A new model system identifies epidermal growth factor receptor-human epidermal growth factor receptor 2 (HER2) and HER2-human epidermal growth factor receptor 3 heterodimers as potent inducers of oesophageal epithelial cell invasion.

Oesophageal squamous cell carcinomas and oesophageal adenocarcinomas show distinct patterns of ErbB expression and dimers. The functional effects of specific ErbB homodimers or heterodimers on oesophageal (cancer) cell behaviour, particularly invasion during early carcinogenesis, remain unknown. Here, a new cellular model system for controlled activation of epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) and EGFR-HER2 or HER2-human epidermal growth factor receptor 3 (HER3) homodimers and heterodimers was studied in non-neoplastic squamous oesophageal epithelial Het-1A cells.

Identifying prebariatric subtypes based on temperament traits, emotion dysregulation, and disinhibited eating: A latent profile analysis.

Objective: The efficacy of bariatric surgery has been proven; however, a subset of patients fails to achieve expected long-term weight loss postoperatively. As differences in surgery outcome may be influenced by heterogeneous psychological profiles in prebariatric patients, previous subtyping models differentiated patients based on temperament traits. The objective of this study was to expand these models by additionally considering emotion dysregulation and disinhibited eating behaviors for subtyping, as these factors were associated with maladaptive eating behaviors and poor postbariatric weight loss outcome.

Kinetics of Circulating MicroRNAs in Response to Cardiac Stress in Patients With Coronary Artery Disease.

Background: Circulating microRNAs (miRNAs/miRs) are regulated in patients with coronary artery disease. The impact of transient coronary ischemia on circulating miRNA levels is unknown. We aimed to investigate circulating miRNA kinetics in response to cardiac stress in patients with or without significant coronary stenosis.

High-concentration protein formulations: How high is high?

High-concentration protein formulation (HCPF) is a term that is used to describe protein formulations, mostly monoclonal antibody (mAb) drugs, at high protein concentration. The concentration is rarely defined, with typical ranges varying between 50 and 150mg/ml for mAbs. The term HCPF is meant to include and express specific solution properties of formulations that are prone to appear at high protein concentrations such as high viscosity, high opalescence, phase separation, gel formation or the increased propensity for protein particle formation.

Probing the potential of CnaB-type domains for the design of tag/catcher systems.

Building proteins into larger, post-translational assemblies in a defined and stable way is still a challenging task. A promising approach relies on so-called tag/catcher systems that are fused to the proteins of interest and allow a durable linkage via covalent intermolecular bonds. Tags and catchers are generated by splitting protein domains that contain intramolecular isopeptide or ester bonds that form autocatalytically under physiological conditions.

Dehydrogenation of cyclic amines by a coordinatively unsaturated Cp*Ir(iii) phosphoramidate complex.

The reaction of a Cp*Ir(iii) phosphoramidate complex with secondary amines gives amine, imine-bound Cp*Ir(iii) hydride complexes resulting from amine dehydrogenation. These well-characterized species could serve as models of relevant intermediates that have been proposed in catalytic amine dehydrogenation using related N,O-chelated Cp*Ir(iii) pyridonate complexes.

Partial Dissociation of Truncated Peptides Influences the Structural Dynamics of the MHCI Binding Groove.

Antigen processing on MHCI involves the exchange of low-affinity peptides by high-affinity, immunodominant ones. This peptide editing process is mediated by tapasin and ERAAP at the peptide C- and N-terminus, respectively. Since tapasin does not contact the peptide directly, a sensing mechanism involving conformational changes likely allows tapasin to distinguish antigen-loaded MHCI molecules from those occupied by weakly bound, non-specific peptides.

Effects of Cycling and Exergaming on Neurotrophic Factors in Elderly Type 2 Diabetic Men - A Preliminary Investigation.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing neurodegenerative diseases. There is growing evidence that repeated exercise-induced transient increases in neurotrophic factors can augment neurogenesis and neuroplasticity. This pilot study compares the effects of 30-min submaximal cycling with those of exergaming (combining exercise and video gaming) at the same duration and same rating of perceived exertion (BORG RPE: 14-15) on serum neurotrophic factors in 8 elderly non-insulin-dependent T2DM patients (71±4 years) (2×2 crossover design).

Bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) Complexes: Probing Amidate and Pyridonate Hemilability.

Four new bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) complexes (3-6), in which the N,O-chelate is an amidate or pyridonate ligand, have been synthesized and characterized. Computational analysis has been used to calculate the relative energies of different stereoisomers and shown how the steric demand of each ligand influences coordination and bonding modes. The electronically saturated complexes have been employed to evaluate 1,3-N,O-chelated metal-ligand interactions.

1,3-N,O-Complexes of late transition metals. Ligands with flexible bonding modes and reaction profiles.

1,3-N,O-Chelating ligands are ubiquitous in nature owing to their occurrence as α-chiral amino acids in metalloproteins. These structural units also display diverse coordination modes, which lend themselves to applications in catalysis as well as novel fundamental stoichiometric reactivity, including the activation of inert bonds. This review comments on recent developments in N,O-ligated late transition metal complexes with an emphasis on preparation, characterization, and reactivity.

A refined polarizable water model for the coarse-grained MARTINI force field with long-range electrostatic interactions.

We present a refined version of the polarizable Martini water model - coined refPOL - designed specifically for the use with long-range electrostatics. The refPOL model improves the agreement with the experimentally measured dielectric constant and the mass density of water at room temperature compared to the original polarizable Martini water force field when particle mesh Ewald electrostatics are employed. Our study reveals that the model remains applicable with various commonly used settings for the non-bonded interactions, including reaction field electrostatics.

Solvent effects on ligand binding to a serine protease.

Solvation plays an important role in virtually all biomolecular recognition and binding processes. However, the consequences of changes in solvation conditions often remain elusive. In this work, we combined isothermal titration calorimetry (ITC) and molecular dynamics (MD) simulations to investigate the effect of solvent composition on the thermodynamics of protein-ligand binding.

Systematic evaluation of CS-Rosetta for membrane protein structure prediction with sparse NOE restraints.

We critically test and validate the CS-Rosetta methodology for de novo structure prediction of α-helical membrane proteins (MPs) from NMR data, such as chemical shifts and NOE distance restraints. By systematically reducing the number and types of NOE restraints, we focus on determining the regime in which MP structures can be reliably predicted and pinpoint the boundaries of the approach. Five MPs of known structure were used as test systems, phototaxis sensory rhodopsin II (pSRII), a subdomain of pSRII, disulfide binding protein B (DsbB), microsomal prostaglandin E2 synthase-1 (mPGES-1), and translocator protein (TSPO).

AvrPm2 encodes an RNase-like avirulence effector which is conserved in the two different specialized forms of wheat and rye powdery mildew fungus.

There is a large diversity of genetically defined resistance genes in bread wheat against the powdery mildew pathogen Blumeria graminis (B. g.) f.

Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines.

An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated.

Oxidation State Dependent Coordination Modes: Accessing an Amidate-Supported Nickel(I) δ-bis(C-H) Agostic Complex.

Amidate-supported two- and three-coordinate Ni complexes were synthesized by reduction of the corresponding Ni precursors. A dramatic change in binding mode is observed upon reduction from Ni to Ni . The Ni derivatives include an unprecedented Ni bis(C-H) agostic complex and a two-coordinate Ni complex.

Hydration Dynamics of a Peripheral Membrane Protein.

Water dynamics in the hydration shell of the peripheral membrane protein annexin B12 were studied using MD simulations and Overhauser DNP-enhanced NMR. We show that retardation of water motions near phospholipid bilayers is extended by the presence of a membrane-bound protein, up to around 10 Å above that protein. Near the membrane surface, electrostatic interactions with the lipid head groups strongly slow down water dynamics, whereas protein-induced water retardation is weaker and dominates only at distances beyond 10 Å from the membrane surface.

Integrating Collaborative Learning and Competition in a Hematology/Oncology Training Program.

New educational methods and structures to improve medical education are needed to face the challenge of an exponential increase and complexity of medical knowledge. Collaborative learning has been increasingly used in education, but its use in medical training programs is in its infancy, and its impact is still unknown; the role of competition in education is more controversial. We introduced these pedagogical methods to the hematology/oncology fellowship program at the University of Arkansas for Medical Sciences to improve attendance and performance at didactic activities and different educational outcomes.

Toward anti-Markovnikov 1-Alkyne O-Phosphoramidation: Exploiting Metal-Ligand Cooperativity in a 1,3-N,O-Chelated Cp*Ir(III) Complex.

Metal-ligand cooperation between iridium(III) and a 1,3-N,O-chelating phosphoramidate ligand has been used to develop a protocol for the intermolecular O-phosphoramidation of 1-alkynes. This selective C-O bond-forming reaction differs from that of standard amidation reactions, highlighting the ability to control N- or O-functionalization based on judicious choice of N,O-chelating ligand and metal center. Advances toward the development of catalytic anti-Markovnikov O-phosphoramidation using iridium(III), including characterization of rare reactive intermediates that invoke 1,3-bidentate donor ligand hemilability, are disclosed.

Release of Entropic Spring Reveals Conformational Coupling Mechanism in the ABC Transporter BtuCD-F.

Substrate translocation by ATP-binding cassette (ABC) transporters involves coupling of ATP binding and hydrolysis in the nucleotide-binding domains (NBDs) to conformational changes in the transmembrane domains. We used molecular dynamics simulations to investigate the atomic-level mechanism of conformational coupling in the ABC transporter BtuCD-F, which imports vitamin B12 across the inner membrane of Escherichia coli. Our simulations show how an engineered disulfide bond across the NBD dimer interface reduces conformational fluctuations and hence configurational entropy.

Phosphoramidate-Supported Cp*Ir(III) Aminoborane H2 B=NR2 Complexes: Synthesis, Structure, and Solution Dynamics.

Reaction of aminoboranes H2 B=NR2 (R=iPr or Cy) with the cationic Cp*Ir(III) phosphoramidate complex [IrCp*{κ(2) -N,O-Xyl(N)P(O)(OEt)2 }][BAr(F) 4 ] generates the aminoborane complexes [IrCp*(H){κ(1) -N-η(2) -HB-Xyl(N)P(OBHNR2 )(OEt)2 }][BAr(F) 4 ] (R=iPr or Cy) in which coordination of a P=O bond with boron weakens the B=N multiple bond. For these complexes, solution- and solid-state, as well as DFT computational techniques, have been employed to substantiate B-N bond rotation of the coordinated aminoborane.

Capturing HBCy2: Using N,O-Chelated Complexes of Rhodium(I) and Iridium(I) for Chemoselective Hydroboration.

1,3-N,O-chelated complexes of Rh(I) and Ir(I) cooperatively and reversibly stabilized the B-H bond of HBCy2 to afford six-membered metallaheterocycles (M=Rh (7) or Ir (8)) having a δ-[M]⋅⋅⋅H-B agostic interaction. Treatment of these Shimoi-type borane adducts 7 or 8 with both an aldehyde and an alkene resulted in chemoselective aldehyde hydroboration and reformation of the 1,3-N,O-chelated starting material. The observed chemoselectivity is inverted from that of free HBCy2 , which is selective for alkene hydroboration.

Molecular mechanism of peptide editing in the tapasin-MHC I complex.

Immune recognition of infected or malignantly transformed cells relies on antigenic peptides exposed at the cell surface by major histocompatibility complex class I (MHC I) molecules. Selection and loading of peptides onto MHC I is orchestrated by the peptide-loading complex (PLC), a multiprotein assembly whose structure has not yet been resolved. Tapasin, a central component of the PLC, stabilises MHC I and catalyses the exchange of low-affinity against high-affinity, immunodominant peptides.

Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch.

Salt bridges in lipid bilayers play a decisive role in the dynamic assembly and downstream signaling of the natural killer and T-cell receptors. Here, we describe the identification of an inter-subunit salt bridge in the membrane within yet another key component of the immune system, the peptide-loading complex (PLC). The PLC regulates cell surface presentation of self-antigens and antigenic peptides via molecules of the major histocompatibility complex class I.

On Using Atomistic Solvent Layers in Hybrid All-Atom/Coarse-Grained Molecular Dynamics Simulations.

Hybrid all-atom/coarse-grained (AA-CG) simulations in which AA solutes are embedded in a CG environment can provide a significant computational speed-up over conventional fully atomistic simulations and thus alleviate the current length and time scale limitations of molecular dynamics (MD) simulations of large biomolecular systems. On one hand, coarse graining the solvent is particularly appealing, since it typically constitutes the largest part of the simulation system and thus dominates computational cost. On the other hand, retaining atomic-level solvent layers around the solute is desirable for a realistic description of hydrogen bonds and other local solvation effects.