Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11.

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent "direct" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex.

Top 10 Tips on Safety From the Air Medical Transport Industry.

The air medical transport industry places a high value on developing and maintaining a culture of safety due to the higher risk nature of its operations. The dynamic nature of response and transport, inherent risks involved with flight, lack of supporting resources, weather conditions, and austere nature of the transport environment are all factors that highlight the need for enhanced safety. As such, the air medical transport industry has developed a robust and unique approach to provider and patient safety involving many tactics not otherwise used in other areas of health care.

Short-Term Outcomes of Expedited Arthroscopic Tensionable Knotless Biologic Tuberoplasty for Massive Irreparable Rotator Cuff Tears.

Massive irreparable rotator cuff tears in the nonarthritic patient are challenging because of the high failure rate and technical difficulty of intraoperative repair. We examined the outcomes of expedited arthroscopic tensionable knotless biologic tuberoplasty for massive irreparable rotator cuff tears. Eleven patients with an average follow-up of 8.

Pediatric Orthopedic Trauma.

The management of pediatric orthopedic trauma continues to evolve rapidly. Whereas the strong healing potential of pediatric patients often allows for the nonoperative treatment of most conditions, many injuries require urgent operative treatment to ensure that patients may return to all activities without disability. Some injuries may require additional follow-up and interventions, as complications such as growth arrests or deformity may occur.

Ethical issues in patients referred for palliative radiation therapy.

Background: As patients with advanced cancer approach end of life, ethical issues may arise. We describe ethical issues encountered by radiation oncologists in this setting.

Methods: A prospective, survey-based study assessed 162 consecutive consults for palliative radiation therapy (PRT) over 4 months at 3 hospitals.

The glutathione cycle shapes synaptic glutamate activity.

Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one-third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate and could influence synaptic excitability.

Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition.

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling.

Supply and demand: How does variation in atmospheric oxygen during development affect insect tracheal and mitochondrial networks?

Atmospheric oxygen is one of the most important atmospheric component for all terrestrial organisms. Variation in atmospheric oxygen has wide ranging effects on animal physiology, development, and evolution. This variation in oxygen has the potential to affect both respiratory systems (the supply side) and mitochondrial networks (the demand side) in animals.

Burden of palliative care issues encountered by radiation oncologists caring for patients with advanced cancer.

Purpose: Radiation oncologists frequently provide care for patients with advanced cancer who are in their last months or weeks of life. This study examined the previously not well-characterized types and frequencies of palliative care issues encountered in consultations for palliative radiation therapy (PRT).

Methods And Materials: This prospective, survey-based study assessed consecutive consults for PRT from May 19, 2014, to September 26, 2014 at 3 Boston-area community and academic, hospital-based centers.

Mapped Grid Methods Applied to the Slow Variable Discretization--Enhanced Renormalized Numerov Approach.

We introduce a hyperspherical coordinate mapping procedure to the slow variable discretization-enhanced renormalized Numerov method that allows for more accurate and cost-effective calculations of cold and ultracold atom-dimer scattering. The mapping procedure allows optimization of the numerical grid point spacing by adjusting to the shape of the interaction potential. We show results for elastic scattering in HeH2 and compare the results to previous MOLSCAT calculations by Forrey et al.

Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs.

Lung disease is a major cause of death in the United States, with current therapeutic approaches serving only to manage symptoms. The most common chronic and life-threatening genetic disease of the lung is cystic fibrosis (CF) caused by mutations in the cystic fibrosis transmembrane regulator (CFTR). We have generated induced pluripotent stem cells (iPSCs) from CF patients carrying a homozygous deletion of F508 in the CFTR gene, which results in defective processing of CFTR to the cell membrane.

State-to-state three-atom time-dependent reactive scattering in hyperspherical coordinates.

We present a time-dependent, hyperspherical wave packet method for calculating three-atom state-to-state S-matrix elements. The wave packet is propagated in time using adiabatically adjusting, principal axes hyperspherical coordinates that treat all arrangement channels equivalently, allowing the simultaneous analysis of the products in all three arrangement channels. We take advantage of the symmetry of the potential energy surface and decompose the initial wave packet into its component irreducible representations, propagating each component separately.

Geometric phase for collinear conical intersections. I. Geometric phase angle and vector potentials.

We present a method for properly treating collinear conical intersections in triatomic systems. The general vector potential (gauge theory) approach for including the geometric phase effects associated with collinear conical intersections in hyperspherical coordinates is presented. The current study develops an introductory method in the treatment of collinear conical intersections by using the phase angle method.

Low-contrast bandgaps of a planar parabolic spiral lattice.

We show that a planar aperiodic lattice, mimicking the appearance of a sunflower, supports photonic bandgaps for weak dielectric contrast. The pattern's high orientational order and spatially uniform modal pitch yields an isotropic Fourier space. A 2D structure of cylinders (=2) in air possesses a wide 21% TM bandgap, versus 5.

Potential energy surfaces for the 1 (4)A('), 2 (4)A(') 1 (4)A(") and 2 (4)A(") states of Li(3).

Global potential energy surfaces for the 1 (4)A('), 2 (4)A('), 1 (4)A("), and 2 (4)A(") spin-aligned states of Li(3) are constructed as sums of a diatomics-in-molecules (DIM) term plus a three-body term. The DIM model, using a large basis set of 15 (4)A(") and 22 (4)A(') states, is used to obtain a "mixed-pairwise additive" contribution to the potential. A global fit of the three-body terms conserves the accuracy of the ab initio points of a full configuration-interaction calculation.

Laser-catalyzed production of ultracold molecules: the 6Li+6Li7Li-->homega6Li-6Li+7Li reaction.

We show that by using laser catalysis, we can employ translationally cold (Tr approximately 1.75 K) collisions to produce ultracold (0.01 mK View Article and Find Full Text PDF

Theory of laser enhancement of ultracold reactions: the fermion-boson population transfer by adiabatic passage of 6Li+6Li7Li(Tr=1 mK)-->6Li6Li+7Li(Tp=1 mK).

We present a new theory of population transfer by adiabatic passage. This theory relates laser catalysis to adiabatic passage, enhancing chemical reactions with the freedom to choose the translational energies of the reactants and products separately. The process, A+BC<-->(Planck's over omega(p) )ABC*(v)<-->(Planck's over omega(s))AB+C, involves two laser fields that are slowly varying so the process is adiabatic, and sufficiently intense so the population of the intermediate bound complex (ABC) is minimized.

Theory of laser enhancement and suppression of cold reactions: the fermion-boson 6Li+7Li2<-->(variant Planck's over 2pi omega0) 6Li7Li+7Li radiative collision.

We present a nonperturbative time-dependent quantum mechanical theory of the laser catalysis and control of a bifurcating A+BC<-->(variant Planck's over 2pi omega(0))ABC*(v)<-->(variant Planck's over 2pi omega(0) )AB+C reaction, with ABC*(v) denoting an intermediate, electronically excited, complex of ABC in the vth vibrational state. We apply this theory to the low collision energy fermion-boson light-induced exchange reaction, (6)Li((2)S)+(7)Li(2)((3)Sigma(u)(+))<-->(variant Planck's over 2pi omega(0))((6)Li(7)Li(7)Li)*<-->(variant Planck's over 2pi omega(0))(6)Li(7)Li((3)Sigma(+))+(7)Li((2)S). We show that at very low collision energies and energetically narrow (approximately 0.

Pestalotiopsin A. Side chain installation and exhaustive probing of olefin metathesis as a possible tool for elaborating the cyclononene ring.

A program directed toward an asymmetric synthesis of pestalotiopsin A is described. The routing begins with the dextrorotatory cyclobutanol 37, which is combined with the enantiomerically defined building blocks ent-15 and 16. These units are incorporated via stereocontrolled 1,2-nucleophilic addition and anti-aldol coupling, respectively.

Pestalotiopsin a. Enantioselective construction of potential building blocks derived from antipodal cyclobutanol intermediates.

D-Glyceraldehyde acetonide has been used as the starting point for accessing the enantiomeric cyclobutanols 11 in optically pure condition. The dextrorotatory enantiomer has been transformed in five steps into the [3.2.

New method for calculating bound states: the A(1) states of Li(3) on the spin-aligned Li(3)(1 (4)A(')) potential energy surface.

In this paper, we present a calculation for the bound states of A(1) symmetry on the spin-aligned Li(3)(1 (4)A(')) potential energy surface. We apply a mixture of discrete variable representation and distributed approximating functional methods to discretize the Hamiltonian. We also introduce a new method that significantly reduces the computational effort needed to determine the lowest eigenvalues and eigenvectors (bound state energies and wave functions of the full Hamiltonian).

In pursuit of pestalotiopsin a via zirconocene-mediated ring contraction.

[reaction: see text] An asymmetric route from the epimeric beta-hydroxy esters 4 and 5 to the densely functionalized (+)-10 and (-)-10, respectively, is described. Either cyclobutanol can be made available as the predominant product. The levorotatory antipode has been transformed into the advanced intermediate 21 bearing side chains destined to become incorporated into the cyclononene ring of the title compound (1).

General laser interaction theory in atom-diatom systems for both adiabatic and nonadiabatic cases.

This paper develops the general theory for laser fields interacting with bimolecular systems. In this study, we choose to use the multipolar gauge on the basis of gauge invariance. We consider both the adiabatic and nonadiabatic cases and find they produce similar interaction pictures.