Epidemiological pattern of classical Borna disease and regional genetic clustering of Borna disease viruses point towards the existence of to-date unknown endemic reservoir host populations

Classical Borna disease (cBD), a non-purulent encephalitis of solipeds and sheep, is endemic in certain areas of central Europe. The etiologic agent is Borna disease virus (BDV), thus far the only member of the family Bornaviridae. Based on epidemiological patterns of cBD and recent phylogenetic findings this review hypothesizes the possible existence of yet unknown BDV reservoir host populations, and analyzes critically BDVs from outside endemic regions.     

Mice lacking the nuclear pore complex protein ALADIN show female infertility but fail to develop a phenotype resembling human triple A syndrome

Triple A syndrome is a human autosomal recessive disorder characterized by adrenal insufficiency, achalasia, alacrima, and neurological abnormalities affecting the central, peripheral, and autonomic nervous systems. In humans, this disease is caused by mutations in the AAAS gene, which encodes ALADIN, a protein that belongs to the family of WD-repeat proteins and localizes to nuclear pore complexes. To analyze the function of the gene in the context of the whole organism and in an attempt to obtain an animal model for human triple A syndrome, we generated mice lacking a functional Aaas gene. The Aaas-/- animals were found to be externally indistinguishable from their wild-type littermates, although their body weight was on the average lower than that of wild-type mice. Histological analysis of various tissues failed to reveal any differences between Aaas-/- and wild-type mice. Aaas-/- mice exhibit unexpectedly mild abnormal behavior and only minor neurological deficits. Our data show that the lack of ALADIN in mice does not lead to a triple A syndrome-like disease. Thus, in mice either the function of ALADIN differs from that in humans, its loss can be readily compensated for, or additional factors, such as environmental conditions or genetic modifiers, contribute to the disease.     

High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants

Hepatitis C virus (HCV) NS3-4A protease is essential for viral replication. All current small molecular weight drugs against NS3-4A are substrate peptidomimetics that have a similar binding and resistance profile. We developed inhibitory peptides (IPs) capping the active site and binding via a novel “tyrosine” finger at an alternative NS3-4A site that is of particular interest for further HCV drug development. The peptides are not cleaved due to a combination of geometrical constraints and impairment of the oxyanion hole function. Selection and optimization through combinatorial phagemid display, protein crystallography, and further modifications resulted in a 32-amino acid peptide with a K_i of 0.53 nm. Inhibition of viral replication in cell culture was demonstrated by fusion to a cell-penetrating peptide. Negligible susceptibility to known (A156V and R155K) resistance mutations of the NS3-4A protease was observed. This work shows for the first time that antiviral peptides can target an intracellular site and reveals a novel druggable site on the HCV protease.     

Mechanism-based screen establishes signalling framework for DNA damage-associated G1 checkpoint response

DNA damage activates checkpoint controls which block progression of cells through the division cycle. Several different checkpoints exist that control transit at different positions in the cell cycle. A role for checkpoint activation in providing resistance of cells to genotoxic anticancer therapy, including chemotherapy and ionizing radiation, is widely recognized. Although the core molecular functions that execute different damage activated checkpoints are known, the signals that control checkpoint activation are far from understood. We used a kinome-spanning RNA interference screen to delineate signalling required for radiation-mediated retinoblastoma protein activation, the recognized executor of G(1) checkpoint control. Our results corroborate the involvement of the p53 tumour suppressor (TP53) and its downstream targets p21(CIP1/WAF1) but infer lack of involvement of canonical double strand break (DSB) recognition known for its role in activating TP53 in damaged cells. Instead our results predict signalling involving the known TP53 phosphorylating kinase PRPK/TP53RK and the JNK/p38MAPK activating kinase STK4/MST1, both hitherto unrecognised for their contribution to DNA damage G1 checkpoint signalling. Our results further predict a network topology whereby induction of p21(CIP1/WAF1) is required but not sufficient to elicit checkpoint activation. Our experiments document a role of the kinases identified in radiation protection proposing their pharmacological inhibition as a potential strategy to increase radiation sensitivity in proliferating cancer cells.     

The co-evolution of language and emotions

We argue that language evolution started like the evolution of reading and writing, through cultural evolutionary processes. Genuinely new behavioural patterns emerged from collective exploratory processes that individuals could learn because of their brain plasticity. Those cultural-linguistic innovative practices that were consistently socially and culturally selected drove a process of genetic accommodation of both general and language-specific aspects of cognition. We focus on the affective facet of this culture-driven cognitive evolution, and argue that the evolution of human emotions co-evolved with that of language. We suggest that complex tool manufacture and alloparenting played an important role in the evolution of emotions, by leading to increased executive control and inter-subjective sensitivity. This process, which can be interpreted as a special case of self-domestication, culminated in the construction of human-specific social emotions, which facilitated information-sharing. Once in place, language enhanced the inhibitory control of emotions, enabled the development of novel emotions and emotional capacities, and led to a human mentality that departs in fundamental ways from that of other apes. We end by suggesting experimental approaches that can help in evaluating some of these proposals and hence lead to better understanding of the evolutionary biology of language and emotions.     

Impact of climate change on voltinism and prospective diapause induction of a global pest insect--Cydia pomonella (L.)

Global warming will lead to earlier beginnings and prolongation of growing seasons in temperate regions and will have pronounced effects on phenology and life-history adaptation in many species. These changes were not easy to simulate for actual phenologies because of the rudimentary temporal (season) and spatial (regional) resolution of climate model projections. We investigate the effect of climate change on the regional incidence of a pest insect with nearly worldwide distribution and very high potential for adaptation to season length and temperature--the Codling Moth, Cydia pomonella. Seasonal and regional climate change signals were downscaled to the hourly temporal scale of a pest phenology model and the spatial scale of pest habitats using a stochastic weather generator operating at daily scale in combination with a re-sampling approach for simulation of hourly weather data. Under future conditions of increased temperatures (2045-2074), the present risk of below 20% for a pronounced second generation (peak larval emergence) in Switzerland will increase to 70-100%. The risk of an additional third generation will increase from presently 0-2% to 100%. We identified a significant two-week shift to earlier dates in phenological stages, such as overwintering adult flight. The relative extent (magnitude) of first generation pupae and all later stages will significantly increase. The presence of first generation pupae and later stages will be prolonged. A significant decrease in the length of overlap of first and second generation larval emergence was identified. Such shifts in phenology may induce changes in life-history traits regulating the life cycle. An accordingly life-history adaptation in photoperiodic diapause induction to shorter day-length is expected and would thereby even more increase the risk of an additional generation. With respect to Codling Moth management, the shifts in phenology and voltinism projected here will require adaptations of plant protection strategies to maintain their sustainability.     

Crystal structures of salicylate 1,2-dioxygenase-substrates adducts: A step towards the comprehension of the structural basis for substrate selection in class III ring cleaving dioxygenases

The crystallographic structures of the adducts of salicylate 1,2-dioxygenase (SDO) with substrates salicylate, gentisate and 1-hydroxy-2-naphthoate, obtained under anaerobic conditions, have been solved and analyzed. This ring fission dioxygenase from the naphthalenesulfonate-degrading bacterium Pseudaminobacter salicylatoxidans BN12, is a homo-tetrameric class III ring-cleaving dioxygenase containing a catalytic Fe(II) ion coordinated by three histidine residues. SDO is markedly different from the known gentisate 1,2-dioxygenases or 1-hydroxy-2-naphthoate dioxygenases, belonging to the same class, because of its unique ability to oxidatively cleave salicylate, gentisate and 1-hydroxy-2-naphthoate. The crystal structures of the anaerobic complexes of the SDO reveal the mode of binding of the substrates into the active site and unveil the residues which are important for the correct positioning of the substrate molecules. Upon binding of the substrates the active site of SDO undergoes a series of conformational changes: in particular Arg127, His162, and Arg83 move to make hydrogen bond interactions with the carboxyl group of the substrate molecules. Unpredicted concerted displacements upon substrate binding are observed for the loops composed of residues 40-43, 75-85, and 192-198 where several aminoacidic residues, such as Leu42, Arg79, Arg83, and Asp194, contribute to the closing of the active site together with the amino-terminal tail (residues 2-15). Differences in substrate specificity are controlled by several residues located in the upper part of the substrate binding cavity like Met46, Ala85, Trp104, and Phe189, although we cannot exclude that the kinetic differences observed could also be generated by concerted conformational changes resulting from amino-acid mutations far from the active site.     

Neutrophil Gelatinase-Associated Lipocalin (NGAL) Predicts Response to Neoadjuvant Chemotherapy and Clinical Outcome in Primary Human Breast Cancer

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.