The ubiquitin receptor Rad23: At the crossroads of nucleotide excision repair and proteasomal degradation

A protein that exemplifies the intimate link between the ubiquitin/proteasome system (UPS) and DNA repair is the yeast nucleotide excision repair (NER) protein Rad23 and its human orthologs hHR23A and hHR23B. Rad23, which was originally identified as an important factor involved in the recognition of DNA lesions, also plays a central role in targeting ubiquitylated proteins for proteasomal degradation, an activity that it shares with other ubiquitin receptors like Dsk2 and Ddi1. Although the finding that Rad23 serves as a ubiquitin receptor explains to a large extent its importance in proteasomal degradation, the precise mode of action of Rad23 in NER and the possible link with the UPS is less clear. In this review, we discuss our present knowledge on the functions of Rad23 in protein degradation and DNA repair and speculate on the importance of the dual roles of Rad23 for the cell's ability to cope with stress conditions.     

Evolution of Asthma Severity in a Cohort of Young Adults: Is There Any Gender Difference?

Introduction

Little is known about the distribution of asthma severity in men and women in the general population. The objective of our study was to describe asthma severity and change in severity according to gender in a cohort of adult asthmatics

Methods

Subjects with asthma were identified from random samples of the 22 to 44 year-olds from the general population, screened for asthma from 1991 to 1993 in 48 centers from 22 countries and followed-up during 1998–2002, as part of the European Community Respiratory Health Survey (ECRHS). All participants to follow-up with current asthma at baseline were eligible for the analysis. To assess change over the follow-up, asthma severity at the two surveys was defined using standardized data on respiratory symptoms, lung function and medication according to the Global Initiative for Asthma (GINA) Guidelines. Another quantitative score (Ronchetti) further considering hospitalizations was also analysed.

Results

The study included 685 subjects with asthma followed-up over a mean period of 8.65 yr (min 4.3-max 11.7). At baseline, asthma severity according to GINA was distributed as intermittent: 40.7%, 31.7% as mild persistent, 14% as moderate persistent, and 13.5% as severe persistent. Using the Ronchetti score derived classification, the distribution of asthma severity was 58% mild, (intermittent and mild persistent), 25.8% moderate, and 15.4% severe. Whatever the classification, there was no significant difference in the severity distribution between men and women. There was also no gender difference in the severity distribution among incident cases which developed asthma between the two surveys. Men with moderate-to-severe asthma at baseline were more likely than women to have moderate-to-severe asthma at follow-up. Using GINA, 69.2% of men vs. 53.1% of women (p = 0.09) with moderate-to-severe asthma at baseline were still moderate-to-severe at follow-up. Using Ronchetti score, 53.3% of men vs. 36.2% of women (p = 0.03) with moderate-to-severe asthma at baseline were still moderate-to-severe at follow-up.

Conclusions

There was no gender difference in asthma severity at the two surveys. However, our findings suggest that asthma severity might be less stable in women than in men.     

Growth of three cattail (<Emphasis Type="Italic">Typha</Emphasis>) taxa in response to elevated CO<Subscript>2</Subscript>

The establishment of non-native species and the increase in atmospheric CO₂, in combination, have the ability to alter current ecosystems. Previous studies have shown that invasive species tend to respond more strongly to CO₂ than natives, but these comparisons have been of different and unrelated species. To assess how response to CO₂ might be related to invasiveness per se, we compared a native (Typha latifolia) with a congeneric invasive (Typha angustifolia), as well as their hybrid (T. × glauca). All three taxa are common components of wetland vegetation, often occurring in near monocultures. An open-top chamber experiment was used to examine the effects of elevated and ambient CO₂ concentrations on the three taxa. All three increased rhizome biomass by 40% in elevated CO₂. Although the absolute increase did not differ among taxa, the invasive T. angustifolia had a much higher proportional response in biomass and photosynthetic rate (45 and 40% respectively). The weaker response of the two larger taxa native T. latifolia (16 and 2%) and hybrid T. × glauca (−4% and −1%) was possibly driven by soil nutrient deficiency, such that they were not able to benefit from increased CO₂. However, under low nutrients the smaller species T. angustifolia may become more a problematic invader in the future.     

Intramuscular triacylglycerol and insulin resistance: Guilty as charged or wrongly accused?

The term lipotoxicity elicits visions of steatotic liver, fat laden skeletal muscles and engorged lipid droplets that spawn a number of potentially harmful intermediates that can wreak havoc on signal transduction and organ function. Prominent among these so-called lipotoxic mediators are signaling molecules such as long chain acyl-CoAs, ceramides and diacyglycerols; each of which is thought to engage serine kinases that disrupt the insulin signaling cascade, thereby causing insulin resistance. Defects in skeletal muscle fat oxidation have been implicated as a driving factor contributing to systemic lipid imbalance, whereas exercise-induced enhancement of oxidative potential is considered protective. The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative. This review centers on mechanisms that connect lipid surplus to insulin resistance in skeletal muscle, as well as those that underlie the antilipotoxic actions of exercise. Emphasis is placed on recent studies that challenge accepted paradigms.     

Role of IL-13 in a model of Strongyloides venezuelensis infection in rats

IL-13 is a cytokine known to play a role in several pulmonary diseases, including asthma and fibrosis. The role of IL-13 in the context of pulmonary changes induced by helminth infection is unclear. Rats experimentally infected with Strongyloides venezuelensis and treated with anti-IL-13 neutralizing antibody were used to evaluate the role of IL-13 on functional and inflammatory changes of host lungs, and on parasite control. S. venezuelensis-induced airway hyperreactivity was IL-13-independent, but IL-13 played an essential role in driving airway mucus production and eosinophil infiltration. IL-13 was important for the control of egg production but not establishment in the intestine.     

Fermentative production of self-toxic fungal secondary metabolites

Fungi are well known for their vast diversity of secondary metabolites that include many life-saving drugs and highly toxic mycotoxins. In general, fungal cultures producing such metabolites are immune to their toxic effects. However, some are known to produce self-toxic compounds that can pose production optimization challenges if the metabolites are needed in large amounts for chemical modification. One such culture, LV-2841, was identified as the lead for one of our exploratory projects. This culture was found to be a slow grower that produced trace amounts of a known metabolite, cercosporamide, under the standard flask fermentation conditions, and extensive medium optimization studies failed to yield higher titers. Poor growth of the culture in liquid media was attributed to the self-toxicity of cercosporamide to the producing organism, and the minimum inhibitory concentration (MIC) of cercosporamide was estimated to be in the range of 8–16 μg/ml. Fermentations carried out in media containing Diaion^® HP20 resin afforded significantly higher titers of the desired compound. While several examples of resin-based fermentations of soil streptomyces have been published, this approach has rarely been used for fungal fermentations. Over a 100-fold increase in the production titer of cercosporamide, a self-toxic secondary metabolite, was achieved by supplementing the production medium with a commercially available neutral adsorbent resin.     

Gene structure,transcripts and calciotropic effects of the PTH family of peptides in <Emphasis Type="Italic">Xenopus</Emphasis> and chicken

Background  

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) belong to a family of endocrine factors that share a highly conserved N-terminal region (amino acids 1-34) and play key roles in calcium homeostasis, bone formation and skeletal development. Recently, PTH-like peptide (PTH-L) was identified in teleost fish raising questions about the evolution of these proteins. Although PTH and PTHrP have been intensively studied in mammals their function in other vertebrates is poorly documented. Amphibians and birds occupy unique phylogenetic positions, the former at the transition of aquatic to terrestrial life and the latter at the transition to homeothermy. Moreover, both organisms have characteristics indicative of a complex system in calcium regulation. This study investigated PTH family evolution in vertebrates with special emphasis on Xenopus and chicken.     

Demonstration by heterologous expression that the Leishmania SCA1 gene encodes an arabinopyranosyltransferase

In part of the life cycle within their sand fly vector, Leishmania major parasites first attach to the fly's midgut through their main surface adhesin lipophosphoglycan (LPG) and later resynthesize a structurally distinct LPG that results in detachment and eventual transmission. One of these structural modifications requires the addition of alpha1,2-D-arabinopyranose caps to beta1,3-galactose side chains in the phosphoglycan repeat unit domain of LPG. We had previously identified two side chain arabinose genes (SCA1/2) that were involved in the alpha1,2-D-Arap capping. SCA1/2 exhibit canonical glycosyltransferase motifs, and overexpression of either gene leads to elevated microsomal alpha1,2-D-ArapT activity, resulting in arabinopyranosylation of beta1,3-Gal side chains in LPG (hereafter called side chain D-arabinopyranosyltransferase [sc-D-ArapT]). Heterologous expression in a null arabinose background was used to determine whether the SCA1 gene encodes the actual sc-D-ArapT. SCA1 expression constructs introduced into both mammalian COS-7 cells and the baculovirus-sf9 cell system exhibited considerable expression of the protein. However, functional sc-D-ArapT activity was observed only in the latter. In in vitro assays incubated with guanidine 59-diphosphate (GDP)-D-[3H]Arap as the sugar donor and utilizing exogenous LPG as an acceptor, significant sc-D-ArapT activity was observed when microsomes from the baculovirus-sf9 cells were incubated in presence of the LPG acceptor. No activity was observed in the absence of LPG. These results demonstrate that SCA1 encodes a sc-D-ArapT and provide the first example of heterologous expression of a D-ArapT gene.     

Quorum sensing: alcohols in a social situation

Many microbes use extracellular signals to transmit information about population density and environmental conditions. Recent evidence suggests that the budding yeast Saccharomyces cerevisiae exhibits this type of regulation and that the signals are aromatic alcohols.     

Long-term paternity skew and the opportunity for selection in a mammal with reversed sexual size dimorphism

Most mammalian groups are characterized by male-biased sexual size dimorphism, in which size-dependent male-male competition and reproductive skew are tightly linked. By comparison, little is known about the opportunity for sexual selection in mammalian systems without male-biased dimorphism, where the traits under sexual selection might be less obvious. We examined 10 years of parentage data in a colony of greater horseshoe bats (Rhinolophus ferrumequinum) to determine the magnitude of male reproductive skew and the opportunity for sexual selection in a mammal in which females are the larger sex. Annual paternity success was weakly skewed but consistent patterns led to strong longitudinal paternity skew among breeders. Just three males accounted for a third of all paternity assignments, representing at least a fifth of all colony offspring born in a decade. Paternity success was in part determined by age but was not influenced by dispersal status. Our results show that paternity skew and the opportunity for sexual selection in a species with reversed sexual size dimorphism can approach levels reported for classical examples of species with polygyny and male-biased dimorphism, even where the traits under sexual selection are not known.