are a high-risk group for obesity and its consequences; therefore, the study aim is to adapt an existing weight management programme for children aged 4-11 years and their families to ensure cultural relevance to Pakistani and Bangladeshi communities, and undertake a feasibility study of the adapted programme.

Chemotaxis of artificial microswimmers in active density waves.

Living microorganisms are capable of a tactic response to external stimuli by swimming toward or away from the stimulus source; they do so by adapting their tactic signal transduction pathways to the environment. Their self-motility thus allows them to swim against a traveling tactic wave, whereas a simple fore-rear asymmetry argument would suggest the opposite. Their biomimetic counterpart, the artificial microswimmers, also propel themselves by harvesting kinetic energy from an active medium, but, in contrast, lack the adaptive capacity.

Extreme events due to localization of energy.

We study a one-dimensional chain of harmonically coupled units in an asymmetric anharmonic soft potential. Due to nonlinear localization of energy, this system exhibits extreme events in the sense that individual elements of the chain show very large excitations. A detailed statistical analysis of extremes in this system reveals some unexpected properties, e.

Nonlinear response of a linear chain to weak driving.

We study the escape of a chain of coupled units over the barrier of a metastable potential. It is demonstrated that a very weak external driving field with a suitably chosen frequency suffices to accomplish speedy escape. The latter requires passage through a transition state, the formation of which is triggered by permanent feeding of energy from a phonon background into humps of localized energy and elastic interaction of the arising breather solutions.

Persistence of uphill anomalous transport in inhomogeneous media.

For systems out of equilibrium and subjected to a static bias force it can often be expected that particle transport will usually follow the direction of this bias. However, counterexamples exist where particles exhibit uphill motion (known as absolute negative mobility, ANM), particularly in the case of coupled particles. Examples in single particle deterministic systems are less common.

Current reversals of coupled driven and damped particles evolving in a tilted potential landscape.

We explore the driven and damped dynamics of two coupled particles evolving in a symmetric and periodic substrate potential that is subjected to a static bias force. In addition, each particle is time-periodically driven with the same magnitude as, but out of phase to, its counterpart. It is shown that, for a certain parameter regime, the coupled particles can become self-organized and go against the direction of the bias force.

Current reversals and current suppression in an open two-degree-of-freedom system.

We explore the scattering of particles evolving in a two-degree-of-freedom Hamiltonian system, in which both degrees of freedom are open. Particles, initially having all kinetic energy, are sent into a so-called "interaction region," where there will be an exchange of energy with particles that are initially at rest. The open nature of both components of this system eliminates any restrictions on which particles can escape from the interaction region.

From collective periodic running states to completely chaotic synchronised states in coupled particle dynamics.

We consider the damped and driven dynamics of two interacting particles evolving in a symmetric and spatially periodic potential. The latter is exerted to a time-periodic modulation of its inclination. Our interest is twofold: First, we deal with the issue of chaotic motion in the higher-dimensional phase space.

Emergence of continual directed flow in hamiltonian systems.

We propose a minimal model for the emergence of a directed flow in autonomous hamiltonian systems. It is shown that internal breaking of the spatiotemporal symmetries, via localized initial conditions, which are unbiased with respect to the transporting degree of freedom, and transient chaos conspire to form the physical mechanism for the occurrence of a current. Most importantly, after passage through the transient chaos, trajectories perform solely regular transporting motion so that the resulting current is of continual ballistic nature.

Half-Fourier acquisition single-shot turbo spin echo imaging in the diagnosis of Morgagni hernia.

Magnetic resonance (MR) imaging with multi-planar, gated Half-Fourier Acquisition Single-Shot Turbo Spin-Echo (HASTE) imaging was performed to evaluate a woman with dysrhythmia. MR examination for right ventricular dysplasia revealed a Morgagni hernia. The HASTE images depicted well the diaphragmatic defect and the organs involved, yielding valuable diagnostic and pre-operative information.

Feasibility and profitability of a radiology department providing trauma US as part of a trauma alert team.

Rationale And Objectives: The purpose of this study was to assess the feasibility and profitability of a radiology department providing a six-point trauma ultrasound (US) examination for abdominal or pelvic free fluid as part of a trauma alert team.

Materials And Methods: The study included 191 trauma alerts, which generated 156 US examinations. A radiologist and a departmental technologist carried beepers and responded to level I and II traumas.

Transesophageal echocardiographic diagnosis of pulmonary arteriovenous malformation. Role of contrast and pulsed Doppler echocardiography.

Contrast echocardiography produced by peripheral injection of agitated saline solution is widely used for detecting intracardiac and intrathoracic extracardiac shunts, like pulmonary arteriovenous malformation (PAVM). Currently, localization of PAVM requires pulmonary angiography even after detection by computed tomography of the chest. Pulsed Doppler along with contrast echocardiography of the pulmonary veins performed during transesophageal echocardiography may aid in the localization of PAVM and in its diagnosis.

Efficacy of oral and intravenous indecainide in ventricular arrhythmias.

To evaluate the efficacy of oral and intravenous indecainide, a new class IC antiarrhythmic agent, 3 separate protocols were performed in patients with benign or potentially lethal ventricular arrhythmias. An open-label intravenous trail in 10 patients was conducted using a dose of 1.7 mg/kg/min under constant monitoring.

Bepridil hydrochloride for treatment of benign or potentially lethal ventricular arrhythmias.

To define the efficacy and safety of a new once-a-day calcium antagonist, bepridil, 21 patients with frequent ventricular premature complexes (VPCs) underwent a 14-day inpatient monitored trial. After Holter monitoring during placebo administration, patients underwent 2 days of a loading dose of bepridil followed by 12 days of bepridil, 400 mg/day. Holter monitoring during therapy showed that 10 patients (48%) had more than a 70% reduction in VPC frequency and 8 of 16 patients (50%) at least a 95% reduction in frequency of nonsustained ventricular tachycardia.

New observations of soft tissue sarcomas with contrast medium-enhanced computed tomography.

Computed tomography examinations were performed on 74 patients who presented to the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania with a known or suspected diagnosis of primary or secondary soft tissue sarcoma. Focal masses were detected on computed tomography study in 59 patients. These masses were classified into three broad categories: centrally necrotic masses with a large predominantly liquefactive center and higher density periphery (29); multilocular, septated masses with distinct linear bands or striations (21); and miscellaneous masses (9).

Comparison of clinical and computed tomographic staging of head and neck tumors.

The extent of tumor was staged independently using conventional clinical methods and high-resolution computed tomography (CT) in 100 patients with tumors at the base of the skull, nasopharynx, oropharynx, hypopharynx, larynx, nose, and paranasal sinuses. Conventional clinical methods used for staging included physical examination, routine biopsy, routine radiography, tomography, and sonography when appropriate. In 10 patients, CT identified tumors that had not been apparent clinically; eight of these were in the nasopharynx and two in the hypopharynx.

External imaging techniques for quantitation of distribution of I-131 F(ab')2 fragments of monoclonal antibody in humans.

We have employed noninvasive, external counting techniques for quantitation of I-131 F(ab')2 fragment of mouse monoclonal antibody localized in metastatic lesions and surrounding liver tissue in humans. This method utilizes counts from diametrically opposed views of tumor deposits and surrounding normal tissue. Corrections were made for patient attenuation, lesion size, and surrounding tissue activity.