Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy.

Unlabelled: The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e.

Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb.

How Far Can Life Cycle Assessment Be Simplified? A Protocol to Generate Simple and Accurate Models for the Assessment of Energy Systems and Its Application to Heat Production from Enhanced Geothermal Systems.

Life cycle assessments (LCAs) quantify environmental impacts of systems and support decision-making processes. LCAs are however time-consuming and difficult to conduct for nonexperts, thus calling for simplified approaches for multicriteria environmental assessments. In this paper, a five-step protocol is presented to generate simplified arithmetic equations from a reference parametrized LCA model of an energy system and its application illustrated for an enhanced geothermal system for heat generation with very low direct emissions in continental Europe.

Bactericidal Disruption of Magnesium Metallostasis in Mycobacterium tuberculosis Is Counteracted by Mutations in the Metal Ion Transporter CorA.

A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating Both families of compounds depleted of intrabacterial magnesium.

Opposing reactions in coenzyme A metabolism sensitize to enzyme inhibition.

(Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb's cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT.

LCA of emerging technologies: addressing high uncertainty on inputs' variability when performing global sensitivity analysis.

In the life cycle assessment (LCA) context, global sensitivity analysis (GSA) has been identified by several authors as a relevant practice to enhance the understanding of the model's structure and ensure reliability and credibility of the LCA results. GSA allows establishing a ranking among the input parameters, according to their influence on the variability of the output. Such feature is of high interest in particular when aiming at defining parameterized LCA models.

Specific Inhibition of the VEGFR-3 Tyrosine Kinase by SAR131675 Reduces Peripheral and Tumor Associated Immunosuppressive Myeloid Cells.

Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) represent prominent components in cancer progression. We previously showed that inhibition of the VEGFR-3 pathway by SAR131675 leads to reduction of TAM infiltration and tumor growth. Here, we found that treatment with SAR131675 prevents the accumulation of immunosuppressive blood and splenic MDSCs which express VEGFR-3, in 4T1 tumor bearing mice.

From LCAs to simplified models: a generic methodology applied to wind power electricity.

This study presents a generic methodology to produce simplified models able to provide a comprehensive life cycle impact assessment of energy pathways. The methodology relies on the application of global sensitivity analysis to identify key parameters explaining the impact variability of systems over their life cycle. Simplified models are built upon the identification of such key parameters.

SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities.

SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC(50) values of 20 and 45 nmol/L, respectively. SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC(50) of about 20 nmol/L.

Late endosomal cholesterol accumulation leads to impaired intra-endosomal trafficking.

Background: Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics.

Methodology/principal Findings: Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated.

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia.

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P.

The secreted form of dengue virus nonstructural protein NS1 is endocytosed by hepatocytes and accumulates in late endosomes: implications for viral infectivity.

The flavivirus nonstructural protein NS1 is expressed as three discrete species in infected mammalian cells: an intracellular, membrane-associated form essential for viral replication, a cell surface-associated form that may be involved in signal transduction, and a secreted form (sNS1), the biological properties of which remain elusive. To determine the distribution of the dengue virus (DEN) sNS1 protein in vivo, we have analyzed by immunohistological means the tissue tropism of purified DEN sNS1 injected intravenously into adult mice. The sNS1 protein was found predominantly associated with the liver, where hepatocytes appeared to represent a major target cell.

Endosome-to-cytosol transport of viral nucleocapsids.

During viral infection, fusion of the viral envelope with endosomal membranes and nucleocapsid release were thought to be concomitant events. We show here that for the vesicular stomatitis virus they occur sequentially, at two successive steps of the endocytic pathway. Fusion already occurs in transport intermediates between early and late endosomes, presumably releasing the nucleocapsid within the lumen of intra-endosomal vesicles, where it remains hidden.

High coding density on the largest Paramecium tetraurelia somatic chromosome.

Paramecium, like other ciliates, remodels its entire germline genome at each sexual generation to produce a somatic genome stripped of transposons and other multicopy elements. The germline chromosomes are fragmented by a DNA elimination process that targets heterochromatin to give a reproducible set of some 200 linear molecules 50 kb to 1 Mb in size. These chromosomes are maintained at a ploidy of 800n in the somatic macronucleus and assure all gene expression.

Role of LBPA and Alix in multivesicular liposome formation and endosome organization.

What are the components that control the assembly of subcellular organelles in eukaryotic cells? Although membranes can clearly be distorted by cytosolic factors, very little is known about the intrinsic mechanisms that control the biogenesis, shape, and organization of organellar membranes. Here, we found that the unconventional phospholipid lysobisphosphatidic acid (LBPA) could induce the formation of multivesicular liposomes that resembled the multivesicular endosomes that exist where this lipid is found in vivo. This process depended on the same pH gradient that exists across endosome membranes in vivo and was selectively controlled by Alix.

A new mouse limb mutation identifies a Twist allele that requires interacting loci on chromosome 4 for its phenotypic expression.

Pluridigite ( Pdt) is a semi-dominant mutation obtained after a mutagenesis experiment with ethyl-nitroso-urea (ENU). The mutant exhibits abnormal skeletal pattern formation characterized by the formation of extra digits (polydactyly) in the preaxial (anterior) part of the hindlimbs. The phenotype shows incomplete penetrance, depending on the genetic background.

[Juvenile polyposis coli. The usefulness of a genetic study and the role of surgical treatment].

We report two cases of familial juvenile polyposis coli. SMAD4 gene mutation was found in our two patients, leading to the definite diagnosis. Colonic cancer occurred in the first patient.

Unusual pattern of Sonic hedgehog expression in the polydactylous mouse mutant Hemimelic extra-toes.

We have examined the dynamic expression of Sonic hedgehog (Shh) in limb buds of the Hemimelic extra-toes (Hx) mutant. An ectopic domain of expression appears in the limb bud at embryonic day 11.5, which is not restricted to the anterior mesenchyme as in other polydactylous mutants, but extends along the entire apical ectodermal ridge.

The PPPY motif of human T-cell leukemia virus type 1 Gag protein is required early in the budding process.

Domains required late in the virus budding process (L domains) have been identified in the Gag proteins of a number of retroviruses. Here we show that the human T-cell leukemia virus type 1 candidate L domain motif PPPY is indeed required for virus production. Strikingly, however, mutation of this motif arrested virus particles at an earlier stage in the budding process than was seen for mutation of the L domain motifs thus far described for retroviruses.

Intracellular distribution of human T-cell leukemia virus type 1 Gag proteins is independent of interaction with intracellular membranes.

Retrovirus Gag proteins are synthesized on free ribosomes, and are sufficient to govern the assembly and release of virus particles. Like type C retroviruses, human T-cell leukemia virus type 1 (HTLV-1) assembles and buds at the plasma membrane. After immunofluorescence staining, HTLV-1 Gag proteins appear as punctuated intracellular clusters, which suggests that they are associated either with intracellular membranes or with the plasma membrane.