Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

P-glycoprotein (P-gp) is one of the best-known mediators of drug efflux-based multidrug resistance in many cancers. This validated therapeutic target is a prototypic, plasma membrane resident ATPBinding Cassette transporter that pumps xenobiotic compounds out of cells. The large, polyspecific drug-binding pocket of P-gp recognizes a variety of structurally unrelated compounds. The transport of these drugs across the membrane is coincident with changes in the size and shape of this pocket during the course of the transport cycle. Here, we present the crystal structures of three inward-facing conformations of mouse P-gp derived from two different crystal forms. One structure has a nanobody bound to the C-terminal side of the first nucleotide-binding domain. This nanobody strongly inhibits the ATP hydrolysis activity of mouse Pgp by hindering the formation of a dimeric complex between the ATP-binding domains, which is essential for nucleotide hydrolysis. Together, these inward-facing conformational snapshots of P-gp demonstrate a range of flexibility exhibited by this transporter, which is likely an essential feature for the binding and transport of large, diverse substrates. The nanobody-bound structure also reveals a unique epitope on P-gp.

Ontogeny of mouse B lymphocytes and inactivation by antigen of early B lymphocytes

Taking advantage of recent findings about membrane fluidity, the authors studied and compared the biosynthetic capacities of fetal or neonatal mouse B (bone marrow derived) lymphocytes (until 10 days after birth) and adult B lymphocytes. Although both early and adult lymphocytes can synthesize surface immunoglobulins, they have a different physiological behavior after interaction with a ligand (anti immunoglobulin sera or antigen), either in vivo or in vitro. Fetal and neonatal lymphocytes bearing surface immunoglobulins do not reexpress their membrane receptors after capping and endocytosis promoted by anti immunoglobulin sera. On the other hand, adult lymphocytes resynthesize completely their receptors after the same treatment. Furthermore, intrafetal injections of hemocyanin in pregnant mice lead to a striking decrease in the number of hemocyanin binding cells. It seems plausible that this non reexpression of surface immunoglobulins could be the first step in tolerance establishment.

Broadband pulse propagation with electromagnetically induced transparency: Splitting of adiabatic and nonadiabatic components

The propagation of a broadband pulse through a dense resonant medium with a narrow transparency window is considered. We show that the pulse splits into a slowly propagating adiabatic part and a fast nonadiabatic part. © 2005 Optical Society of America.

Expression, purification and X-ray crystallographic analysis of the Helicobacter pylori blood group antigen-binding adhesin BabA

Helicobacter pylori is a human pathogen that colonizes about 50% of the world's population, causing chronic gastritis, duodenal ulcers and even gastric cancer. A steady emergence of multiple antibiotic resistant strains poses an important public health threat and there is an urgent requirement for alternative therapeutics. The blood group antigen-binding adhesin BabA mediates the intimate attachment to the host mucosa and forms a major candidate for novel vaccine and drug development. Here, the recombinant expression and crystallization of a soluble BabA truncation (BabA^25-460) corresponding to the predicted extracellular adhesin domain of the protein are reported. X-ray diffraction data for nanobody-stabilized BabA^25-460 were collected to 2.25Å resolution from a crystal that belonged to space group P21, with unit-cell parameters a = 50.96, b = 131.41, c = 123.40Å, α = 90.0, β = 94.8, γ = 90.0°, and which was predicted to contain two BabA^25-460-nanobody complexes per asymmetric unit.

Global carbon dioxide emissions from inland waters

Carbon dioxide (CO2) transfer from inland waters to the atmosphere, known as CO2 evasion, is a component of the global carbon cycle. Global estimates of CO2 evasion have been hampered, however, by the lack of a framework for estimating the inland water surface area and gas transfer velocity and by the absence of a global CO2 database. Here we report regional variations in global inland water surface area, dissolved CO2 and gas transfer velocity. We obtain global CO2 evasion rates of 1.8petagrams of carbon (Pg C) per year from streams and rivers and 0.32Pg Cyr-1 from lakes and reservoirs, where the upper and lower limits are respectively the 5th and 95th confidence interval percentiles. The resulting global evasion rate of 2.1 Pg Cyr-1 is higher than previous estimates owing to a larger stream and river evasion rate. Our analysis predicts global hotspots in stream and river evasion, with about 70 per cent of the flux occurring over just 20 per cent of the land surface. The source of inland water CO2 is still not known with certainty and new studies are needed to research the mechanisms controlling CO2 evasion globally. © 2013 Macmillan Publishers Limited. All rights reserved.

Age-related immune reconstitution during highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children [2] (multiple letters)

SCOPUS: le.j

Toward understanding the essence of post-translational modifications for the Mycobacterium tuberculosis immunoproteome

CD4⁺ T cells are prominent effector cells in controlling Mycobacterium tuberculosis (Mtb) infection but may also contribute to immunopathology. Studies probing the CD4⁺ T cell response from individuals latently infected with Mtb or patients with active tuberculosis using either small or proteome-wide antigen screens so far revealed a multi-antigenic, yet mostly invariable repertoire of immunogenic Mtb proteins. Recent developments in mass spectrometry-based proteomics have highlighted the occurrence of numerous types of post-translational modifications (PTMs) in proteomes of prokaryotes, including Mtb. The well-known PTMs in Mtb are glycosylation, lipidation, or phosphorylation, known regulators of protein function or compartmentalization. Other PTMs include methylation, acetylation, and pupylation, involved in protein stability. While all PTMs add variability to the Mtb proteome, relatively little is understood about their role in the anti-Mtb immune responses. Here,we reviewMtb protein PTMs and methods to assess their role in protective immunity against Mtb. © 2014 van Els, Corbière, Smits, vanGaans-van den Brink, Poelen, Mascart, Meiring and Locht.

Social tourism today: Stakeholders, and supply and demand factors

As highlighted in the previous chapter, the definitions and consequently the expression of social tourism have developed and changed since its inception in the 19th century. In post-modern times there has been a significant evolution of the needs, the expectations and the possibilities (or opportunities) for holidaymaking and travel in general for the majority of people in Europe. Socio-political, economic and technological developments have forged a new context for tourism and created new travel opportunities (see Chapter 6). While the numbers of tourism trips have grown steadily over time, tourism participation levels in Europe have largely stabilised: there are still a number of groups in contemporary society who are excluded from tourism. Social tourism has adapted to societal changes and has changed its focus from factory workers and manual labourers towards the current main four target groups.

PHARMACORADIOLOGIE ET PHARMACOTHERAPIE LYMPHATIQUES

SCOPUS: NotDefined.j

Fundamental limits to few-cycle pulse generation from compression of broadband supercontinua generated in photonic crystal fiber

The compression properties of octave-spanning supercontinuum spectra generated in photonic crystal fibers are studied using stochastic nonlinear Schrödinger equation simulations. The conditions under which sub-5 fs pulses can be obtained after compression are identified. © 2004 Optical Society of America.

CRYPTOSPORIDIUM RELATED TO MEASLES DIARRHOEA IN RWANDA

SCOPUS: le.j

The complexity of Drosophila innate immunity

Metazoans rely on efficient mechanisms to oppose infections caused by pathogens. The immediate and first-line defense mechanism(s) in metazoans, referred to as the innate immune system, is initiated upon recognition of microbial intruders by germline encoded receptors and is executed by a set of rapid effector mechanisms. Adaptive immunity is restricted to vertebrate species and it is controlled and assisted by the innate immune system. Interestingly, most of the basic signaling cascades that regulate the primeval innate defense mechanism(s) have been well conserved during evolution, for instance between humans and the fruit fly, Drosophila melanogaster. Being devoid of adaptive signaling and effector systems, Drosophila has become an established model system for studying pristine innate immune cascades and reactions. In general, an immune response is evoked when microorganisms pass the fruit fly’s physical barriers (e.g. cuticle, epithelial lining of gut and trachea), and it is mainly executed in the hemolymph, the equivalent of the mammalian blood. Innate immunity in the fruit fly consists of a phenoloxidase (PO) response, a cellular response (hemocytes), an antiviral response, and the NF-κB dependent production of antimicrobial peptides referred to as the humoral response. The JAK/STAT and Jun kinase signaling cascades are also implicated in the defence against pathogens.

Making community media work: Community media identities and their articulation in an Antwerp neighbourhood development project

SCOPUS: ch.b

Special Issues in the Young and Pregnant Patient with Breast Cancer

This chapter presents a series of multiple choice questions and answers on the special issues in the young and pregnant patient with breast cancer. It also presents a series of case studies with questions and answers on the special issues in the young and pregnant patient with breast cancer. The chapter examines whether the genomic testing by Oncotype DX or MammaPrint be helpful in managing the patient. It also examines the factors that are the most important in determining the risk of chemotherapyinduced amenorrhea (CIA) in the patient, and a role for sentinel lymph node biopsy (SLNB) in patients diagnosed with breast cancer during pregnancy. The chapter discusses counselling of a patient who became accidentally pregnant on maintenance therapy with trastuzumab or tamoxifen. In addition, It examines the options that could be offered to preserve fertility.

Giant cell arteritis

Giant cell arteritis (GCA) or Horton's disease is a systemic granulomatous vasculitis of medium–and large–sized arteries. This is an antigen–driven disease with local T–cell and macrophage activation in the vessel wall and with an important role of proinflammatory cytokines. GCA is also called “temporal arteritis” because it involves often the superficial temporal arteries. The condition affects especially the extracranial branches of the carotid artery, but recently, GCA has been recognised to also affect limb arteries and the aorta with high prevalence.