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Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders.

Females must be able to perceive and assess male signals, especially when they occur simultaneously with those of other males. Previous studies show female Schizocosa ocreatawolf spiders display receptivity to isolated visual or vibratory courtship signals, but increased receptivity to multimodal courtship. It is unknown whether this is true when females are presented with a choice between simultaneous multimodal and isolated unimodal male courtship. We used digital playback to present females with a choice simulating simultaneous male courtship in different sensory modes without variation in information content: 1) isolated unimodal visual versus vibratory signals; 2) multimodal versus vibratory signals; and 3) multimodal versus visual signals. When choosing between isolated unimodal signals (visual or vibratory), there were no significant differences in orientation latency and number of orientations, approaches or receptive displays directed to either signal. When given a choice between multimodal versus vibratory-only male courtship signals, females were more likely to orient to the multimodal stimulus, and directed significantly more orients, approaches and receptivity behaviors to the multimodal signal. When presented with a choice between multimodal and visual-only signals, there were significantly more orients and approaches to the multimodal signal, but no significant difference in female receptivity. Results suggest that signal modes are redundant and equivalent in terms of qualitative responses, but when combined, multimodal signals quantitatively enhance detection and/or reception. This study confirms the value of testing preference behavior using a choice paradigm, as female preferences may depend on the context (e.g., environmental context and social context) in which they are presented with male signals.

Chemokine receptors are considered to belong to the group of G protein‐coupled receptors that use the first transmembrane domain as signal anchor sequence for membrane insertion instead of a cleavable N‐terminal signal sequence. Chemokine recognition is determined by the N‐termini of chemokine receptors. Here, we show that the chemokine receptor CCR7, which is essential for directed migration of adaptive immune cells, possesses a 24 amino acids long N‐terminal signal sequence that is unique among chemokine receptors. This sequence is cleaved off the mature human and mouse protein. Introducing single point mutations in the hydrophobic core h‐region or in the polar C‐terminal segment (c‐region) of the signal sequence to interfere with its cleavage retained CCR7 in the ER and prevented its surface expression. Furthermore, we demonstrate the correct topology of the 35 amino acids short extracellular N‐tail of CCR7 in a deletion mutant lacking the natural signal sequence. This signal sequence deletion mutant of CCR7 is fully functional as it efficiently binds its ligand, elicits chemokine‐induced calcium mobilization, and directs cell migration. However, we show that the signal sequence promotes efficient recruitment of the GPCR to ER exit sites, thereby controlling efficient ER to Golgi trafficking of CCR7 on its way to reach the plasma membrane. A unique cleavable signal sequence among chemokine receptors regulates CCR7 trafficking along the secretory pathway by facilitating coupling to the ER export machinery.

Helicobacter pyloriis a common pathogen that is estimated to infect half of the human population, causing several diseases such as duodenal ulcer. Despite one of the first pathogens to be sequenced, its proteome remains poorly characterized as about one-third of its proteins have no functional annotation. Here, we integrate and analyze known protein interactions with proteomic and genomic data from different sources. We find that proteins with similar abundances tend to interact. Such an observation is accompanied by a trend of interactions to appear between proteins of similar functions, although some show marked cross-talk to others. Protein function prediction with protein interactions is significantly improved when interactions from other bacteria are included in our network, allowing us to obtain putative functions of more than 300 poorly or previously uncharacterized proteins. Proteins that are critical for the topological controllability of the underlying network are significantly enriched with genes that are up-regulated in the spiral compared with the coccoid form of H. pylori. Determining their evolutionary conservation, we present evidence that 80 protein complexes are identical in composition with their counterparts in Escherichia coli, while 85 are partially conserved and 120 complexes are completely absent. Furthermore, we determine network clusters that coincide with related functions, gene essentiality, genetic context, cellular localization, and gene expression in different cellular states.

Chemokine receptors are seven transmembrane-domain receptors belonging to class A of G-protein-coupled receptors (GPCRs). The receptors together with their chemokine ligands constitute the chemokine system, which is essential for directing cell migration and plays a crucial role in a variety of physiologic and pathologic processes. Given the importance of orchestrating cell migration, it is vital that chemokine receptor signaling is tightly regulated to ensure appropriate responses. Recent studies highlight a key role for cholesterol in modulating chemokine receptor activities. The steroid influences the spatial organization of GPCRs within the membrane bilayer, and consequently can tune chemokine receptor signaling. The effects of cholesterol on the organization and function of chemokine receptors and GPCRs in general include direct and indirect effects (Fig. 1). Here, we review how cholesterol and some key metabolites modulate functions of the chemokine system in multiple ways. We emphasize the role of cholesterol in chemokine receptor oligomerization, thereby promoting the formation of a signaling hub enabling integration of distinct signaling pathways at the receptor-membrane interface. Moreover, we discuss the role of cholesterol in stabilizing particular receptor conformations and its consequence for chemokine binding. Finally, we highlight how cholesterol accumulation, its deprivation, or cholesterol metabolites contribute to modulating cell orchestration during inflammation, induction of an adaptive immune response, as well as to dampening an anti-tumor immune response.

AbstractBoth airborne acoustic signals and substrate-borne vibrations are prevalent modes of animal communication, particularly in arthropods. While a wide variety of animals utilize one or both of these modalities, the connection between them is still ambiguous in many species. Spiders as a group are not known for using, or even perceiving, acoustic signals, despite being well-adapted for vibratory communication. Males of the “purring” wolf spider Gladicosa gulosaare reported to produce audible signals during courtship, although the literature on this species is largely anecdotal. Using a laser Doppler vibrometer and an omnidirectional microphone in controlled conditions, we recorded and characterized the visual and mechanical (both substrate-borne and airborne) signals of this species in an attempt to provide a qualitative and quantitative overview of its signal properties. We found that the vibratory signal is composed of two primary repeating and alternating elements, consisting of pulses of stridulation and percussive strikes, as well as a less common, but repeatable, third element. We also characterized a measurable airborne component to the signal that is significantly correlated with the amplitude of the vibratory signal, which we suggest is a by-product of the strong vibration. Neither modality correlated significantly with male body size or condition. Although the exact role of the acoustic component is unclear, we speculate that the unique properties of signalling in this species may have value in answering new questions about animal communication.

AbstractSpatially distinct pools of the small GTPase Cdc42 were observed, but the major focus of research so far has been to investigate its signaling at the plasma membrane. We recently showed that the Golgi pool of Cdc42 is relevant for cell polarity and that it is regulated by GM130, a Golgi matrix protein. Loss of GM130 abrogated cell polarity and consistent with the notion that polarity is frequently impaired in cancer, we found that GM130 is downregulated in colorectal cancer. Whether the loss of GM130 solely affects polarity, or whether it affects other processes relevant for tumorigenesis remains unclear. In a panel of breast cancer cells lines, we investigated the consequences of GM130 depletion on traits of relevance for tumor progression, such as survival, proliferation, adhesion, migration and invasion. We show that cellular assays that depend on polarity, such as chemotaxis and wound scratch assays, are only of limited use to investigate the role of polarity modulators in cancer. Depletion of GM130 increases cellular velocity and increases the invasiveness of breast cancer cells, therefore supporting the view that alterations of polarity contribute to tumor progression.

Helicobacter pyloriinfections cause gastric ulcers and play a major role in the development of gastric cancer. In 2001, the first protein interactome was published for this species, revealing over 1500 binary protein interactions resulting from 261 yeast two-hybrid screens. Here we roughly double the number of previously published interactions using an ORFeome-based, proteome-wide yeast two-hybrid screening strategy. We identified a total of 1515 protein–protein interactions, of which 1461 are new. The integration of all the interactions reported in H. pyloriresults in 3004 unique interactions that connect about 70% of its proteome. Excluding interactions of promiscuous proteins we derived from our new data a core network consisting of 908 interactions. We compared our data set to several other bacterial interactomes and experimentally benchmarked the conservation of interactions using 365 protein pairs (interologs) of E. coliof which one third turned out to be conserved in both species.

Eavesdropping on communication is widespread among animals, e.g. bystanders observing male–male contests, female mate choice copying and predator detection of prey cues. Some animals also exhibit signal matching, e.g. overlapping of competitors' acoustic signals in aggressive interactions. Fewer studies have examined male eavesdropping on conspecific courtship, although males could increase mating success by attending to others' behaviour and displaying whenever courtship is detected. In this study, we show that field-experienced male Schizocosa ocreatawolf spiders exhibit eavesdropping and signal matching when exposed to video playback of courting male conspecifics. Male spiders had longer bouts of interaction with a courting male stimulus, and more bouts of courtship signalling during and after the presence of a male on the video screen. Rates of courtship (leg tapping) displayed by individual focal males were correlated with the rates of the video exemplar to which they were exposed. These findings suggest male wolf spiders might gain information by eavesdropping on conspecific courtship and adjust performance to match that of rivals. This represents a novel finding, as these behaviours have previously been seen primarily among vertebrates.

The Consortium for Snake Genomics is in the process of sequencing the genome and creating transcriptomic resources for the Burmese python. Here, we describe how this will be done, what analyses this work will include, and provide a timeline.