Structure and immune recognition of trimeric pre-fusion HIV-1 Env.

The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.

IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells.

Objective: Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn's disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation.

Immunohistochemical toolkit for tracking and quantifying xenotransplanted human stem cells.

Aim: Biomarker-based tracking of human stem cells xenotransplanted into animal models is crucial for studying their fate in the field of cell therapy or tumor xenografting.

Materials & Methods: Using immunohistochemistry and in situ hybridization, we analyzed the expression of three human-specific biomarkers: Ku80, human mitochondria (hMito) and Alu.

Results: We showed that Ku80, hMito and Alu biomarkers are broadly expressed in human tissues with no or low cross-reactivity toward rat, mouse or pig tissues.

Iminosemiquinone radical ligands enable access to a well-defined redox-active Cu(II)-CF₃ complex.

The reaction of a copper complex bearing iminosemiquinone ligands with a CF3(+) source provides an unprecedented Cu(II)-CF3 complex through ligand-based oxidation. Reactivity of this complex leads to nucleophilic trifluoromethylation of the ligand, suggesting an electronic interplay that results in a formal umpolung of the initial CF3(+).

Engraftment and lineage potential of adult hematopoietic stem and progenitor cells is compromised following short-term culture in the presence of an aryl hydrocarbon receptor antagonist.

Hematopoietic stem cell gene therapy for HIV/AIDS is a promising alternative to lifelong antiretroviral therapy. One of the limitations of this approach is the number and quality of stem cells available for transplant following in vitro manipulations associated with stem cell isolation and genetic modification. The development of methods to increase the number of autologous, gene-modified stem cells available for transplantation would overcome this barrier.

Direct evidence of an elongation factor-Tu/Ts·GTP·Aminoacyl-tRNA quaternary complex.

During protein synthesis, elongation factor-Tu (EF-Tu) bound to GTP chaperones the entry of aminoacyl-tRNA (aa-tRNA) into actively translating ribosomes. In so doing, EF-Tu increases the rate and fidelity of the translation mechanism. Recent evidence suggests that EF-Ts, the guanosine nucleotide exchange factor for EF-Tu, directly accelerates both the formation and dissociation of the EF-Tu-GTP-Phe-tRNA(Phe) ternary complex (Burnett, B.

The bright future of single-molecule fluorescence imaging.

Single-molecule Förster resonance energy transfer (smFRET) is an essential and maturing tool to probe biomolecular interactions and conformational dynamics in vitro and, increasingly, in living cells. Multi-color smFRET enables the correlation of multiple such events and the precise dissection of their order and timing. However, the requirements for good spectral separation, high time resolution, and extended observation times place extraordinary demands on the fluorescent labels used in such experiments.

A theoretical model to describe progressions and regressions for exercise rehabilitation.

This article aims to describe a new theoretical model to simplify and aid visualisation of the clinical reasoning process involved in progressing a single exercise. Exercise prescription is a core skill for physiotherapists but is an area that is lacking in theoretical models to assist clinicians when designing exercise programs to aid rehabilitation from injury. Historical models of periodization and motor learning theories lack any visual aids to assist clinicians.

Solid-state hierarchical cyclodextrin-based supramolecular polymer constructed by primary, secondary, and tertiary azido interactions.

The crystallization of a di-azido-α-cyclodextrin revealed a polymeric self-assembly involving a variety of azido-type interactions. The crystal arrangement relies on the cooperativity of a primary azido inclusion, a secondary azido-azido interaction involving an unprecedented distribution of canonical forms, and a tertiary azido-groove interaction. The second azido group brings in a major contribution to the supramolecular structure illustrating the benefit of a difunctionalization for the generation of hierarchy.

Tandem C-H activation/arylation catalyzed by low-valent iron complexes with bisiminopyridine ligands.

Tandem C-H activation/arylation between unactivated arenes and aryl halides catalyzed by iron complexes that bear redox-active non-innocent bisiminopyridine ligands is reported. Similar reactions catalyzed by first-row transition metals have been shown to involve substrate-based aryl radicals, whereas our catalytic system likely involves ligand-centered radicals. Preliminary mechanistic investigations based on spectroscopic and reactivity studies, in conjunction with DFT calculations, led us to propose that the reaction could proceed through an inner-sphere C-H activation pathway, which is rarely observed in the case of iron complexes.

Synthesis of triangular tripalladium cations as noble-metal analogues of the cyclopropenyl cation.

The first C3 -symmetric 44-core-valence-electron triangular palladium clusters, [{(SAr')(PAr3 )Pd}3 ](+) , have been synthesized by activation of the CS bond of isothioureas. Owing to delocalized metal-metal bonding, these stable complexes are the first noble-metal analogues of the π-aromatic cyclopropenyl cation [C3 H3 ](+) , with their all-metal aromaticity involving d-type atomic orbitals.

Biased predecisional processing of leading and nonleading alternatives.

When people obtain information about choice alternatives in a set one attribute at a time, they rapidly identify a leading alternative. Although previous research has established that people then distort incoming information, it is unclear whether distortion occurs through favoring of the leading alternative, disfavoring of the trailing alternative, or both. Prior examinations have not explored the predecisional treatment of the nonleading alternative (or alternatives) because they conceptualized distortion as a singular construct in binary choice and measured it using a relative item comparing the evaluation of both alternatives simultaneously.

The contribution of reactive oxygen species to the photobleaching of organic fluorophores.

Photoexcitation of fluorophores commonly used for biological imaging applications generates reactive oxygen species (ROS) which can cause bleaching of the fluorophore and damage to the biological system under investigation. In this study, we show that singlet oxygen contributes relatively little to Cy5 and ATTO 647N photobleaching at low concentrations in aqueous solution. We also show that Cy5 generates significantly less ROS when covalently linked to the protective agents, cyclooctatetraene (COT), nitrobenzyl alcohol (NBA) or Trolox.

Ultra-stable organic fluorophores for single-molecule research.

Fluorescence provides a mechanism for achieving contrast in biological imaging that enables investigations of molecular structure, dynamics, and function at high spatial and temporal resolution. Small-molecule organic fluorophores have proven essential for such efforts and are widely used in advanced applications such as single-molecule and super-resolution microscopy. Yet, organic fluorophores, like all fluorescent species, exhibit instabilities in their emission characteristics, including blinking and photobleaching that limit their utility and performance.

The central role of protein S12 in organizing the structure of the decoding site of the ribosome.

The ribosome decodes mRNA by monitoring the geometry of codon-anticodon base-pairing using a set of universally conserved 16S rRNA nucleotides within the conformationally dynamic decoding site. By applying single-molecule FRET and X-ray crystallography, we have determined that conditional-lethal, streptomycin-dependence mutations in ribosomal protein S12 interfere with tRNA selection by allowing conformational distortions of the decoding site that impair GTPase activation of EF-Tu during the tRNA selection process. Distortions in the decoding site are reversed by streptomycin or by a second-site suppressor mutation in 16S rRNA.

Implementing routine screening for distress, the sixth vital sign, for patients with head and neck and neurologic cancers.

This study examined the benefits of incorporating screening for distress as a routine part of care for patients with head and neck and neurologic cancers in a tertiary cancer center. Using a comparative 2-cohort pre-post implementation sequential design, consecutive outpatients with head and neck and neurologic cancers were recruited into 2 separate cohorts. Cohort 1 included patients attending clinics during April 2010, before the implementation of the screening program.

Noise intensity-intensity correlations and the fourth cumulant of photo-assisted shot noise.

We report the measurement of the fourth cumulant of current fluctuations in a tunnel junction under both dc and ac (microwave) excitation. This probes the non-Gaussian character of photo-assisted shot noise. Our measurement reveals the existence of correlations between noise power measured at two different frequencies, which corresponds to two-mode intensity correlations in optics.

Atraumatic painless compartment syndrome.

Acute compartment syndrome is a time-sensitive diagnosis and surgical emergency because it poses a threat to life and the limbs. It is defined by Matsen et al (Surg Gynecol Obstet. 1978;147(6):943–949) as "a condition in which increased pressure within a limited space compromises the circulation and function of the tissues within that space.

Tuning a riboswitch response through structural extension of a pseudoknot.

Structural and dynamic features of RNA folding landscapes represent critical aspects of RNA function in the cell and are particularly central to riboswitch-mediated control of gene expression. Here, using single-molecule fluorescence energy transfer imaging, we explore the folding dynamics of the preQ1 class II riboswitch, an upstream mRNA element that regulates downstream encoded modification enzymes of queuosine biosynthesis. For reasons that are not presently understood, the classical pseudoknot fold of this system harbors an extra stem-loop structure within its 3'-terminal region immediately upstream of the Shine-Dalgarno sequence that contributes to formation of the ligand-bound state.

A prospective, multicenter study of bovine pericardium membrane with cancellous particulate allograft for localized alveolar ridge augmentation.

Resorption of the alveolar ridge may lead to ridge deformities that make dental implant placement difficult or impossible. Augmentation of the alveolar ridge may restore appropriate ridge form to allow implant placement. Forty-four patients with edentulous spaces completed this multicenter prospective trial to clinically and radiographically evaluate the efficacy of a bovine pericardium membrane and a particulate mineralized cancellous bone allograft in promoting lateral ridge augmentation.

Transport dynamics in a glutamate transporter homologue.

Glutamate transporters are integral membrane proteins that catalyse neurotransmitter uptake from the synaptic cleft into the cytoplasm of glial cells and neurons. Their mechanism of action involves transitions between extracellular (outward)-facing and intracellular (inward)-facing conformations, whereby substrate binding sites become accessible to either side of the membrane. This process has been proposed to entail transmembrane movements of three discrete transport domains within a trimeric scaffold.

Small-molecule photostabilizing agents are modifiers of lipid bilayer properties.

Small-molecule photostabilizing or protective agents (PAs) provide essential support for the stability demands on fluorescent dyes in single-molecule spectroscopy and fluorescence microscopy. These agents are employed also in studies of cell membranes and model systems mimicking lipid bilayer environments, but there is little information about their possible effects on membrane structure and physical properties. Given the impact of amphipathic small molecules on bilayer properties such as elasticity and intrinsic curvature, we investigated the effects of six commonly used PAs--cyclooctatetraene (COT), para-nitrobenzyl alcohol (NBA), Trolox (TX), 1,4-diazabicyclo[2.

Fragment-based ligand design of novel potent inhibitors of tankyrases.

Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding.

Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.

High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.