Aurora-A/STK15/BTAK overexpression induces centrosome amplification, chromosomal instability, and transformation in human urothelial cells

Aurora-A/STK15/BTAK kinase encoding gene, located on chromosome 20q13, is frequently amplified and overexpressed in human cancers. Sen et al. previously demonstrated that Aurora-A amplification and overexpression are associated with aneuploidy and clinically aggressive bladder cancer (J Natl Cancer Inst (2002) 94, 1320-1329). To examine if this association is the direct result of Aurora-A gene amplification and overexpression, an immortalized human urothelial cell line (SV-HUC) was infected with an adenoviral Aurora-A-green fluorescent protein (Ad-Aurora-A-GFP) fusion construct inducing ectopic expression of the resulting fusion protein. Controls included mock-infected and adenoviral-GFP infected cells. Ectopic expression of transduced Aurora-A did not alter the doubling time of the SV-HUC cells but significantly increased the number of cells with multiple centrosomes displaying aneuploidy and increased colony formation in soft agar. This is the first report demonstrating that overexpression of Aurora-A induces centrosome anomalies together with chromosomal instability and malignant transformation-associated phenotypic changes in immortalized human urothelial cells, thus supporting the hypothesis that this gene plays an important role in the development of aggressive bladder cancer

Cystinosin, MPDU1, SWEETs and KDELR Belong to a Well-Defined Protein Family with Putative Function of Cargo Receptors Involved in Vesicle Trafficking

Classification of proteins into families based on remote homology often helps prediction of their biological function. Here we describe prediction of protein cargo receptors involved in vesicle formation and protein trafficking. Hidden Markov model profile-to-profile searches in protein databases using endoplasmic reticulum lumen protein retaining receptors (KDEL, Erd2) as query reveal a large and diverse family of proteins with seven transmembrane helices and common topology and, most likely, similar function. Their coding genes exist in all eukaryota and in several prokaryota. Some are responsible for metabolic diseases (cystinosis, congenital disorder of glycosylation), others are candidate genes for genetic disorders (cleft lip and palate, certain forms of cancer) or solute uptake and efflux (SWEETs) and many have not yet been assigned a function. Comparison with the properties of KDEL receptors suggests that the family members could be involved in protein trafficking and serve as cargo receptors. This prediction sheds new light on a range of biologically, medically and agronomically important proteins and could open the way to discovering the function of many genes not yet annotated. Experimental testing is suggested

When too much isn’t enough: Does current food production meet global nutritional needs?

Sustainably feeding the next generation is often described as one of the most pressing “grand challenges” facing the 21st century. Generally, scholars propose addressing this problem by increasing agricultural production, investing in technology to boost yields, changing diets, or reducing food waste. In this paper, we explore whether global food production is nutritionally balanced by comparing the diet that nutritionists recommend versus global agricultural production statistics. Results show that the global agricultural system currently overproduces grains, fats, and sugars while production of fruits and vegetables and protein is not sufficient to meet the nutritional needs of the current population. Correcting this imbalance could reduce the amount of arable land used by agriculture by 51 million ha globally but would increase total land used for agriculture by 407 million ha and increase greenhouse gas emissions. For a growing population, our calculations suggest that the only way to eat a nutritionally balanced diet, save land and reduce greenhouse gas emissions is to consume and produce more fruits and vegetables as well as transition to diets higher in plant-based protein. Such a move will help protect habitats and help meet the Sustainable Development Goals

Properties of an alkali-thermo stable xylanase from Geobacillus thermodenitrificans A333 and applicability in xylooligosaccharides generation

An extracellular thermo-alkali-stable and cellulase-free xylanase from Geobacillus thermodenitrificans A333 was purified to homogeneity by ion exchange and size exclusion chromatography. Its molecular mass was 44 kDa as estimated in native and denaturing conditions by gel filtration and SDS-PAGE analysis, respectively. The xylanase (GtXyn) exhibited maximum activity at 70 °C and pH 7.5. It was stable over broad ranges of temperature and pH retaining 88 % of activity at 60 °C and up to 97 % in the pH range 7.5–10.0 after 24 h. Moreover, the enzyme was active up to 3.0 M sodium chloride concentration, exhibiting at that value 70 % residual activity after 1 h. The presence of other metal ions did not affect the activity with the sole exceptions of K+ that showed a stimulating effect, and Fe2+, Co2+ and Hg2+, which inhibited the enzyme. The xylanase was activated by non-ionic surfactants and was stable in organic solvents remaining fully active over 24 h of incubation in 40 % ethanol at 25 °C. Furthermore, the enzyme was resistant to most of the neutral and alkaline proteases tested. The enzyme was active only on xylan, showing no marked preference towards xylans from different origins. The hydrolysis of beechwood xylan and agriculture-based biomass materials yielded xylooligosaccharides with a polymerization degree ranging from 2 to 6 units and xylobiose and xylotriose as main products. These properties indicate G. thermodenitrificans A333 xylanase as a promising candidate for several biotechnological applications, such as xylooligosaccharides preparation

Topical use of MMC in the upper aerodigestive tract: a review on the side effects

Not much is known about the side effects of mitomycin C (MMC), an anti-fibrogenetic agent, in the upper aerodigestive tract. However, its use in ophthalmology is widely known and without quantitatively important side effects. A literature review was performed for side effects of MMC in the upper aerodigestive tract. Forty-six articles, describing the use of MMC to prevent scarring, were retracted from PubMed. Thirty-two are human studies. MMC is used in different concentrations (0.1–10 mg/ml) with different application times (2–5 min) and frequencies (up to 4 times). Five hundred and thirty-eight patients were included in those publications, of whom 19 developed side effects (3.53%). No side effects developed in studies, where post-application irrigation with saline was reported. The longest mean follow-up period is 75.5 months. Direct relations between the reported side effects and MMC seem absent in most studies. Serious complications seem to occur when MMC is used in high concentrations. Unfortunately, sometimes crucial information is lacking. One patient was described who supposedly developed laryngeal carcinoma after repeated treatment of hyperkeratosis and anterior commissure webbing. Animal studies show that excessive fibrin production can lead to acute airway obstruction. In conclusion, topical application of MMC on a wound with consecutive irrigation with saline can be performed safely to prevent scar formation in circular structures of the upper aerodigestive tract. Long-term yearly control of the application site seems advisable

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed

Pleiotropic Roles of a Ribosomal Protein in Dictyostelium discoideum

The cell cycle phase at starvation influences post-starvation differentiation and morphogenesis in Dictyostelium discoideum. We found that when expressed in Saccharomyces cerevisiae, a D. discoideum cDNA that encodes the ribosomal protein S4 (DdS4) rescues mutations in the cell cycle genes cdc24, cdc42 and bem1. The products of these genes affect morphogenesis in yeast via a coordinated moulding of the cytoskeleton during bud site selection. D. discoideum cells that over- or under-expressed DdS4 did not show detectable changes in protein synthesis but displayed similar developmental aberrations whose intensity was graded with the extent of over- or under-expression. This suggested that DdS4 might influence morphogenesis via a stoichiometric effect – specifically, by taking part in a multimeric complex similar to the one involving Cdc24p, Cdc42p and Bem1p in yeast. In support of the hypothesis, the S. cerevisiae proteins Cdc24p, Cdc42p and Bem1p as well as their D. discoideum cognates could be co-precipitated with antibodies to DdS4. Computational analysis and mutational studies explained these findings: a C-terminal domain of DdS4 is the functional equivalent of an SH3 domain in the yeast scaffold protein Bem1p that is central to constructing the bud site selection complex. Thus in addition to being part of the ribosome, DdS4 has a second function, also as part of a multi-protein complex. We speculate that the existence of the second role can act as a safeguard against perturbations to ribosome function caused by spontaneous variations in DdS4 levels

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe