Evolutionary Transition from Pathogenicity to Commensalism: Global Regulator Mutations Mediate Fitness Gains through Virulence Attenuation.

Symbiotic interactions are indispensable for metazoan function, but their origin and evolution remain elusive. We use a controlled evolution experiment to demonstrate the emergence of novel commensal interactions between Pseudomonas aeruginosa, an initially pathogenic bacterium, and a metazoan host, Caenorhabditis elegans. We show that commensalism evolves through loss of virulence, because it provides bacteria with a double fitness advantage: Increased within-host fitness and a larger host population to infect.

[Reversible cerebral vasoconstriction syndrome. Challenge for diagnostics and intensive care therapy].

Reversible cerebral vasoconstriction syndrome (RCVS) is a disease of unclear incidence frequently affecting middle aged women and is usually associated with use of adrenergic or serotoninergic substances. The exclusion of relevant differential diagnoses, such as aneurysmal subarachnoid hemorrhage, primary cerebral angiitis, posterior reversible encephalopathy syndrome and carotid artery dissection is critical in terms of time and significance. Thunderclap headache as well as multiple and multilocular vasospasms with direct or indirect angiography without substantial findings in cerebrospinal fluid diagnostics are typical symptoms.

When experimental selection for virulence leads to loss of virulence.

Information on virulence evolution is critical for understanding disease dynamics. Theory predicts that under certain evolutionary conditions virulence should increase; for example, during host-parasite coevolution. Although these theoretical predictions are supported by natural observations, tests of these hypotheses using experimental evolution have yielded confounding and contradictory results, with discrepancies often being seen among experiments.

Cancer across the tree of life: cooperation and cheating in multicellularity.

Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times.

Evidence of soft dipole resonance in ^{11}li with isoscalar character.

The first conclusive evidence of a dipole resonance in ^{11}Li having isoscalar character observed from inelastic scattering with a novel solid deuteron target is reported. The experiment was performed at the newly commissioned IRIS facility at TRIUMF. The results show a resonance peak at an excitation energy of 1.

Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia.

Background: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy.

Effect of soil temperature on optical frequency transfer through unidirectional dense-wavelength-division-multiplexing fiber-optic links.

Results of optical frequency transfer over a carrier-grade dense-wavelength-division-multiplexing (DWDM) optical fiber network are presented. The relation between soil temperature changes on a buried optical fiber and frequency changes of an optical carrier through the fiber is modeled. Soil temperatures, measured at various depths by the Royal Netherlands Meteorology Institute (KNMI) are compared with observed frequency variations through this model.

Effect of prednisone on type I interferon signature in rheumatoid arthritis: consequences for response prediction to rituximab.

Introduction: Elevated type I interferon (IFN) response gene (IRG) expression has proven clinical relevance in predicting rituximab non-response in rheumatoid arthritis (RA). Interference between glucocorticoids (GCs) and type I IFN signaling has been demonstrated in vitro. Since GC use and dose are highly variable among patients before rituximab treatment, the aim of this study was to determine the effect of GC use on IRG expression in relation to rituximab response prediction in RA.

Proteasome inhibitors as experimental therapeutics of autoimmune diseases.

Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6.

Using a sequential regimen to eliminate bacteria at sublethal antibiotic dosages.

We need to find ways of enhancing the potency of existing antibiotics, and, with this in mind, we begin with an unusual question: how low can antibiotic dosages be and yet bacterial clearance still be observed? Seeking to optimise the simultaneous use of two antibiotics, we use the minimal dose at which clearance is observed in an in vitro experimental model of antibiotic treatment as a criterion to distinguish the best and worst treatments of a bacterium, Escherichia coli. Our aim is to compare a combination treatment consisting of two synergistic antibiotics to so-called sequential treatments in which the choice of antibiotic to administer can change with each round of treatment. Using mathematical predictions validated by the E.

Radiological and pathological features associated with IDH1-R132H mutation status and early mortality in newly diagnosed anaplastic astrocytic tumours.

Background: Glioblastoma can occur either de novo or by the transformation of a low grade tumour; the majority of which harbor a mutation in isocitrate dehydrogenase (IDH1). Anaplastic tumours are high-grade gliomas that may represent the final step in the evolution of a secondary glioblastoma or the initial presentation of an early primary glioblastoma. We sought to determine whether pathological and/or radiological variables exist that can reliably distinguish IDH1-R132H-positive from IDH1-R132H-negative tumours and to identify variables associated with early mortality.

Cis- and trans-regulatory mechanisms of gene expression in the ASJ sensory neuron of Caenorhabditis elegans.

The identity of a given cell type is determined by the expression of a set of genes sharing common cis-regulatory motifs and being regulated by shared transcription factors. Here, we identify cis and trans regulatory elements that drive gene expression in the bilateral sensory neuron ASJ, located in the head of the nematode Caenorhabditis elegans. For this purpose, we have dissected the promoters of the only two genes so far reported to be exclusively expressed in ASJ, trx-1 and ssu-1.

Sustained macrophage infiltration upon multiple intra-articular injections: an improved rat model of rheumatoid arthritis for PET guided therapy evaluation.

To widen the therapeutic window for PET guided evaluation of novel anti-RA agents, modifications were made in a rat model of rheumatoid arthritis (RA). Arthritis was induced in the right knee of Wistar rats with repeated boosting to prolong articular inflammation. The contralateral knee served as control.

Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine.

Unlabelled: We aimed to determine whether the multidrug-resistance-proteins MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the antimetabolites cytarabine (Ara-C), gemcitabine (GEM), and the L-nucleoside analog troxacitabine. For this purpose we used HEK293 and the transfected HEK/MRP4 (59-fold increased MRP4) or HEK/MRP5i (991-fold increased MRP5) as model systems and tested the cells for drug sensitivity using a proliferation test. Drug accumulation was performed by using radioactive Ara-C, and for GEM and troxacitabine with HPLC with tandem-MS or UV detection.

Molecular basis of resistance to proteasome inhibitors in hematological malignancies.

Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic efficacy of bortezomib is hampered by the emergence of acquired resistance, for which multifactorial mechanisms have been identified. This review summarizes the current status of the molecular mechanisms underlying resistance to proteasome inhibitors that emerged in preclinical therapeutic studies, and discusses these findings in the clinical perspective of novel therapeutic modalities of hematological malignancies.

Bonding situation in Be[N(SiMe3)2]2 – an experimental and computational study.

The solid state structure of Be[N(SiMe3)2]2 (1) was determined by in situ crystallisation and the bonding situation investigated by quantum chemical calculations. The Be-N bond is predominantly ionic, but some evidence for the presence of a partial Be-N double bond character was found.

Development of a non-melanoma skin cancer detection model.

Background: The incidence and prevalence of skin cancer is rising. A detection model could support the (screening) process of diagnosing non-melanoma skin cancer.

Methods: A questionnaire was developed containing potential actinic keratosis (AK) and basal cell carcinoma (BCC) characteristics.

Effects of three-nucleon forces and two-body currents on Gamow-Teller strengths.

We optimize chiral interactions at next-to-next-to leading order to observables in two- and three-nucleon systems and compute Gamow-Teller transitions in 14C and (22,24)O using consistent two-body currents. We compute spectra of the daughter nuclei 14N and (22,24)F via an isospin-breaking coupled-cluster technique, with several predictions. The two-body currents reduce the Ikeda sum rule, corresponding to a quenching factor q2≈0.

Metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion: case report.

Peripheral nerve tumors are soft-tissue tumors that can occur in any nerve throughout the body. The majority of peripheral nerve tumors arise from elements of the nerve sheath with the two most common being neurofibromas and schwannomas. More than 90% of all peripheral nerve tumors are benign.

Imputation accuracy is robust to cattle reference genome updates.

Genotype imputation is routinely applied in a large number of cattle breeds. Imputation has become a need due to the large number of SNP arrays with variable density (currently, from 2900 to 777,962 SNPs). Although many authors have studied the effect of different statistical methods on imputation accuracy, the impact of a (likely) change in the reference genome assembly on imputation from lower to higher density has not been determined so far.

Pre-mRNA splicing in cancer: the relevance in oncogenesis, treatment and drug resistance.

Introduction: Aberrant pre-mRNA splicing in cancer is emerging as an important determinant of oncogenesis, response to treatment and anticancer drug resistance. At the same time, the spliceosome has become a target for a novel class of pre-clinical chemotherapeutics with a potential future application in cancer treatment. Taken together, these findings offer novel opportunities for the enhancement of the efficacy of cancer therapy.