Discovery, isolation, and characterization of diazeniumdiolate siderophores.

The C-diazeniumdiolate (N-nitrosohydroxylamine) group in the amino acid graminine (Gra) is a newly discovered Fe(III) ligand in microbial siderophores. Graminine was first identified in the siderophore gramibactin, and since this discovery, other Gra-containing siderophores have been identified, including megapolibactins, plantaribactin, gladiobactin, trinickiabactin (gramibactin B), and tistrellabactins. The C-diazeniumdiolate is photoreactive in UV light which provides a convenient characterization tool for this type of siderophore.

Tistrellabactins A and B Are Photoreactive -Diazeniumdiolate Siderophores from the Marine-Derived Strain KA081020-065.

The -diazeniumdiolate group in the amino acid graminine is emerging as a new microbially produced Fe(III) coordinating ligand in siderophores, which is photoreactive. While the few siderophores reported from this class have only been isolated from soil-associated microbes, here we report the first -diazeniumdiolate siderophores tistrellabactins A and B, isolated from the bioactive marine-derived strain KA081020-065. The structural characterization of the tistrellabactins reveals unique biosynthetic features including an NRPS module iteratively loading glutamine residues and a promiscuous adenylation domain yielding either tistrellabactin A with an asparagine residue or tistrellabactin B with an aspartic acid residue at analogous positions.

-Diazeniumdiolate Graminine in the Siderophore Gramibactin Is Photoreactive and Originates from Arginine.

Siderophores are synthesized by microbes to facilitate iron acquisition required for growth. Catecholate, hydroxamate, and α-hydroxycarboxylate groups comprise well-established ligands coordinating Fe(III) in siderophores. Recently, a -type diazeniumdiolate ligand in the newly identified amino acid graminine (Gra) was found in the siderophore gramibactin (Gbt) produced by DSM 17151.

Resistance to Checkpoint Inhibition in Cancer Immunotherapy.

The interaction of the host immune system with tumor cells in the tissue microenvironment is essential in understanding tumor immunity and development of successful cancer immunotherapy. The presence of lymphocytes in tumors is highly correlated with an improved outcome. T cells have a set of cell surface receptors termed immune checkpoints that when activated suppress T cell function.

Immune Checkpoint Inhibitors as Switch or Continuation Maintenance Therapy in Solid Tumors: Rationale and Current State.

First-line chemotherapy for many solid tumors is limited by toxicity. There is a growing interest in maintenance therapy as a strategy for prolonging the benefits of first-line therapy while minimizing toxicity. Maintenance therapy can comprise either continuation of an agent given as part of the first-line regimen (continuation maintenance) or treatment with a new agent (switch maintenance).

Identification of Portimine B, a New Cell Permeable Spiroimine That Induces Apoptosis in Oral Squamous Cell Carcinoma.

Spiroimines are a class of compounds produced by marine dinoflagellates with a wide range of toxicity and therapeutic potential. The smallest of the cyclic imines, portimine, is far less toxic than other known members in several animal models. Portimine has also been shown to induce apoptosis and reduce the growth of a variety of cancer cell lines at low nanomolar concentrations.

Metabolic and antioxidant profiles of herbal infusions and decoctions.

This study implements NMR metabolomics and spectrophotometric studies (Folin-Ciocalteu, FRAP, ABTS) to infusions and decoctions of ten plant species in order to assess and compare the metabolic and antioxidant profiles for each botanical family. Multivariate and univariate data analyses highlighted the differences among the samples and pinpointed specific classes of compounds for each plant species as well as infusions and decoctions. The identified phenolic compounds by NMR, as well as the antioxidant profile, framed a trend of increased values in infusions compared to the decoctions.

First records of Pseudodoros nigricollis Becker (Diptera: Syrphidae) from Cyprus.

Background: The hoverfly Pseudodoros nigricollis Becker, 1903 is a rarely collected species, of which information on its distribution and ecology is poorly understood.

New Information: In this paper the first records of the hoverfly Pseudodoros nigricollis from Cyprus are provided and discussed. The discovery indicates that this Afrotropical species is approaching the European continent.

Response surface methodology toward the optimization of high-energy carotenoid extraction from Aristeus antennatus shrimp.

High-energy assisted extraction techniques, like ultrasound assisted extraction (UAE) and microwave assisted extraction (MAE), are widely applied over the last years for the recovery of bioactive compounds such as carotenoids, antioxidants and phenols from foods, animals and herbal natural sources. Especially for the case of xanthophylls, the main carotenoid group of crustaceans, they can be extracted in a rapid and quantitative way with the use of UAE and MAE. Response surface methodology (RSM) is used for the optimization of extraction methodologies, also being applied to optimize high energy techniques.

DrugOn: a fully integrated pharmacophore modeling and structure optimization toolkit.

During the past few years, pharmacophore modeling has become one of the key components in computer-aided drug design and in modern drug discovery. DrugOn is a fully interactive pipeline designed to exploit the advantages of modern programming and overcome the command line barrier with two friendly environments for the user (either novice or experienced in the field of Computer Aided Drug Design) to perform pharmacophore modeling through an efficient combination of the PharmACOphore, Gromacs, Ligbuilder and PDB2PQR suites. Our platform features a novel workflow that guides the user through each logical step of the iterative 3D structural optimization setup and drug design process.

Ventilator caregiver education through the use of high-fidelity pediatric simulators: a pilot study.

Introduction. Home ventilator programs (HVP) have been developed to train parents of critically ill children. Simulators are used in health care, but not often for parents.

Outcomes of children treated with tracheostomy and positive-pressure ventilation at home.

Background: Long-term outcomes for children who survive on tracheostomy and positive-pressure ventilation (TPPV) at home are not well known.

Methods: A retrospective review of 20 years of clinical data at a single institution was performed. Outcome measures included 5-year survival, decannulation rate, and neurocognition.

Terrestrial slugs (Gastropoda, Pulmonata) in the NATURA 2000 areas of Cyprus island.

Terrestrial slugs of the Island of Cyprus were recently studied in the framework of a study of the whole terrestrial malacofauna of the island. The present work was carried out in the Natura 2000 conservation areas of the island in 155 sampling sites over three years (2004-2007). Museum collections as well as literature references were included.

Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib.

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus.

Methods: Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins were carried out by expressing the mutant FasL cDNA in mammalian cells and analysis its effects on Fas-mediated programmed cell death.

Early progressive encephalopathy in boys and MECP2 mutations.

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic.

p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2.

Cell cycle progression is negatively regulated by the pocket proteins pRb, p107, and p130. However, the mechanisms responsible for this inhibition are not fully understood. Here, we show that overexpression of p107 in fibroblasts inhibits Cdk2 activation and delays S phase entry.

The Rb-family protein p107 inhibits translation by a PDK1-dependent mechanism.

The Rb family of proteins, which consists of Rb, p107 and p130, are critical regulators of cell proliferation. In addition to their inhibitory effects on cell cycle progression, Rb-family proteins repress transcription by RNA polymerases I and III, and may therefore restrain cell growth. However, it is not known if Rb, p107 or p130 have direct effects on protein synthesis.

The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways.

The lymphotoxin-beta receptor (LTbetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB. In addition to activation of the classical NF-kappaB, ligation of this receptor induces the processing of the cytosolic NF-kappaB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-kappaB2 requires NIK and IKKalpha, while NEMO/IKKgamma is dispensable for p100 processing.

The carboxyl-terminal region of IkappaB kinase gamma (IKKgamma) is required for full IKK activation.

IkappaB kinase gamma (IKKgamma) (also known as NEMO, Fip-3, and IKKAP-1) is the essential regulatory component of the IKK complex; it is required for NF-kappaB activation by various stimuli, including tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), phorbol esters, lipopolysaccharides, and double-stranded RNA. IKKgamma is encoded by an X-linked gene, deficiencies in which may result in two human genetic disorders, incontinentia pigmenti (IP) and hypohidrotic ectodermal dysplasia with severe immunodeficiency. Subsequent to the linkage of IKKgamma deficiency to IP, we biochemically characterized the effects of a mutation occurring in an IP-affected family on IKK activity and NF-kappaB signaling.

Effects of megestrol acetate on weight gain, body composition, and pulmonary function in patients with cystic fibrosis.

Objectives: Malnutrition is a negative prognostic indicator in patients with cystic fibrosis (CF) and may accentuate pulmonary decline. We tested whether megestrol acetate would have beneficial effects on growth in patients with CF and pancreatic insufficiency.

Study Design: We performed a randomized, double-blind, placebo controlled study.

Posterior cruciate ligament architecture: evaluation under microsurgical dissection.

Purpose: Our objective was to verify the fiber anatomy of the posterior cruciate ligament (PCL) and to measure the main dimensions and the femoral and tibial attachment site distances of the ligament after microsurgical dissection. We hypothesized that PCL anatomy is more complex than the 2 traditionally characterized bands.

Type Of Study: This is a purely anatomic description of microdissections of the PCL, focused on the fine anatomy of the ligament.

Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti.

IKK gamma/NEMO is the essential regulatory subunit of the I kappa B kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-kappa B activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis.

MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration.

Exposure of eukaryotic cells to extracellular stimuli results in activation of mitogen-activated protein kinase (MAPK) cascades composed of MAPKs, MAPK kinases (MAP2Ks), and MAPK kinase kinases (MAP3Ks). Mammals possess a large number of MAP3Ks, many of which can activate the c-Jun N-terminal kinase (JNK) MAPK cascade when overexpressed, but whose biological function is poorly understood. We examined the function of the MAP3K MEK kinase 1 (MEKK1) in proinflammatory signaling.