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Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp168. To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp168 variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
Downy mildews caused by obligate biotrophic oomycetes result in severe crop losses worldwide. Among these pathogens, Pseudoperonospora cubensis and P. humuli, two closely related oomycetes, adversely affect cucurbits and hop, respectively. Discordant hypotheses concerning their taxonomic relationships have been proposed based on host–pathogen interactions and specificity evidence and gene sequences of a few individuals, but population genetics evidence supporting these scenarios is missing. Furthermore, nuclear and mitochondrial regions of both pathogens have been analyzed using microsatellites and phylogenetically informative molecular markers, but extensive comparative population genetics research has not been done. Here, we genotyped 138 current and historical herbarium specimens of those two taxa using microsatellites (SSRs). Our goals were to assess genetic diversity and spatial distribution, to infer the evolutionary history of P. cubensis and P. humuli, and to visualize genome-scale organizational relationship between both pathogens. High genetic diversity, modest gene flow, and presence of population structure, particularly in P. cubensis, were observed. When tested for cross-amplification, 20 out of 27 P. cubensis-derived gSSRs cross-amplified DNA of P. humuli individuals, but few amplified DNA of downy mildew pathogens from related genera. Collectively, our analyses provided a definite argument for the hypothesis that both pathogens are distinct species, and suggested further speciation in the P. cubensis complex.
The taxonomy of cyclostome bryozoans is founded on characters of the skeleton, but molecular sequence data have increasingly shown that established higher taxa are not monophyletic. Here we describe the skeletal morphology of a new species from Guadeloupe (French West Indies) with erect ramose colonies consisting of long, curved zooids that are typical of the suborder Cerioporina among living cyclostomes. However, molecular evidence from nuclear ribosomal RNA genes 18S and 28S places the new taxon in the suborder Rectangulata, where this colony-form has not been previously recorded. It nests firmly within the genus Disporella Gray, 1848, in a strongly supported clade that also includes Plagioecia patina (Lamarck, 1816) (Tubuliporina) and the sister taxa Doliocoitis cyanea Gordon & Taylor, 2001 (Rectangulata) and Favosipora rosea Gordon & Taylor, 2001 (Cerioporina). The short and robust branches of the new Guadeloupe cyclostome, here named Disporella guada Harmelin, Taylor & Waeschenbach sp. nov., are well adapted to life in shallow rocky sites exposed to severe wave action, which appear to be its exclusive habitat.
Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the co-factor is required for structural stability of ULK4. Here, we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4-specific activation loop, which stabilizes the C helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin-associated proteins and several active kinases suggesting interesting regulatory roles for ULK4.
A new family, Electrocambalidae fam. nov. of the suborder Cambalidea is described from Cretaceous Burmese amber based on two new genera, Electrocambala gen. nov. and Kachincambala gen. nov. with four new species, Electrocambala ornata gen. et sp. nov., E. cretacea gen. et sp. nov., Kachincambala muelleri gen. et sp. nov. and K. distorta gen. et sp. nov. The specimens are described combining classical light microscopy with drawings and photography, and modern micro-computed tomography (μCT). Morphological characters otherwise obscured are examined and visualized by creating volume renderings and 3D-segmentations from μCT data. Electrocambalidae fam. nov. is characterized by the following character combination: (1) a forward shift of leg pair 3, resulting in an apparently legless 3rd body ring, (2) presence of metazonital setae, and (3) extensive pilosity on the head. Although some of these characters are shared with other Juliformia they are unique in this combination. The described fossils are the oldest and first Mesozoic Spirostreptida and Cambalidea known and ca 70 million years older than previous records of the group.
Microthlaspi erraticum is widely distributed in temperate Eurasia, but restricted to Ca2+-rich habitats, predominantly on white Jurassic limestone, which is made up by calcium carbonate, with little other minerals. Thus, naturally occurring Microthlaspi erraticum individuals are confronted with a high concentration of Ca2+ ions while Mg2+ ion concentration is relatively low. As there is a competitive uptake between these two ions, adaptation to the soil condition can be expected. In this study, it was the aim to explore the genomic consequences of this adaptation by sequencing and analysing the genome of Microthlaspi erraticum. Its genome size is comparable with other diploid Brassicaceae, while more genes were predicted. Two Mg2+ transporters known to be expressed in roots were duplicated and one showed a significant degree of positive selection. It is speculated that this evolved due to the pressure to take up Mg2+ ions efficiently in the presence of an overwhelming amount of Ca2+ ions. Future studies on plants specialized on similar soils and affinity tests of the transporters are needed to provide unequivocal evidence for this hypothesis. If verified, the transporters found in this study might be useful for breeding Brassicaceae crops for higher yield on Ca2+-rich and Mg2+ -poor soils.
Coronuloid barnacles are epibionts of several marine vertebrates (including cetaceans and sea turtles) as well as invertebrates, and are assigned to two families of turtle barnacles (Chelonibiidae Pilsbry, 1916 and Platylepadidae Newman & Ross, 1976) and one family of whale barnacles (Coronulidae Leach, 1817). Chelonibiids and coronulids have a scanty, albeit significant fossil record extending back to the Eocene and Pliocene, respectively; in turn, the fossil record of platylepadids is limited to a single record from the Upper Pleistocene. Here we report on an isolated carinolateral compartment of Platylepas Gray, 1825, the type genus of the family, from Lower Pleistocene (Gelasian) epibathyal deposits exposed at Milazzo (Sicily, Italy). This specimen is here designated holotype of a new species, †Platylepas mediterranea sp. nov. We argue that, like most extant members of Platylepas, †P. mediterranea sp. nov. lived partially embedded in the skin of a sea turtle. This record of an extinct platylepadid – the first from the Mediterranean region and the second worldwide – pushes back the fossil record of Platylepadidae to the lowermost Quaternary, thus possibly supporting an even earlier (e.g., Neogene) timing for the origin of this family and adding a new chapter to the evolutionary history of one of the most diverse and successful lineages of epizoic crustaceans.
Five new species in four new genera from Western Australia are described. All species have valve characters that are reminiscent of the genus Heterocypris Claus, 1892 and also have similar valve outlines, with highly arched valves. However, all species have a hemipenis morphology that is totally different from the typical form in Heterocypris. In Patcypris gen. nov. (with type species P. outback gen. et sp. nov.), the lateral lobe is large and shaped as a pickaxe, while the medial lobe is divided into two distal lobes. Trilocypris gen. nov. (with type species T. horwitzi gen. et sp. nov.) is characterised by a hemipenis that has three, instead of two, distal lobes. In Bilocypris gen. nov. (with type species B. fortescuensis gen. et sp. nov. and a second species, B. mandoraensis gen. et sp. nov.), the lateral lobe of the hemipenis is spatulate, rather than boot-shaped, and the medial lobe is bilobed. Billcypris gen. nov. (with type species B. davisae gen. et sp. nov.) has a large and sub-rectangular lateral lobe and a pointed medial lobe. We discuss the taxonomic value of the traditional and new morphological characters and speculate that the diversity of this cluster of genera and species may be greater than currently known.
Attractiveness ratings for musicians and non-musicians: An evolutionary-psychology perspective
(2019)
From an evolutionary perspective, musical behavior such as playing an instrument can be considered as part of an individual’s courting behavior. Playing a musical instrument or singing might fulfill a function similar to that of a bird’s colored feathers: attracting attention. Therefore, musicians may be rated as more attractive than non-musicians. In an online survey, 137 volunteers (95 female) with ages ranging from 16 to 39 years rated the attractiveness of fictitious persons of the opposite sex described in short verbal profiles. These profiles differed with respect to whether the described person made music or not. Additionally, the musicians’ profiles varied with regard to whether the described person played music or sang in public or in private only. Results show that musicians’ profiles were not generally rated as more attractive than non-musicians’, but attractiveness did vary according to setting: private musicians were rated as most attractive, followed by non-musicians and public musicians. Furthermore, results indicate that participants who played a musical instrument or sang themselves gave higher ratings to profiles of musicians. But for participants who do not make music themselves, higher attractiveness ratings for musicians playing instruments or sing in private settings were found. These results indicate that the impression of sharing a common interest (making music) and furthermore making music in private instrumental settings seems to make people attractive to other people. No additional support for the sexual selection hypotheses for the evolution of music was provided by the current results. The musical status of the rater affected his or her judgements, with musicians rating other people as more attractive if they share the common interest in making music. Not the display of being a musician seems to be critical for attractiveness ratings but the perceived or imagined similarity by the rater created by information on musicality, fostering the theoretical significance of the communication aspect of music.
Inhibitory interneurons govern virtually all computations in neocortical circuits and are in turn controlled by neuromodulation. While a detailed understanding of the distinct marker expression, physiology, and neuromodulator responses of different interneuron types exists for rodents and recent studies have highlighted the role of specific interneurons in converting rapid neuromodulatory signals into altered sensory processing during locomotion, attention, and associative learning, it remains little understood whether similar mechanisms exist in human neocortex. Here, we use whole-cell recordings combined with agonist application, transgenic mouse lines, in situ hybridization, and unbiased clustering to directly determine these features in human layer 1 interneurons (L1-INs). Our results indicate pronounced nicotinic recruitment of all L1-INs, whereas only a small subset co-expresses the ionotropic HTR3 receptor. In addition to human specializations, we observe two comparable physiologically and genetically distinct L1-IN types in both species, together indicating conserved rapid neuromodulation of human neocortical circuits through layer 1.