Active process mediates species-specific tuning of Drosophila ears

The courtship behavior of Drosophilid flies has served as a long-standing model for studying the bases of animal communication. During courtship, male flies flap their wings to send a complex pattern of airborne vibrations to the antennal ears of the females. These "courtship songs" differ in their spectrotemporal composition across species and are considered a crucial component of the flies' premating barrier. However, whether the species-specific differences in song structure are also reflected in the receivers of this communication system, i.e., the flies' antennal ears, has remained unexplored. Here we show for seven members of the melanogaster species group that (1) their ears are mechanically tuned to different best frequencies, (2) the ears' best frequencies correlate with high-frequency pulses of the conspecific courtship songs, and (3) the species-specific tuning relies on amplificatory mechanical feedback from the flies' auditory neurons. As a result of its level-dependent nature, the active mechanical feedback amplification is particularly useful for the detection of small stimuli, such as conspecific song pulses, and becomes negligible for sensing larger stimuli, such as the flies' own wingbeat during flight.     

Sensory transduction: the 'swarm intelligence' of auditory hair bundles

In vertebrate hair cells, the hair bundle is responsible for the conversion of mechanical vibrations into electrical signals. In a combined experimental and computational tour de force, a group of researchers now presents a quantitative model that explains how the bundle's specific microarchitecture gives rise to its exquisite mechanosensory properties.     

Expression and shedding of endothelial protein C receptor in prostate cancer cells

Background  

Increasing evidences show that beyond its role in coagulation, endothelial protein C receptor (EPCR) interferes with carcinogenesis. Pro-carcinogenic effects of EPCR were linked with a raised generation of activated protein C (aPC) and anti-apoptotic signalling. This study was carried out to analyze the expression, cell surface exposition, and shedding of EPCR in normal and malignant prostate cell lines.     

Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development

The obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound inclusion that acquires host sphingomyelin (SM), a process that is essential for replication as well as inclusion biogenesis. Previous studies demonstrate that SM is acquired by a Brefeldin A (BFA)-sensitive vesicular trafficking pathway, although paradoxically, this pathway is dispensable for bacterial replication. This finding suggests that other lipid transport mechanisms are involved in the acquisition of host SM. In this work, we interrogated the role of specific components of BFA-sensitive and BFA-insensitive lipid trafficking pathways to define their contribution in SM acquisition during infection. We found that C. trachomatis hijacks components of both vesicular and non-vesicular lipid trafficking pathways for SM acquisition but that the SM obtained from these separate pathways is being utilized by the pathogen in different ways. We show that C. trachomatis selectively co-opts only one of the three known BFA targets, GBF1, a regulator of Arf1-dependent vesicular trafficking within the early secretory pathway for vesicle-mediated SM acquisition. The Arf1/GBF1-dependent pathway of SM acquisition is essential for inclusion membrane growth and stability but is not required for bacterial replication. In contrast, we show that C. trachomatis co-opts CERT, a lipid transfer protein that is a key component in non-vesicular ER to trans-Golgi trafficking of ceramide (the precursor for SM), for C. trachomatis replication. We demonstrate that C. trachomatis recruits CERT, its ER binding partner, VAP-A, and SM synthases, SMS1 and SMS2, to the inclusion and propose that these proteins establish an on-site SM biosynthetic factory at or near the inclusion. We hypothesize that SM acquired by CERT-dependent transport of ceramide and subsequent conversion to SM is necessary for C. trachomatis replication whereas SM acquired by the GBF1-dependent pathway is essential for inclusion growth and stability. Our results reveal a novel mechanism by which an intracellular pathogen redirects SM biosynthesis to its replicative niche.     

Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson''s disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP''s main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P_2df = 10⁻⁶, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10⁻⁷) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: OR_Replication = 0.59, P_Replication = 10⁻³; OR_Pooled = 0.51, P_Pooled = 7×10⁻⁸. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10⁻³), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10⁻¹³). Imputation revealed a block of SNPs that achieved P_2df<5×10⁻⁸ in GWAIS, and OR = 0.41, P = 3×10⁻⁸ in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.     

Intraspecific variability in Karlodinium veneficum: Growth rates, mixotrophy, and lipid composition

We isolated eleven strains of the harmful algal bloom (HAB)-forming dinoflagellate Karlodinium veneficum during a bloom event in the NW Mediterranean coastal waters and we studied the inter-strain variability in several of their physiological and biochemical traits. These included autotrophic growth parameters, feeding capabilities (mixotrophy), lipid composition, and, in some cases, their responses to biotic and abiotic factors. The strains were found to differ in their growth rates (0.27–0.53 d⁻¹) and in the maximum cell concentrations achieved during stationary phase (6.1 × 10⁴–8.6 × 10⁴ cells mL⁻¹). Their ingestion performance, when offered Rhodomonas salina as prey, was also diverse (0.22–1.3 cells per K. veneficum per day; 8–52% of their daily ration). At least two strains survived for several months under strict heterotrophic conditions (no light, low inorganic nutrients availability, and R. salina as food source). These strains also showed very distinct fatty acid compositions, with very low contents of monounsaturated and polyunsaturated fatty acids. According to a Bray Curtis similarity analysis, three or four strain groups able to perform different roles in bloom development were identified. We further analyzed one strain from each of the two most distinct groups with respect to prey concentration, light intensity, nutrient availability, and we determined the functional responses (growth and feeding rates) to food concentration. Taken together, the results served to highlight the role of mixotrophy and clone variability in the formation of HABs.     

Dynamical and structural analysis of a T cell survival network identifies novel candidate therapeutic targets for large granular lymphocyte leukemia

The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-LGL states of 54 components of the network, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions. We further test and validate one of these newly identified states experimentally. Specifically, we verify the prediction that the node SMAD is over-active in leukemic T-LGL by demonstrating the predominant phosphorylation of the SMAD family members Smad2 and Smad3. Our systematic perturbation analysis using dynamical and structural methods leads to the identification of 19 potential therapeutic targets, 68% of which are corroborated by experimental evidence. The novel therapeutic targets provide valuable guidance for wet-bench experiments. In addition, we successfully identify two new candidates for engineering long-lived T cells necessary for the delivery of virus and cancer vaccines. Overall, this study provides a bird's-eye-view of the avenues available for identification of therapeutic targets for similar diseases through perturbation of the underlying signal transduction network.     

Modeling the human intestinal Mucin (MUC2) C-terminal cystine knot dimer

Intestinal mucus, a viscous secretion that lines the mucosa, is believed to be a barrier to absorption of many therapeutic compounds and carriers, and is known to play an important physiological role in controlling pathogen invasion. Nevertheless, there is as yet no clear understanding of the barrier properties of mucus, such as the nature of the molecular interactions between drug molecules and mucus components as well as those that govern gel formation. Secretory mucins, large and complex glycoprotein molecules, are the principal determinants of the viscoelastic properties of intestinal mucus. Despite the important role that mucins play in controlling transport and in diseases such as cystic fibrosis, their structures remain poorly characterized. The major intestinal secretory mucin gene, MUC2, has been identified and fully sequenced. The present study was undertaken to determine a detailed structure of the cysteine-rich region within the C-terminal end of human intestinal mucin (MUC2) via homology modeling, and explore possible configurations of a dimer of this cysteine-rich region, which may play an important role in governing mucus gel formation. Based on sequence–structure alignments and three-dimensional modeling, a cystine knot tertiary structure homologous to that of human chorionic gonadotropin (HCG) is predicted at the C-terminus of MUC2. Dimers of this C-terminal cystine knot (CTCK) were modeled using sequence alignment based on HCG and TGF-beta, followed by molecular dynamics and simulated annealing. Results support the formation of a cystine knot dimer with a structure analogous to that of HCG.