bluuebunny/crossref_metadata_2025 huggingface dataset:
Anal Sphincter Anatomy Prepregnancy to Postdelivery Among the Same Primiparous Women on Dynamic Magnetic Resonance Imaging
Authors: Meriwether Kate V. , Lockhart Mark E. , Meyer Isuzu , Richter Holly E.
Published: October 2017

Objectives

The authors used 2-dimensional images from pelvic 3 T magnetic resonance imaging (MRI) to characterize changes in the internal anal sphincter (IAS) and external anal sphincter (EAS) from prepregnancy to postdelivery in the same cohort.

Methods

This secondary analysis studied a prospective cohort of women undergoing 3 T MRI before their first pregnancy and 6 or more months after delivery. Radial thickness was measured at 12, 3, 9, and 6 o'clock from axial proximal and mid views and oblique distal views of the IAS, and at 3 and 9 o'clock from oblique views of the EAS. Measurements were compared prepregnancy to postdelivery; 10 women had 80% power (α = 0.05) to detect a 0.85-mm change.

Results

Nineteen women completed initial 3 T MRI, 15 achieved pregnancy and birth, and 10 completed postdelivery MRI (4 vaginal birth and 6 Cesarean delivery). Mean change in measurement from prepregnancy to postdelivery was −0.01 mm ± 1.03 mm for the distal 12 o'clock IAS (P = 0.98) and +0.19 ± 0.64 mm for the lateral EAS (P = 0.32). All prepregnancy and postdelivery women had discontinuous EA sphincters at 6 and 12 o'clock. There were no statistically significant changes from prepregnancy to postdelivery in any IAS or EAS location (all >0.05) for the entire cohort, those with vaginal birth, or after Cesarean.

Conclusions

Anal sphincter measurements on MRI did not change significantly in nulliparous women prepregnancy to postdelivery at any location, and the EAS was not measurable at 12 o'clock in any women at either time point, challenging classic concepts of EAS anatomy.
Nascent life cycles and the emergence of higher-level individuality
Authors: Ratcliff William C. , Herron Matthew , Conlin Peter L. , Libby Eric
Published: October 2017

Evolutionary transitions in individuality (ETIs) occur when formerly autonomous organisms evolve to become parts of a new, ‘higher-level’ organism. One of the first major hurdles that must be overcome during an ETI is the emergence of Darwinian evolvability in the higher-level entity (e.g. a multicellular group), and the loss of Darwinian autonomy in the lower-level units (e.g. individual cells). Here, we examine how simple higher-level life cycles are a key innovation during an ETI, allowing this transfer of fitness to occur ‘for free’. Specifically, we show how novel life cycles can arise and lead to the origin of higher-level individuals by (i) mitigating conflicts between levels of selection, (ii) engendering the expression of heritable higher-level traits and (iii) allowing selection to efficiently act on these emergent higher-level traits. Further, we compute how canonical early life cycles vary in their ability to fix beneficial mutations via mathematical modelling. Life cycles that lack a persistent lower-level stage and develop clonally are far more likely to fix ‘ratcheting’ mutations that limit evolutionary reversion to the pre-ETI state. By stabilizing the fragile first steps of an evolutionary transition in individuality, nascent higher-level life cycles may play a crucial role in the origin of complex life.

This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.
The topology of evolutionary novelty and innovation in macroevolution
Authors: Erwin Douglas H.
Published: October 2017

Sewall Wright's fitness landscape introduced the concept of evolutionary spaces in 1932. George Gaylord Simpson modified this to an adaptive, phenotypic landscape in 1944 and since then evolutionary spaces have played an important role in evolutionary theory through fitness and adaptive landscapes, phenotypic and functional trait spaces, morphospaces and related concepts. Although the topology of such spaces is highly variable, from locally Euclidean to pre-topological, evolutionary change has often been interpreted as a search through a pre-existing space of possibilities, with novelty arising by accessing previously inaccessible or difficult to reach regions of a space. Here I discuss the nature of evolutionary novelty and innovation within the context of evolutionary spaces, and argue that the primacy of search as a conceptual metaphor ignores the generation of new spaces as well as other changes that have played important evolutionary roles.

This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.
Innovation and social transmission in experimental micro-societies: exploring the scope of cumulative culture in young children
Authors: McGuigan Nicola , Burdett Emily , Burgess Vanessa , Dean Lewis , Lucas Amanda , Vale Gillian , Whiten Andrew
Published: October 2017

The experimental study of cumulative culture and the innovations essential to it is a young science, with child studies so rare that the scope of cumulative cultural capacities in childhood remains largely unknown. Here we report a new experimental approach to the inherent complexity of these phenomena. Groups of 3–4-year-old children were presented with an elaborate array of challenges affording the potential cumulative development of a variety of techniques to gain increasingly attractive rewards. In contrast to a prior study, we found evidence for elementary forms of cumulative cultural progress, with inventions of solutions at lower levels spreading to become shared innovations, and some children then building on these to create more advanced but more rewarding innovations. This contrasted with markedly more constrained progress when children worked only by themselves, or if groups faced only the highest-level challenges from the start. Further experiments that introduced higher-level inventions via the inclusion of older children, or that created ecological change, with the easiest habitual solutions no longer possible, encouraged higher levels of cumulative innovation. Our results show children are not merely ‘cultural sponges’, but when acting in groups, display the beginnings of cycles of innovation and observational learning that sustain cumulative progress in problem solving.

This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.
Inferring processes of cultural transmission: the critical role of rare variants in distinguishing neutrality from novelty biases
Authors: O'Dwyer James P. , Kandler Anne
Published: October 2017

Neutral evolution assumes that there are no selective forces distinguishing different variants in a population. Despite this striking assumption, many recent studies have sought to assess whether neutrality can provide a good description of different episodes of cultural change. One approach has been to test whether neutral predictions are consistent with observed progeny distributions, recording the number of variants that have produced a given number of new instances within a specified time interval: a classic example is the distribution of baby names. Using an overlapping generations model, we show that these distributions consist of two phases: a power-law phase with a constant exponent of

, followed by an exponential cut-off for variants with very large numbers of progeny. Maximum-likelihood estimations of the model parameters provide a direct way to establish whether observed empirical patterns are consistent with neutral evolution. We apply our approach to a complete dataset of baby names from Australia. Crucially, we show that analyses based on only the most popular variants, as is often the case in studies of cultural evolution, can provide misleading evidence for underlying transmission hypotheses. While neutrality provides a plausible description of progeny distributions of abundant variants, rare variants deviate from neutrality. Further, we develop a simulation framework that allows the detection of alternative cultural transmission processes. We show that anti-novelty bias is able to replicate the complete progeny distribution of the Australian dataset.

This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.
Cognitive innovations and the evolutionary biology of expertise
Authors: Dukas Reuven
Published: October 2017

Animal life can be perceived as the selective use of information for maximizing survival and reproduction. All organisms including bacteria and protists rely on genetic networks to build and modulate sophisticated structures and biochemical mechanisms for perceiving information and responding to environmental changes. Animals, however, have gone through a series of innovations that dramatically increased their capacity to acquire, retain and act upon information. Multicellularity was associated with the evolution of the nervous system, which took over many tasks of internal communication and coordination. This paved the way for the evolution of learning, initially based on individual experience and later also via social interactions. The increased importance of social learning also led to the evolution of language in a single lineage. Individuals' ability to dramatically increase performance via learning may have led to an evolutionary cycle of increased lifespan and greater investment in cognitive abilities, as well as in the time necessary for the development and refinement of expertise. We still know little, however, about the evolutionary biology, genetics and neurobiological mechanisms that underlie such expertise and its development.

This article is part of the themed issue ‘Process and pattern in innovations from cells to societies’.
Meaning Guides Attention in Real-World Scene Images: Evidence from Eye Movements and Meaning Maps
Authors: Henderson John M. , Hayes Taylor R.
Published: October 2017

We compared the influences of meaning and salience on attentional guidance in scene images. Meaning was captured by “meaning maps” representing the spatial distribution of semantic information in scenes. Meaning maps were coded in a format that could be directly compared to maps of image salience generated from image features. We investigated the degree to which meaning versus image salience predicted human viewers’ spatial distribution of attention over scenes, with attention operationalized as duration-weighted fixation density. The results showed that both meaning and salience predicted the distribution of attention, but that when the correlation between meaning and salience was statistically controlled, meaning accounted for unique variance in attention but salience did not. This pattern was observed for early as well as late fixations, for fixations following short as well as long saccades, and for fixations including or excluding the centers of the scenes. The results strongly suggest that meaning guides attention in real world scenes. We discuss the results from the perspective of a cognitive relevance theory of attentional guidance in scenes.
Contribution of transition and stabilization processes to speciation is a function of the ancestral trait state and selective environment in Hakea
Authors: Lamont Byron B. , El-ahmir Sh-hoob M. , Lim Sim Lin , Groom Philip K. , He Tianhua
Published: October 2017

Currently the origin and trajectories of novel traits are emphasised in evolutionary studies, the role of stabilization is neglected, and interpretations are often post hoc rather than as hypothesised responses to stated agents of selection. Here we evaluated the impact of changing environmental conditions on trait evolution and stabilization and their relative contribution to diversification in a prominent Australian genus, Hakea (Proteaceae). We assembled a time-based phylogeny for Hakea, reconstructed its ancestral traits for six attributes and determined their evolutionary trajectories in response to the advent or increasing presence of fire, seasonality, aridity, nectar-feeding birds and (in)vertebrate herbivores/granivores. The ancestral Hakea arose 18 million years ago (Ma) and was broad-leaved, non-spinescent, insect-pollinated, had medium-sized, serotinous fruits and resprouted after fire. Of the 190 diversification events that yielded the 82 extant species analysed, 8–50% involved evolution, stabilization or re-evolution (reversal) of individual novel traits. Needle leaves appeared 14 Ma and increased through the Neogene/Quaternary coinciding with intensifying seasonality and aridity. Spinescence arose 12 Ma consistent with the advent of vertebrate herbivores. Bird-pollination appeared 14 Ma in response to advent of the Meliphagidae in the early Miocene. Small and large woody fruits evolved from 12 Ma as alternative defenses against granivory. Fire-caused death evolved 14 Ma, accounting for 50% of subsequent events, as fire became less stochastic. Loss of serotiny began in the late Miocene as non-fireprone habitats became available but only contributed 8% of events. Innovation and subsequent stabilization of functional traits promoted the overall species diversification rate in Hakea by 15 times such that only three species now retain the ancestral phenotype. Our approach holds great promise for understanding the processes responsible for speciation of organisms when the ancestral condition can be identified and the likely selective agents are understood.
Genome-Wide Association Study of Body Fat Distribution identifies Novel Adiposity Loci and Sex-Specific Genetic Effects
Authors: Rask-Andersen Mathias , Karlsson Torgny , Ek Weronica E , Johansson Åsa
Published: October 2017

Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested as more pathogenic compared to fat stored in other compartments of the body. In this study, we performed genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. A total of 97 loci, were identified to be associated with body fat distribution, 40 of which have not previously been associated with an anthropometric trait. A high degree of sex-heterogeneity was observed and associations were primarily observed in females, particularly for distribution of fat to the legs or trunk. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues a well as several enzymatically active members of the ADAMTS family of metalloproteinases, which are involved in extracellular matrix maintenance and remodeling.
Bipolar filaments of human nonmuscle myosin 2-A and 2-B have distinct motile and mechanical properties
Authors: Melli Luca , Billington Neil , Sun Sara A. , Bird Jonathan E. , Nagy Attila , Friedman Thomas B. , Takagi Yasuharu , Sellers James R.
Published: October 2017

Nonmuscle myosin 2 (NM-2) powers cell motility and tissue morphogenesis by assembling into bipolar filaments that interact with actin. Although the enzymatic properties of purified NM-2 motor fragments have been determined, the emergent properties of filament ensembles are unknown. Using single myosin filament in vitro motility assays, we report fundamental differences in filaments formed of different NM-2 motors. Filaments consisting of NM2-B moved processively along actin, while under identical conditions, NM2-A filaments did not. By more closely mimicking the physiological milieu, either by increasing solution viscosity or by copolymerization with NM2-B, NM2-A containing filaments moved processively. Our data demonstrate that both the kinetic and mechanical properties of these two myosins, in addition to the stochiometry of NM-2 subunits, can tune filament mechanical output. We propose altering NM-2 filament composition is a general cellular strategy for tailoring force production of filaments to specific functions such as maintaining tension or remodeling actin.
Distinct contributions of functional and deep neural network features to representational similarity of scenes in human brain and behavior
Authors: Groen Iris I. A. , Greene Michelle R. , Baldassano Christopher , Fei-Fei Li , Beck Diane M. , Baker Chris I.
Published: October 2017

Inherent correlations between visual and semantic features in real-world scenes make it difficult to determine how different scene properties contribute to neural representations. Here, we assessed the contributions of multiple properties to scene representation by partitioning the variance explained in human behavioral and brain measurements by three feature models whose inter-correlations were minimizeda priorithrough stimulus preselection. Behavioral assessments of scene similarity reflected unique contributions from a functional feature model indicating potential actions in scenes as well as high-level visual features from a deep neural network (DNN). In contrast, similarity of cortical responses in scene-selective areas was uniquely explained by mid- and high-level DNN features only, while an object label model did not contribute uniquely to either domain. The striking dissociation between functional and DNN features in their contribution to behavioral and brain representations of scenes indicates that scene-selective cortex represents only a subset of behaviorally relevant scene information.
Down Feather Structure Varies Between Low- and High-Altitude Torrent Ducks (MerganettaArmata) in the Andes
Authors: Cheek Rebecca G. , Alza Luis , McCracken Kevin G.
Published: October 2017

Feathers are one of the defining characteristics of birds and serve a critical role in thermal insulation and physical protection against the environment. Feather structure is known to vary among individuals, and it has been suggested that populations exposed to different environmental conditions may exhibit different patterns in feather structure. We examined both down and contour feathers from two populations of male Torrent Ducks (Merganetta armata) from Lima, Peru, including one high-altitude population from the Chancay-Huaral River at approximately 3500 meters (m) elevation and one low-altitude population from the Chillón River at approximately 1500 m. Down feather structure differed significantly between the two populations. Ducks from the high-altitude population had longer, denser down compared with low-altitude individuals. Contour feather structure varied greatly among individuals but showed no significant difference between populations. These results suggest that the innermost, insulative layer of plumage (the down), may have developed in response to lower ambient temperatures at high elevations. The lack of observable differences in the contour feathers may be due to the general constraints of the waterproofing capability of this outer plumage layer.

El plumaje es una característica que define a las aves y cumple roles críticos en el aislamiento térmico y protección física del ambiente. Se sabe que la estructura de las plumas varía ente individuos, y se ha sugerido que poblaciones expuestas a diferentes condiciones ambientales pueden exhibir diferentes patrones en la estructura de las plumas. En este estudio se examinaron tanto el plumón como las plumas de contorno de machos adultos del Pato de los Torrentes (Merganetta armata) de dos poblaciones, una en el río Chancay-Huaral a 3,500 msnm y otra en el río Chillón a 1,500 msnm, ubicadas en Lima, Perú. La estructura de los plumones difiere significativamente entre las dos poblaciones. Los patos de la población a grandes elevaciones tienen plumones largos, y densos comparados con los individuos de las partes bajas. La estructura de las plumas de contorno varía ampliamente entre individuos pero no muestra diferencias significativas entre poblaciones. Estos resultados sugieren que las diferencias entre las capas interiores de aislamiento del plumaje (plumón), haberse desarrollado como respuesta en ambientes de bajas temperaturas a grandes elevaciones. En cambio la falta de detectables diferencias en las plumas de contorno puede ser debido a la constante selección en la capacidad impermeable de la capa de plumas exteriores.
A multi-state model of chemoresistance to characterize phenotypic dynamics in breast cancer
Authors: Howard Grant R. , Johnson Kaitlyn E. , Rodriguez Ayala Areli , Yankeelov Thomas E. , Brock Amy
Published: October 2017

The development of resistance to chemotherapy is a major cause of treatment failure in breast cancer. Although several molecular mechanisms of chemotherapeutic resistance are well studied, a quantitative understanding of the dynamics of resistant subpopulations within a heterogeneous tumor cell population remains elusive. While mathematical models describing the dynamics of heterogeneous cancer cell populations have been proposed, few have been experimentally validated due to the complex nature of resistance that limits the ability of a single phenotypic marker to sufficiently isolate drug resistant subpopulations. In this work, we address this problem with a combined experimental and modeling system that uses drug sensitivity data to reveal the composition of multiple subpopulations differing in their level of drug resistance. We calibrate time-resolved dose-response data to three mathematical models to interrogate the models’ ability to capture the dynamics of drug. All three models demonstrated an increase in population level resistance following drug exposure. The candidate models were compared by Akaike information criterion and the model selection criteria identified a multi-state model incorporating the role of population heterogeneity and cellular plasticity. To validate the ability of this model to identify the composition of subpopulations, we mixed wild-type MCF-7 and MCF-7/ADR resistant cells at various proportions and evaluated the corresponding model output. Our blinded two-state model was able to estimate the proportions of cell subtypes, with the measured proportions falling within the 95 percent confidence intervals on the parameter estimations and at an R-squared value of 0.986. To the best of our knowledge, this contribution represents the first work to combine experimental time-resolved drug sensitivity data with a mathematical model of resistance development.
Universal transcriptomic signature of age reveals temporal scaling ofCaenorhabditis elegansaging trajectories
Authors: Tarkhov Andrei E. , Alla Ramani , Ayyadevara Srinivas , Pyatnitskiy Mikhail , Menshikov Leonid I. , Reis Robert Shmookler , Fedichev Peter O.
Published: October 2017

We collected 60 age-dependent transcriptomes forC. elegansstrains including four exceptionally long-lived mutants (mean adult lifespan extended up to 9.4-fold) and three examples of RNAi treatments that increased lifespan by 19 – 35%. Principal Component Analysis (PCA) reveals aging as a transcriptomic drift along a single direction, consistent across the vastly diverse biological conditions and coinciding with the first principal component, a hallmark of the criticality of the underlying gene regulatory network. We, therefore, expected that the organism’s aging state could be characterized by a single number closely related to vitality deficit or biological age. The “aging trajectory”, i.e. the dependence of the biological age on chronological age, is then a universal stochastic function modulated by the network stiffness; a macroscopic parameter reflecting the network topology and associated with the rate of aging. To corroborate this view, we used publicly available datasets to define a transcriptomic biomarker of age and observed that the rescaling of age by lifespan simultaneously brings together aging trajectories of transcription and survival curves. In accordance with the theoretical prediction, the limiting mortality value at the plateau agrees closely with the mortality rate doubling exponent estimated at the cross-over age near the average lifespan. Finally, we used the transcriptomic signature of age to identify possible life-extending drug compounds and successfully tested a handful of the top ranking molecules inC. eleganssurvival assays and achieved up to a +30% extension of mean and median lifespan.
Calling song maturity in two-spotted cricket,Gryllus bimaculatus: its patterns and a possible physical explanation
Authors: Miyashita Atsushi
Published: October 2017

Males ofGryllus bimaculatus(two-spotted cricket) emit acoustic signals by stridulating two forewings. One of their songs, calling song, plays a role in attracting females to mate, yet the significance of each song trait in attracting conspecific females remains unclear. Among such traits, the relevance of frequency component (i.e. song pitch) has been underestimated, as orthopterans had long been believed incapable of song pitch recognition. However, recent literatures suggested that ears of orthopteran species are capable of frequency recognition as mammalians do. My previous report demonstrated that their calling song recorded from mature adults has constant and pure peak frequency component around 5.7 kHz, further supporting a biological significance of the frequency component. In this study, I tracked its change over time in sexual maturity phase (i.e. from early adult phase). 300 calling songs were recorded over time from a pool of 122 adult crickets, as it required large number of animals because the crickets rarely sing at very early adult stage. A maturation process of calling song was observed, where the peak frequency distributed lower and more variable frequency in early adult phase (e.g. mean peak value was 4.9 kHz on day 3), then it gradually increased and converged to 5.8 kHz with two weeks. The coefficient of variance also decreased over the process, showing minimum around day 20. Also, I found that the young crickets (supposed to emit immature song), emit perfectly tuned calling song with 5.8 kHz peak in helium-substituted (80% Helium and 20% Oxygen) environment. These findings suggest that the robustly regulated frequency of the calling song is acquired during the early-to-mid adult stage, and it may be associated with sexual maturity of males. Also, the helium-substitution experiment suggests that physical resistance from surrounding gas molecules negatively impacts stability of calling songs of young males, implying that a muscle development and/or forewing hardening may help song maturation. This study highlights a biological significance of the frequency component, such that females may adaptively select sexually mature males based on the song trait.
MeShClust: an intelligent tool for clustering DNA sequences
Authors: James Benjamin T. , Luczak Brian B. , Girgis Hani Z.
Published: October 2017

Sequence clustering is a fundamental step in analyzing DNA sequences. Widely-used software tools for sequence clustering utilize greedy approaches that are not guaranteed to produce the best results. These tools are sensitive to one parameter that determines the similarity among sequences in a cluster. Often times, a biologist may not know the exact sequence similarity. Therefore, clusters produced by these tools do not likely match the real clusters comprising the data if the provided parameter is inaccurate. To overcome this limitation, we adapted the mean shift algorithm, an unsupervised machine-learning algorithm, which has been used successfully thousands of times in fields such as image processing and computer vision. The theory behind the mean shift algorithm, unlike the greedy approaches, guarantees convergence to the modes, e.g. cluster centers. Here we describe the first application of the mean shift algorithm to clustering DNA sequences. MeShClust is one of few applications of the mean shift algorithm in bioinformatics. Further, we applied supervised machine learning to predict the identity score produced by global alignment using alignment-free methods. We demonstrate MeShClust’s ability to cluster DNA sequences with high accuracy even when the sequence similarity parameter provided by the user is not very accurate.
Short-term effects of sound localization training in virtual reality
Authors: Steadman Mark A. , Kim Chungeun , Lestang Jean-Hugues , Goodman Dan F. M. , Picinali Lorenzo
Published: October 2017

Head-related transfer functions (HRTFs) capture the direction-dependant way that sound interacts with the head and torso. In virtual audio systems, which aim to emulate these effects, non-individualized, generic HRTFs are typically used leading to an inaccurate perception of virtual sound location. Training has the potential to exploit the brain’s ability to adapt to these unfamiliar cues. In this study, three virtual sound localization training paradigms were evaluated; one provided simple visual positional confirmation of sound source location, a second introduced game design elements (“gamification”) and a final version additionally utilized head-tracking to provide listeners with experience of relative sound source motion (“active listening”). The results demonstrate a significant effect of training after a small number of short (12-minute) training sessions, which is retained across multiple days. Gamification alone had no significant effect on the efficacy of the training, but active listening resulted in a significantly greater improvements in localization accuracy. In general, improvements in virtual sound localization following training generalized to a second set of non-individualized HRTFs, although some HRTF-specific changes were observed in polar angle judgement for the active listening group. The implications of this on the putative mechanisms of the adaptation process are discussed.
Zebrafish yolk syncytial nuclei migrate along a dynamic microtubule network
Authors: Fei Zhonghui , Bae Koeun , Parent Serge E. , Goodwin Katharine , Tanentzapf Guy , Bruce Ashley E.E.
Published: October 2017

In teleosts, the yolk syncytial layer is a multinucleate syncytium that functions as an extraembryonic signaling center to pattern the mesendoderm, coordinate morphogenesis and supply nutrients to the embryo. The zebrafish is an excellent system for studying this morphogenetically active tissue. The external yolk syncytial nuclei (e-YSN) undergo microtubule dependent epiboly movements that distribute the nuclei over the yolk. How e-YSN epiboly proceeds, and what role the yolk microtubule network plays is not understood but currently it is proposed that e-YSN are pulled vegetally as the microtubule network shortens from the vegetal pole. Data from our live imaging studies suggest that the yolk microtubule network is dismantled from the animal and vegetal regions and show that a region of stabilized microtubules forms before nuclear migration begins. e-YSN do not appear to be pulled vegetally but rather move along a dynamic microtubule network. We also show that overexpression of the KASH domain of Syne2a impairs e-YSN movement, implicating the LINC complex in e-YSN migration. This work provides new insights into the role of microtubules in morphogenesis of an extraembryonic tissue.

Summary Statement

Analysis of yolk syncytial nuclear migration during zebrafish epiboly reveals that nuclei migrate along and largely beneath a dynamically yolk microtubule network.
High degree of virulence gene diversity in Streptococcus pyogenes isolated in Central Italy
Authors: Bencardino Daniela , Luca Maria Chiara Di , Petrelli Dezemona , Prenna Manuela , Vitali Luca Agostino
Published: October 2017

Globally, Streptococcus pyogenes poses a continuous burden on human health, causing both self-limiting and life-threatening diseases. Therefore, studying the profile of virulence genes and their combinations is essential to monitor the epidemiology and pathogenetic potential of this important species. Thus, the aim of this study was to analyze some genetic features of clinical strains collected in Italy in 2012.

We conducted fibronectin-collagen-T antigen (FCT) region typing and emm typing in 122 S. pyogenes strains. Furthermore, several additional virulence genes were screened by polymerase chain reaction.

We found correlations between emm types and FCT region profiles. emm1 strains were mainly associated with FCT2 and FCT6, while emm89 and emm12 strains were associated with FCT4. FCT5 was mainly represented in emm4, emm6, and emm75 strains. Noteworthy, we defined subtypes for each FCT type based on the differences in single and multiple loci compared to the reference scheme used for the classification of the FCT region. In addition, new FCT types were identified. Cluster analysis based on virulence gene profiling showed a non-random distribution within each emm type.

This study showed the high variability of S. pyogenes strains and the great diversification that this pathogen has undergone during its evolution in the human host.
Mapping of the Fondaparinux Binding Site of JR-FL gp120 by High Resolution Hydroxyl Radical Protein Footprinting and Computational Docking
Authors: Misra Sandeep K. , Sood Amika , Soares Paulo A. , Pomin Vitor H. , Woods Robert J. , Sharp Joshua S.
Published: October 2017

The adhesion of HIV gp120 antigen to human cells is modulated in part by interactions with heparan sulfate. The HXB2 strain of gp120 has been shown to interact with heparin primarily through the V3 loop, although other domains including the C-terminal domain were also implicated. However, the JR-FL strain (representative of CCR5-interacting strains that make up newest infections) was shown to have a drastically lowered affinity to heparin due to the loss of several basic residues in the V3 loop, and deletion of the V3 loop in JR-FL gp120 was shown to abrogate some, but not all, heparin binding. Here, we use high resolution hydroxyl radical protein footprinting to measure the changes in protein surface oxidation levels that result from the binding of a model heparin fragment (fondaparinux). Protection in both the V3 loop and the N-terminus of JR-FP gp120 is observed. The well-defined composition of fondaparinux allowed us to perform docking simulations, which showed two clusters of fondaparinux binding: the V3 loop, and a domain consisting of the N- and C-termini. Together, the experimental and theoretical results indicate the heparin/heparan sulfate binding sites on JR-FL gp120 and the efficient interaction of fondaparinux, a widely exploited therapeutic carbohydrate, on gp120.
Elucidation of dose-dependent transcriptional events immediately following ionizing radiation exposure
Authors: Rouchka Eric C. , Flight Robert M. , Fasciotto Brigitte H. , Estrada Rosendo , Eaton John W. , Patibandla Phani K. , Waigel Sabine J. , Li Dazhuo , Kirtley John K. , Sethu Palaniappan , Keynton Robert S.
Published: October 2017

Long duration space missions expose astronauts to ionizing radiation events associated with highly energetic and charged heavy particles. Such exposure can result in chromosomal aberrations increasing the likelihood of the development of cancer. Early detection and mitigation of these events is critical in providing positive outcomes. In order to aid in the development of portable devices used to measure radiation exposure, we constructed a genome-wide screen to detect transcriptional changes in peripheral blood lymphocytes shortly after (approximately 1 hour) radiation exposure at low (0.3 Gy), medium (1.5 Gy) and high (3.0 Gy) doses compared to control (0.0 Gy) using Affymetrix®Human Gene 1.0 ST v1 microarrays. Our results indicate a number of sensitive and specific transcriptional profiles induced by radiation exposure that can potentially be implemented as biomarkers for radiation exposure as well as dose effect. For overall immediate radiation exposure,KDELC1,MRPS30,RARS, andHEXIM1were determined to be effective biomarkers whilePRDM9,CHST4, andSLC26A10were determined to be biomarkers specific to 0.3 Gy exposure;RPH,CCDC96,WDYHV1, andIFNA16were identified for 1.5 Gy exposure; andCWC15,CHCHD7, andDNAAF2were determined to be sensitive and specific to 3.0 Gy exposure. The resulting raw and analyzed data are publicly available through NCBI's Gene Expression Ominibus via accession GSE64375.
Programmable RNA recognition using a CRISPR-associated Argonaute
Authors: Lapinaite Audrone , Doudna Jennifer A. , Cate Jamie H. D.
Published: October 2017

Argonaute proteins (Agos) are present in all domains of life. While the physiological function of eukaryotic Agos in regulating gene expression is well documented, the biological roles of many of their prokaryotic counterparts remain enigmatic. In some bacteria, Agos are associated with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci and use non-canonical 5’-hydroxyled guide RNAs (gRNAs) for nucleic acid targeting. Here we show that using 5-bromo-2′-deoxyuridine (BrdU) as the 5’ nucleotide of gRNAs stabilizes in vitro reconstituted CRISPR-associated Marinitoga piezophila Argonaute-gRNA complexes (MpAgo RNPs) and significantly improves their specificity and affinity for RNA targets. Using reconstituted MpAgo RNPs with 5’-BrdU modified gRNAs, we mapped the seed region of the gRNA, and identified the nucleotides of the gRNA that play the most significant role in targeting specificity. We also show that these MpAgo RNPs can be programmed to distinguish between substrates that differ by a single nucleotide, using permutations at the 6th and 7th positions in the gRNA. Using these specificity features, we employed MpAgo RNPs to detect specific Adenosine to Inosine edited RNAs in a complex mixture. These findings broaden our mechanistic understanding of the interactions of Argonautes with guide and substrate RNAs, and demonstrate that MpAgo RNPs with 5’-BrdU modified gRNAs can be used as a highly-specific RNA-targeting platform to probe RNA biology.

SIGNIFICANCE

Argonaute proteins are present in bacteria, archaea and eukaryotes. They play an important role in a wide range of biological processes, from transcriptional and translational gene expression regulation to defense against viruses and silencing of mobile genetic elements. Here we present mechanistic insights into the interactions of the CRISPR-associated Marinitoga piezophila Argonaute (MpAgo) with its guide RNA (gRNA) and RNA substrates. By modifying the 5’-nucleotide of the gRNA, we demonstrate that MpAgo-gRNA complexes (RNPs) are easily programmable, have high affinity to fully complementary RNA substrates, and can discriminate by over 300 fold between substrates that differ by only a single nucleotide. These MpAgo RNPs should be useful for probing endogenous RNAs in living cells.
geck: trio-based comparative benchmarking of variant calls
Authors: Kómár Péter , Kural Deniz
Published: October 2017

Motivation

Classical methods of comparing the accuracies of variant calling pipelines are based on truth sets of variants whose genotypes are previously determined with high confidence. An alternative way of performing benchmarking is based on Mendelian constraints between related individuals. Statistical analysis of Mendelian violations can provide truth set-independent benchmarking information, and enable benchmarking less-studied variants and diverse populations.

Results

We introduce a statistical mixture model forcomparing two variant calling pipelines from genotype data they produce after running on individual members of a trio. We determine the accuracy of our model by comparing the precision and recall of GATK Unified Genotyper and Haplotype Caller on the high-confidence SNPs of the NIST Ashkenazim trio and the two independent Platinum Genome trios. We show that our method is able to estimate differential precision and recall between the two pipelines with 10-3 uncertainty.

Availability

The Python library geck, and usage examples are available at the following URL: https://github.com/sbg/geck

Contact

peter.komar@sbgdinc.com

Supplementary information

Supplementary materials are available at bioRxiv.
Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase
Authors: Zhang Siwei , Fan Gaofeng , Hao Yuan , Hammell Molly , Wilkinson John Erby , Tonks Nicholas K.
Published: October 2017

Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. In a loss-of-function PTPome screen, our laboratory identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. Now, our TCGA (The Cancer Genome Atlas) database analyses illustrate a correlation between low PTPN23 expression and poor survival in breast cancers of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1Dβ cells induced breast tumors within 56 wk. In PTPN23-depleted tumors, we detected hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN as well as Tyr142 in β-catenin. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN in two different models. We demonstrated that tumor outgrowth from PTPN23-deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, double knockout of FYN and PTPN23 via CRISPR/CAS9 also attenuated tumor outgrowth from PTPN23 knockout Cal51 cells. Overall, this mechanistic analysis of the tumor-suppressive function of PTPN23 in breast cancer supports the identification of FYN as a therapeutic target for breast tumors with heterozygous or homozygous loss of PTPN23.
A mutually exclusive stem–loop arrangement in roX2 RNA is essential for X-chromosome regulation in Drosophila
Authors: Ilik Ibrahim Avsar , Maticzka Daniel , Georgiev Plamen , Gutierrez Noel Marie , Backofen Rolf , Akhtar Asifa
Published: October 2017

The X chromosome provides an ideal model system to study the contribution of RNA–protein interactions in epigenetic regulation. In male flies, roX long noncoding RNAs (lncRNAs) harbor several redundant domains to interact with the ubiquitin ligase male-specific lethal 2 (MSL2) and the RNA helicase Maleless (MLE) for X-chromosomal regulation. However, how these interactions provide the mechanics of spreading remains unknown. By using the uvCLAP (UV cross-linking and affinity purification) methodology, which provides unprecedented information about RNA secondary structures in vivo, we identified the minimal functional unit of roX2 RNA. By using wild-type and various MLE mutant derivatives, including a catalytically inactive MLE derivative, MLEGET, we show that the minimal roX RNA contains two mutually exclusive stem–loops that exist in a peculiar structural arrangement: When one stem–loop is unwound by MLE, an alternate structure can form, likely trapping MLE in this perpetually structured region. We show that this functional unit is necessary for dosage compensation, as mutations that disrupt this formation lead to male lethality. Thus, we propose that roX2 lncRNA contains an MLE-dependent affinity switch to enable reversible interactions of the MSL complex to allow dosage compensation of the X chromosome.
Complexes of nickel(II) and copper(II) with 1,2,4-triazole-3-carboxylic acid and of cobalt(III) with 3-amino-1,2,4-triazole-5-carboxylic acid
Authors: Liu Feng-Yi , Zhou Dong-Mei , Zhao Xiao-Lan , Kou Jun-Feng
Published: October 2017

Because of their versatile coordination modes and strong coordination ability for metals, triazole ligands can provide a wide range of possibilities for the construction of metal–organic frameworks. Three transition-metal complexes, namely bis(μ-1,2,4-triazol-4-ide-3-carboxylato)-κ3
N
2,O:N
1;κ3
N
1:N
2,O-bis[triamminenickel(II)] tetrahydrate, [Ni2(C3HN3O2)2(NH3)6]·4H2O, (I), catena-poly[[[diamminediaquacopper(II)]-μ-1,2,4-triazol-4-ide-3-carboxylato-κ3
N
1:N
4,O-[diamminecopper(II)]-μ-1,2,4-triazol-4-ide-3-carboxylato-κ3
N
4,O:N
1] dihydrate], {[Cu2(C3HN3O2)2(NH3)4(H2O)2]·2H2O}
n
, (II), (μ-5-amino-1,2,4-triazol-1-ide-3-carboxylato-κ2
N
1:N
2)di-μ-hydroxido-κ4
O:O-bis[triamminecobalt(III)] nitrate hydroxide trihydrate, [Co2(C3H2N4O2)(OH)2(NH3)6](NO3)(OH)·3H2O, (III), with different structural forms have been prepared by the reaction of transition metal salts, i.e. NiCl2, CuCl2 and Co(NO3)2, with 1,2,4-triazole-3-carboxylic acid or 3-amino-1,2,4-triazole-5-carboxylic acid hemihydrate in aqueous ammonia at room temperature. Compound (I) is a dinuclear complex. Extensive O—H...O, O—H...N and N—H...O hydrogen bonds and π–π stacking interactions between the centroids of the triazole rings contribute to the formation of the three-dimensional supramolecular structure. Compound (II) exhibits a one-dimensional chain structure, with O—H...O hydrogen bonds and weak O—H...N, N—H...O and C—H...O hydrogen bonds linking anions and lattice water molecules into the three-dimensional supramolecular structure. Compared with compound (I), compound (III) is a structurally different dinuclear complex. Extensive N—H...O, N—H...N, O—H...N and O—H...O hydrogen bonding occurs in the structure, leading to the formation of the three-dimensional supramolecular structure.
Synthesis, crystal structure and activity evaluation of novel 3,4-dihydro-1-benzoxepin-5(2H)-one derivatives as protein–tyrosine kinase (PTK) inhibitors
Authors: Li Ning , Yao Binrong , Wang Chunhua , Meng Qingguo , Hou Guige
Published: October 2017

Four new 3,4-dihydro-1-benzoxepin-5(2H)-one derivatives, namely (E)-4-(5-bromo-2-hydroxybenzylidene)-6,8-dimethoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (7), (E)-4-[(E)-3-(5-bromo-2-hydroxyphenyl)allylidene]-6,8-dimethoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (8), (E)-4-(5-bromo-2-hydroxybenzylidene)-6-hydroxy-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, C18H15BrO5, (9), and (E)-4-[(E)-3-(5-bromo-2-hydroxyphenyl)allylidene]-6-hydroxy-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (10), have been synthesized and characterized by FT–IR, NMR and MS. The structure of (9) was confirmed by single-crystal X-ray diffraction. Crystal structure analysis shows that molecules of (9) are connected into a one-dimensional chain in the [010] direction through classical hydrogen bonds and these chains are further extended into a three-dimensional network via C—H...O interactions. The inhibitory activities of these compounds against protein–tyrosine kinases (PTKs) show that 6-hydroxy-substituted compounds (9) and (10) are more effective for inhibiting ErbB1 and ErbB2 than are 6-methoxy-substituted compounds (7) and (8). This may be because (9) and (10) could effectively bind to the active pockets of the protein through intermolecular interactions.
Crystal structures of the solid solutions Na3Zn0.912Cd0.088B5O10and Na3Zn0.845Mg0.155B5O10
Authors: Chen Xue-An , Zhang Ya-Hua , Chang Xin-An , Xiao Wei-Qiang
Published: October 2017

Two new pentaborates, trisodium zinc cadmium pentaborate, Na3Zn0.912Cd0.088B5O10, and trisodium zinc magnesium pentaborate, Na3Zn0.845Mg0.155B5O10, have been synthesized by high-temperature solution reactions at 1023 K. Their crystal structures were determined by single-crystal X-ray diffraction. Both solid solutions crystallize in the orthorhombic form of the parent compound Na3ZnB5O10(space group typePbca,Z= 8) and contain the double ring [B5O10]5−anion composed of one BO4tetrahedron and four BO3triangles as the basic structural motif. The anions are bridged by tetrahedrally coordinated and occupationally disorderedM2+(M= Zn/Cd, Zn/Mg) cationsviacommon O atoms to form [MB5O10]n3n−layers. The intralayer intersecting channels and the interlayer voids are occupied by Na+cations to balance the charge.
Di-μ-chlorido-bis{bis[N,N-bis(trimethylsilyl)amido]titanium(III)}
Authors: Quadri Coralie C. , Törnroos Karl W. , Le Roux Erwan
Published: October 2017

The molecular structure of the title compound, [Ti2Cl2(C6H18NSi2)4], shows a binuclear motif of TiIIIatoms, formulated as [Ti(μ-Cl)(N(SiMe3)2)2]2, with two μ-Cl atoms bridging two ((Me3Si)2N)2Ti moieties. The coordination environment of both central TiIIIatoms is distorted tetrahedral, with a nearly planar four-membered Ti2Cl2core [Ti—Cl—Ti—Cl = 2.796 (15)°].