The E3 ubiquitin ligase component FBXW7 modulates homeostasis and inhibits tumorigenesis in the murine intestine.

Embryonic NANOG (NANOG1) is considered as an important regulator of pluripotency while NANOGP8 (NANOGpseudogene) plays a role in tumorigenesis. Herein, we show NANOG is expressed from both NANOG1 and NANOGP8 in human colorectal cancers (CRC). Enforced NANOG1-expression increases clonogenic potential and tumor formation in xenograft models, although it is expressed only in a small subpopulation of tumor cells and is colocalized with endogenous nuclear b-catenin

One of the attractive properties of artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of Plasmodium falciparum to artemisinin. This emerging artemisinin resistance threatens to undermine the effectiveness of antimalarial combination therapies. Herein, we describe the medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexual blood stages that cause disease, and activity against gametocyte activation that is required for transmission. Furthermore, we confirm that selective PKG inhibitors have a slow speed of kill, while chemoproteomic analysis suggests for the first time serine/arginine protein kinase 2 (SRPK2) targeting as a novel strategy for developing antimalarial compounds with extremely fast-killing properties.

Interactions between transcription and signaling are fundamentally important for understanding both the structure and function of genetic pathways and their role in diseases such as cancer. The finding that β-catenin/TCF4

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Vancomycin is a glycopeptide antibiotic commonly used to treat resistant gram-positive infections in neonates. While adult dosing guidelines are generally well established, a lack of consensus for optimal dosing regimens in neonates remains.• The large variance in pharmacokinetic values in premature neonates compared with full-term infants is a major barrier to the development of optimal dosing regimens. Pharmacokinetic values have been reported for vancomycin in neonates. However, the studies have included small groups with differing, clinical conditions, serum sampling times and pharmacokinetic models. There are many proposed neonatal dosing guidelines for vancomycin, but few, if any, have been prospectively evaluated. In addition, the complexity of the dose and interval selection has led to errors in use. WHAT THIS STUDY ADDS• The purpose of this investigation was to determine population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight and to study the effect of the co-administration of amoxicillin-clavulanic acid and spironolactone on the pharmacokinetics of vancomycin in this cohort of patients. The aim was to find covariates with a relevant influence on the pharmacokinetic parameters of this drug, and to use this information for the design of an initial dosing schedule of vancomycin in neonates. Additionally, the obtained population pharmacokinetic parameters can be used to perform modifications of the initial dosing schedule in neonates with serum concentrations outside of the therapeutic range, by means of a Bayesian approach. AIMTo determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates. METHODSUsing nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1-48.1 weeks and 0.7-3.7 kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (V d) of vancomycin. RESULTSWeight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and Vd of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7 kg) were estimated to be 0.066 l h -1 kg -1 (95% CI 0.059, 0.073 l h -1 kg -1) and 0.572 l kg -1 (95% CI 0.505, 0.639 l kg), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n = 41), which were compared with observed concentrations to determine the predictive performance of...

The process of bioethanol production from biomass comprises pretreatments and enzyme-mediated hydrolysis to convert lignocellulose into fermentable sugars. Because of the recalcitrant character of cellulose, the enzymatic hydrolysis is considered the major challenge in this process to be economically competitive. These technical difficulties highlight the need for the discovery of new enzymes to optimize and lower the cost of current technologies. Microorganisms have developed efficient systems for cellulose degradation. Among cellulolytic microbes, Thermobifida fusca possesses great physiological and cellulolytic characteristics (thermostability, high activity and tolerance to a broad pH range) making it an interesting organism to be studied from an applied perspective. In this review we describe the main enzymes/proteins produced by T.fusca (cellulases, xylanases, mannanase, manosidase, CBM33 and CelR), the effect of substrate on T. fusca proteome, enzyme improvement approaches, synergism between enzymes/proteins and artificial cellulosomes.

Genetically modified Lactococcus lactis, non-pathogenic bacteria expressing the FNIII7-10 fibronectin fragment as a protein membrane have been used to create a living biointerface between synthetic materials and mammalian cells. This FNIII7-10 fragment comprises the RGD and PHSRN sequences of fibronectin to bind α5β1 integrins and triggers signalling for cell adhesion, spreading and differentiation. We used L. lactis strain to colonize material surfaces and produce stable biofilms presenting the FNIII7-10 fragment readily available to cells. Biofilm density is easily tunable and remains stable for several days. Murine C2C12 myoblasts seeded over mature biofilms undergo bipolar alignment and form differentiated myotubes, a process triggered by the FNIII7-10 fragment. This biointerface based on living bacteria can be further modified to express any desired biochemical signal, establishing a new paradigm in biomaterial surface functionalisation for biomedical applications.

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