bluuebunny/crossref_metadata_2025 huggingface dataset:
Bonobos voluntarily hand food to others but not toys or tools
Authors: Krupenye Christopher , Tan Jingzhi , Hare Brian
Published: September 2018

A key feature of human prosociality isdirect transfers, the most active form of sharing in which donors voluntarily hand over resourcesin their possession. Direct transfers buffer hunter-gatherers against foraging shortfalls. The emergence and elaboration of this behaviour thus likely played a key role in human evolution by promoting cooperative interdependence and ensuring that humans' growing energetic needs (e.g. for increasing brain size) were more reliably met. According to thestrong prosociality hypothesis, among great apes only humans exhibit sufficiently strong prosocial motivations to directly transfer food. Theversatile prosociality hypothesissuggests instead that while other apes may make transfers in constrained settings, only humans share flexibly across food and non-food contexts. In controlled experiments, chimpanzees typically transfer objects but not food, supporting both hypotheses. In this paper, we show in two experiments that bonobos directly transfer food but not non-food items. These findings show that, in some contexts, bonobos exhibit a human-like motivation for direct food transfer. However, humans share across a far wider range of contexts, lending support to the versatile prosociality hypothesis. Our species' unusual prosocial flexibility is likely built on a prosocial foundation we share through common descent with the other apes.
Human-like Cmah inactivation in mice increases running endurance and decreases muscle fatigability: implications for human evolution
Authors: Okerblom Jonathan , Fletes William , Patel Hemal H. , Schenk Simon , Varki Ajit , Breen Ellen C.
Published: September 2018

Compared to other primates, humans are exceptional long-distance runners, a feature that emerged in genusHomoapproximately 2 Ma and is classically attributed to anatomical and physiological adaptations such as an enlarged gluteus maximus and improved heat dissipation. However, no underlying genetic changes have currently been defined. Two to three million years ago, an exon deletion in the CMP-Neu5Ac hydroxylase (CMAH) gene also became fixed in our ancestral lineage.Cmahloss in mice exacerbates disease severity in multiple mouse models for muscular dystrophy, a finding only partially attributed to differences in immune reactivity. We evaluated the exercise capacity ofCmah−/−mice and observed an increased performance during forced treadmill testing and after 15 days of voluntary wheel running.Cmah−/−hindlimb muscle exhibited more capillaries and a greater fatigue resistancein situ. Maximal coupled respiration was also higher inCmahnull miceex vivoand relevant differences in metabolic pathways were also noted. Taken together, these data suggest thatCMAHloss contributes to an improved skeletal muscle capacity for oxygen use. If translatable to humans,CMAHloss could have provided a selective advantage for ancestralHomoduring the transition from forest dwelling to increased resource exploration and hunter/gatherer behaviour in the open savannah.
p15 encoded by Garlic virus X is a pathogenicity factor and RNA silencing suppressor
Authors: Zhang Tianhao , Zhao Xing , Jiang Liangliang , Yang Xue , Chen Ying , Song Xijiao , Lu Yuwen , Peng Jiejun , Zheng Hongying , Wu Yuanhua , MacFarlane Stuart , Chen Jianping , Yan Fei
Published: September 2018

Garlic virus X(GarVX) encodes a 15 kDa cysteine-rich protein (CRP). To investigate the function(s) of p15, its subcellular localization, role as a symptom determinant and capacity to act as a viral suppressor of RNA silencing (VSR) were analysed. Results showed that GFP-tagged p15 was distributed in the cytoplasm, nucleus and nucleolus. Expression of p15 from PVX caused additional systemic foliar malformation and led to increased accumulation of PVX, showing that p15 is a virulence factor for reconstructed PVX-p15. Moreover, using a transient agro-infiltration patch assay and a Turnip crinkle virus (TCV) movement complementation assay, it was demonstrated that p15 possesses weak RNA silencing suppressor activity. Removal of an amino acid motif resembling a nuclear localization signal (NLS) prevented p15 from accumulating in the nucleus but did not abolish its silencing suppression activity. This study provides the first insights into the multiple functions of the GarVX p15 protein.
Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission
Authors: Thompson Robin N. , Wymant Chris , Spriggs Rebecca A. , Raghwani Jayna , Fraser Christophe , Lythgoe Katrina A.
Published: September 2018

Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment) acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmissions, when trying to discern the complex factors governing single or multiple variant transmission.
Using genetics to examine a general liability to childhood psychopathology
Authors: Riglin Lucy , Thapar Ajay K , Leppert Beate , Martin Joanna , Richards Alexander , Anney Richard , Smith George Davey , Tilling Kate , Stergiakouli Evie , Lahey Benjamin B. , O’Donovan Michael C , Collishaw Stephan , Thapar Anita
Published: September 2018

Psychiatric disorders show phenotypic as well as genetic overlaps. There are however also marked developmental changes throughout childhood. We investigated the extent to which, for a full range of early childhood psychopathology, a general “p” factor was explained by genetic liability, as indexed by multiple different psychiatric polygenic risk scores (PRS) and whether these relationships altered with age. The sample was a UK, prospective, population-based cohort with psychopathology data at age 7 (N=8161) and age 13 (N=7017). PRS were generated from large published genome-wide association studies. At both ages, we found evidence for a childhood “p” factor as well as for specific factors. Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) PRS were associated with this general “p” factor at both ages but depression and autism spectrum disorder (ASD) PRS were not. Schizophrenia, ADHD and depression PRS were also associated with specific factors but there was evidence for developmental changes.

Funding

This work was supported by the Wellcome Trust (204895/Z/16/Z).
GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice
Authors: Murata Koshi , Kinoshita Tomoki , Fukazawa Yugo , Kobayashi Kenta , Kobayashi Kazuto , Miyamichi Kazunari , Okuno Hiroyuki , Bito Haruhiko , Sakurai Yoshio , Yamaguchi Masahiro , Mori Kensaku , Manabe Hiroyuki
Published: September 2018

Olfaction guides goal-directed behaviours including feeding. To investigate how central olfactory neural circuits control feeding behaviour in mice, we performed retrograde tracing from the lateral hypothalamus (LH), an important feeding centre. We observed a cluster of retrogradely labelled cells distributed in the posteroventral region of the olfactory peduncle. Histochemical analyses revealed that a majority of these retrogradely labelled projection neurons expressed glutamic acid decarboxylase 65/67 (GAD65/67), but not vesicular glutamate transporter 1 (VGluT1). We named this region with GABAergic projection neurons the ventral olfactory nucleus (VON) to discriminate it from the conventional olfactory peduncle. VON neurons were less immunoreactive for DARPP-32, a striatal neuron marker, in comparison to those in the olfactory tubercle and nucleus accumbens, which distinguished the VON from the ventral striatum. Fluorescent labelling confirmed synaptic contacts between VON neurons and olfactory bulb projection neurons. Rabies-virus-mediated trans-synaptic labelling revealed that VON neurons received synaptic inputs from the olfactory bulb, other olfactory cortices, horizontal limb of the diagonal band, and prefrontal cortex. Collectively, these results identified novel GABAergic projection neurons in the olfactory cortex that can integrate olfactory sensory and top-down inputs and send inhibitory output to the LH, which may contribute to forming odour-guided LH-related behaviours.
Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration
Authors: Collin Vanessa , Gravel Annie , Kaufer Benedikt B. , Flamand Louis
Published: September 2018

Human herpesviruses 6A and 6B (HHV-6A/B) are two betaherpesviruses that readily integrate their genomes into the telomeres of human chromosomes. To date, the cellular or viral proteins that facilitate HHV-6A/B integration remain elusive. In the present study, we demonstrate that the immediate early protein 1 (IE1) of HHV-6A/B colocalizes with telomeres during infection. Moreover, IE1 associates with PML-NBs, a nuclear complex that regulates multiples cellular mechanism including DNA repair and antiviral responses. Furthermore, we could demonstrate that IE1 targets all PML isoforms and that both proteins colocalize at telomeres. To determine the role of PML in HHV-6A/B integration, we generated PML knockout cell lines using CRISPR/Cas9. Intriguingly, in the absence of PML, the IE1 protein could still localize to telomeres albeit less frequently. More importantly, HHV-6A/B integration was impaired in the absence of PML, indicating that it plays a role in the integration process. Taken together, we identified the first cellular protein that aids in the integration of HHV-6A/B and shed light on this targeted integration mechanism.

Author summary

Human herpesviruses type 6A and 6B are relatively common viruses whose infections can be life threatening in patients with a compromised immune system. A rather unique feature of these viruses is their ability to integrate their genome in human chromosomes. Integration takes place is a specialized region of the chromosomes known as telomeres, a region that controls cellular lifespan. To date, the mechanisms leading to HHV-6A and HHV-6B integration remain elusive. Our laboratory has identified that the IE1 protein of HHV-6A and HHV-6B target the telomeres. Moreover, we have shown that IE1 associates with a cellular protein, PML, that is responsible for the regulation of important cellular mechanisms such as the life span of cells and DNA repair. Hence, we studied the role of PML in HHV-6 integration. Our study demonstrates that in absence of PML, the HHV-6A and HHV-6B integrate 50-70% less frequently. Thus, our study unveils the first cellular protein involved in HHV-6A and HHV-6 chromosomal integration.
When one phenotype is not enough – divergent evolutionary trajectories govern venom variation in a widespread rattlesnake species
Authors: Zancolli Giulia , Calvete Juan J. , Cardwell Michael D. , Greene Harry W. , Hayes William K. , Hegarty Matthew J. , Herrmann Hans-Werner , Holycross Andrew T. , Lannutti Dominic I. , Mulley John F. , Sanz Libia , Travis Zachary D. , Whorley Joshua R. , Wüster Catharine E. , Wüster Wolfgang
Published: September 2018

Understanding the relationship between genome, phenotypic variation, and the ecological pressures that act to maintain that variation, represents a fundamental challenge in evolutionary biology. Functional polymorphisms typically segregate in spatially isolated populations [1, 2] and/or discrete ecological conditions [3-5], whereas dissecting the evolutionary processes involved in adaptive geographic variation across a continuous spatial distribution is much more challenging [6]. Additionally, pleiotropic interactions between genes and phenotype often complicate the identification of specific genotype-phenotype links [7-8], and thus of the selective pressures acting on them. Animal venoms are ideal systems to overcome these constraints: they are complex and variable, yet easily quantifiable molecular phenotypes with a clear function and a direct link to both genome and fitness [9]. Here, we use dense and widespread population-level sampling of the Mohave rattlesnake, Crotalus scutulatus, and show that genomic structural variation at multiple loci underlies extreme geographic variation in venom composition, which is maintained despite extensive gene flow. Unexpectedly, selection for diet does not explain venom variation, contrary to the dominant paradigm of venom evolution, and neither does neutral population structure caused by past vicariance. Instead, different toxin genes correlate with distinct environmental factors, suggesting that divergent selective pressures can act on individual loci independently of their genomic proximity or co-expression patterns. Local-scale spatial heterogeneity thus appears to maintain a remarkably ancient complex of molecular phenotypes, which have been retained in populations that diverged more than 1.5-2 MYA, representing an exceptional case of long-term structural polymorphism. These results emphasize how the interplay between genomic architecture and spatial heterogeneity in selective pressures may facilitate the retention of functional polymorphisms of an adaptive phenotype.
Hormonal regulation of social ascent and temporal patterns of behavior in an African cichlid
Authors: Alward Beau A. , Hilliard Austin T. , York Ryan A. , Fernald Russell D.
Published: September 2018

For many species, social rank determines which individuals perform certain social behaviors and when. Higher ranking or dominant (DOM) individuals maintain status through aggressive interactions and perform courtship behaviors while non-dominant (ND) individuals do not. In some species ND individuals ascend (ASC) in social rank when the opportunity arises. Many important questions related to the mechanistic basis of social ascent remain to be answered. We probed whether androgen signaling regulates social ascent in male Astatotilapia burtoni, an African cichlid whose social hierarchy can be readily controlled in the laboratory. As expected, androgen receptor (AR) antagonism abolished reproductive behavior during social ascent. However, we discovered multiple AR-dependent—and AR-independent—temporal behavioral patterns that typify social ascent and dominance. AR antagonism in ASC males reduced the speed of behavioral performance compared to DOM males. Socially ascending males, independent of AR activation, were more likely than DOM males to follow aggressive displays with another aggressive display. Further analyses revealed differences in the sequencing of aggressive and courtship behaviors, wherein DOM males were more likely than ASC males to follow male-directed aggression with courtship displays. Strikingly, this difference was driven mostly by ASC males taking longer to transition from aggression to courtship, suggesting ASC males can perform certain DOM-typical temporal behavioral patterns. Our results indicate androgen signaling drives social ascent, but hormonal signaling and social experience shape the full suite of DOM-typical behavioral patterns.
Accurate error control in high dimensional association testing using conditional false discovery rates
Authors: Liley James , Wallace Chris
Published: September 2018

High-dimensional hypothesis testing is ubiquitous in the biomedical sciences, and informative covariates may be employed to improve power. The conditional false discovery rate (cFDR) is widely-used approach suited to the setting where the covariate is a set of p-values for the equivalent hypotheses for a second trait. Although related to the Benjamini-Hochberg procedure, it does not permit any easy control of type-1 error rate, and existing methods are over-conservative. We propose a new method for type-1 error rate control based on identifying mappings from the unit square to the unit interval defined by the estimated cFDR, and splitting observations so that each map is independent of the observations it is used to test. We also propose an adjustment to the existing cFDR estimator which further improves power. We show by simulation that the new method more than doubles potential improvement in power over unconditional analyses compared to existing methods. We demonstrate our method on transcriptome-wide association studies, and show that the method can be used in an iterative way, enabling the use of multiple covariates successively. Our methods substantially improve the power and applicability of cFDR analysis.
Contribution of FEF to attentional periodicity during visual search: a TMS study
Authors: Dugué Laura , Beck Alexy Asaf , Marque Philippe , VanRullen Rufin
Published: September 2018

Visual search, looking for a target embedded among distractors, has long been used to study attention. Current theories postulate a two-stage process in which early visual areas perform feature extraction, while higher-order regions perform attentional selection. Such a model implies iterative communication between low- and high-level regions to sequentially select candidate targets in the array, focus attention on these elements, and eventually permit target recognition. This leads to two predictions: (1) high-level, attentional regions and (2) early visual regions should both be iteratively (periodically) involved during the search. Here, we used Transcranial Magnetic Stimulation (TMS) applied over the Frontal-Eye Field (FEF), known to be involved in attentional selection, at various delays while observers performed a difficult, attentional search task. We observed a periodic pattern of interference at 7 Hz (theta) suggesting that the FEF is periodically involved during this difficult search task. We further compared this result with two previous studies (Dugué et al., 2011; 2015a) in which a similar TMS procedure was applied over the early visual cortex (V1) while observers performed the same task. This analysis revealed, for both studies, the same pattern of interference, i.e. V1 is periodically involved during this difficult search task, at the theta frequency. Together, these converging findings confirm our predictions that difficult search is supported by the periodic involvement of both low- and high-level regions, at the theta frequency.

Significant statement

Attention models postulate a two-stage process during visual search in which early visual regions perform feature extraction, while higher-order regions perform attentional selection, these two levels iteratively (periodically) communicating until target recognition. Using TMS, we tested whether there is a causal link between both attentional and early visual regions, and attentional search performance. We showed that a difficult, attentional search is supported by the periodic involvement of both V1 and the FEF, at the theta frequency (∼6-7 Hz). This finding support the idea that visual search tasks are processed by a hierarchical system involving periodic, iterative connections between low- and high-level regions allowing successful attentional exploration.
Oxidative stress, telomere length, and frailty in an old age population
Authors: Martínez-Ezquerro José Darío , Rodriguez-Castañeda Aleida , Ortiz-Ramirez Mauricio , Sanchez-Garcia Sergio , Rosas-Vargas Haydee , Sanchez-Arenas Rosalinda , Garcia-delaTorre Paola
Published: September 2018

Background

A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. On the other hand, oxidative stress and telomere length have been suggested as biomarkers of aging.

Objective

To study the association of oxidative stress, telomere length, and frailty in an old age population.

Methods

This was a cross-sectional study based on 2015 data from 202 members from a cohort of older adults (n=202; gender F/M ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species (ROS) were measured by dichlorofluorescin diacetate, and lipid peroxidation by malondialdehyde. Telomere length was determined using qPCR with SYBR Green Master Mix.

Results

Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress on telomere length or frailty.

Conclusions

Telomere length could eventually be used as a marker to discriminate between healthy and unhealthy aging as expressed by frailty phenotype. However, oxidative stress seems as just a biological process of aging.
Biological variation in the sizes, shapes and locations of visual cortical areas in the mouse
Authors: Waters Jack , Lee Eric , Gaudreault Nathalie , Griffin Fiona , Lecoq Jerome , Slaughterbeck Cliff , Sullivan David , Farrell Colin , Perkins Jed , Reid David , Feng David , Graddis Nile , Garrett Marina , Li Yang , Long Fuhui , Mochizuki Chris , Roll Kate , Zhuang Jun , Thompson Carol
Published: September 2018

Visual cortex is organized into discrete sub-regions or areas that are arranged into a hierarchy and serve different functions in the processing of visual information. In our previous work, we noted that retinotopic maps of cortical visual areas differed between mice, but did not quantify these differences or determine the relative contributions of biological variation and measurement noise. Here we quantify the biological variation in the size, shape and locations of 11 visual areas in the mouse. We find that there is substantial biological variation in the sizes of visual areas, with some visual areas varying in size by two-fold across the population of mice.
Stable Carbon Isotopes in Zea mays
Authors: Twohey Robert J. , Roberts Lucas M. , Studer Anthony J.
Published: September 2018

The increasing demand for food production and predicted climate change scenarios highlight the need for improvements in crop sustainability. The efficient use of water will become increasingly important for rainfed agricultural crops even in fertile regions that have historically received ample precipitation. Improvements in water-use efficiency in Zea mays have been limited, and warrants a renewed effort aided by molecular breeding approaches. Progress has been constrained by the difficulty of measuring water-use in a field environment. The stable carbon isotope composition (δ13C) of the leaf has been proposed as an integrated signature of carbon fixation with a link to stomatal conductance. However, additional factors affecting leaf δ13C exist, and a limited number of studies have explored this trait in Z. mays. Here we present an extensive characterization of leaf δ13C in Z. mays. Significant variation in leaf δ13C exists across diverse lines of Z. mays, which we show to be heritable across several environments.

Furthermore, we examine temporal and spatial variation in leaf δ13C to determine the optimum sampling time to maximize the use of leaf δ13C as a trait. Finally, our results demonstrate the relationship between transpiration and leaf δ13C in the field and the greenhouse. Decreasing transpiration and soil moisture are associated with decreasing leaf δ13C. Taken together these results outline a strategy for using leaf δ13C and reveal its usefulness as a measure of transpiration efficiency under well-watered conditions rather than a predictor of performance under drought.

Significance Statement

This study identifies sources of variation in stable carbon isotopes of maize leaves and establishes the framework for connecting leaf δ13C and transpiration efficiency.
Unsupervised Learning of Persistent and Sequential Activity
Authors: Pereira Ulises , Brunel Nicolas
Published: September 2018

Two strikingly distinct types of activity have been observed in various brain structures during delay periods of delayed response tasks: Persistent activity (PA), in which a sub-population of neurons maintains an elevated firing rate throughout an entire delay period; and Sequential activity (SA), in which sub-populations of neurons are activated sequentially in time. It has been hypothesized that both types of dynamics can be ‘learned’ by the relevant networks from the statistics of their inputs, thanks to mechanisms of synaptic plasticity. However, the necessary conditions for a synaptic plasticity rule and input statistics to learn these two types of dynamics in a stable fashion are still unclear. In particular, it is unclear whether a single learning rule is able to learn both types of activity patterns, depending on the statistics of the inputs driving the network. Here, we first characterize the complete bifurcation diagram of a firing rate model of multiple excitatory populations with an inhibitory mechanism, as a function of the parameters characterizing its connectivity. We then investigate how an unsupervised temporally asymmetric Hebbian plasticity rule shapes the dynamics of the network. Consistent with previous studies, we find that for stable learning of PA and SA, an additional stabilization mechanism, such as multiplicative homeostatic plasticity, is necessary. Using the bifurcation diagram derived for fixed connectivity, we study analytically the temporal evolution and the steady state of the learned recurrent architecture as a function of parameters characterizing the external inputs. Slow changing stimuli lead to PA, while fast changing stimuli lead to SA. Our network model shows how a network with plastic synapses can stably and flexibly learn PA and SA in an unsupervised manner.
Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent
Authors: Mok Ka-Wai , Saxena Nivedita , Heitman Nicholas , Grisanti Laura , Srivastava Devika , Muraro Mauro , Jacob Tina , Sennett Rachel , Wang Zichen , Su Yutao , Yang Lu M. , Ma’ayan Avi , Ornitz David M. , Kasper Maria , Rendl Michael
Published: September 2018

Cell fate transitions are essential for specialization of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we show that dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes, are specified before niche formation and function. With 3D/4D microscopy we identify unclustered DC precursors. With population-based and single-cell transcriptomics we define a molecular time-lapse of dynamic niche signatures and the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then consolidate DC niche formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for DC-precursor specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.

Graphical Abstract

HIGHLIGHTS

Precursors of the hair follicle niche are specified before niche cluster formation

Bulk/single cell RNA-seq defines early niche fate at molecular transitional state

Successive waves of transcription factor/signaling genes mark niche fate acquisition

Niche fate acquisition is not “pre-programmed” and requires FGF20 from progenitors
Bioinformatics workflows for genomic analysis of tumors from Patient Derived Xenografts (PDX): challenges and guidelines
Authors: Woo Xing Yi , Srivastava Anuj , Graber Joel H. , Yadav Vinod , Sarsani Vishal Kumar , Simons Al , Beane Glen , Grubb Stephen , Ananda Guruprasad , Liu Rangjiao , Stafford Grace , Chuang Jeffrey H. , Airhart Susan D. , Karuturi R. Krishna Murthy , George Joshy , Bult Carol J.
Published: September 2018

Bioinformatics workflows for analyzing genomic data obtained from xenografted tumor (e.g., human tumors engrafted in a mouse host) must address several challenges, including separating mouse and human sequence reads and accurate identification of somatic mutations and copy number aberrations when paired normal DNA from the patient is not available. We report here data analysis workflows that address these challenges and result in reliable identification of somatic mutations, copy number alterations, and transcriptomic profiles of tumors from patient derived xenograft models. We validated our analytical approaches using simulated data and by assessing concordance of the genomic properties of xenograft tumors with data from primary human tumors in The Cancer Genome Atlas (TCGA). The commands and parameters for the workflows are available at https://github.com/TheJacksonLaboratory/PDX-Analysis-Workflows.
A multidrug resistant clinical P. aeruginosa isolate in the MLST550 clonal complex: uncoupled quorum sensing modulates the interplay of virulence and resistance
Authors: Cao Huiluo , Xia Tingying , Li Yanran , Xu Zeling , Bougouffa Salim , Lo Yat Kei , Bajic Vladimir B. , Luo Haiwei , Woo Patrick C.Y. , Yan Aixin
Published: September 2018

Pseudomonas aeruginosa is a prevalent and pernicious pathogen equipped with both extraordinary capabilities to infect the host and to develop antimicrobials resistance (AMR). Monitoring the emergence of AMR high risk clones and understanding the interplay of their pathogenicity and antibiotic resistance is of paramount importance to avoid resistance dissemination and to control P. aeruginosa infections. In this study, we report the identification of a multidrug resistant (MDR) P. aeruginosa strain PA154197 isolated from a blood stream infection in Hong Kong. PA154197 belongs to a distinctive MLST550 clonal complex shared by two international P. aeruginosa isolates VW0289 and AUS544. Comparative genome and transcriptome analysis with the reference strain PAO1 led to the identification of a variety of genetic variations in antibiotic resistance genes and the hyper-expression of three multidrug efflux pumps MexAB-OprM, MexEF-OprN, and MexGHI-OpmD in PA154197. Unlike many resistant isolates displaying an attenuated virulence, PA154197 produces a significantly high level of the P. aeruginosa major virulence factor pyocyanin (PYO) and displays an uncompromised virulence compared to PAO1. Further analysis revealed that the secondary quorum sensing system Pqs which primarily controls the PYO production is hyper-active in PA154197 independent of the master QS systems Las and Rhl. Together, these investigations disclose a unique, uncoupled QS mediated pathoadaptation mechanism in clinical P. aeruginosa which may account for the high pathogenic potentials and antibiotics resistance in the MDR isolate PA154197.
Prior precision modulates the minimisation of prediction error in human auditory cortex
Authors: Hsu Yi-Fang , Waszak Florian , Hämäläinen Jarmo A.
Published: September 2018

The predictive coding model of perception proposes that successful representation of the perceptual world depends upon cancelling out the discrepancy between prediction and sensory input (i.e., prediction error). Recent studies further suggest a distinction between prediction error associated with non-predicted stimuli of different prior precision (i.e., inverse variance). However, it is not fully understood how prediction error from different precision levels is minimised in the predictive process. The current research used magnetoencephalography (MEG) to examine whether prior precision modulates the cortical dynamics of the making of perceptual inferences. We presented participants with cycles of repeated tone quartets which consisted of three prime tones and one probe tone. Within each cycle, the three prime tones remained identical while the probe tones changed at some random point (e.g., from repetition of 123X to repetition of 123Y). Therefore, the repetition of probe tones can reveal the development of perceptual inferences in low and high precision contexts depending on its position within the cycle. We found that the two conditions resemble each other in terms of N1m modulation (as both were associated with N1m suppression) but differ in terms of N2m modulation. While repeated probe tones in low precision context did not exhibit any modulatory effect, repeated probe tones in high precision context elicited a suppression and rebound of the N2m source power. The differentiation suggested that the minimisation of prediction error in low and high precision contexts likely involves distinct mechanisms.
Ancestral admixture is the main determinant of global biodiversity in fission yeast
Authors: Tusso Sergio , Nieuwenhuis Bart P.S. , Sedlazeck Fritz J. , Davey John W. , Jeffares Daniel , Wolf Jochen B. W.
Published: September 2018

Mutation and recombination are key evolutionary processes governing phenotypic variation and reproductive isolation. We here demonstrate that biodiversity within all globally known strains of Schizosaccharomyces pombe arose through admixture between two divergent ancestral lineages. Initial hybridization occurred ~20 sexual outcrossing generations ago consistent with recent, human-induced migration at the onset of intensified transcontinental trade. Species-wide heritable phenotypic variation was explained near-exclusively by strain-specific arrangements of alternating ancestry components with evidence for transgressive segregation. Reproductive compatibility between strains was likewise predicted by the degree of shared ancestry. To assess the genetic determinants of ancestry block distribution across the genome, we characterized the type, frequency and position of structural genomic variation (SV) using nanopore and single-molecule real time sequencing, discovering over 800 SVs. Despite being associated with double-strand break initiation points, SV exerted overall little influence on the introgression landscape or on reproductive compatibility that exist between strains. In contrast, we find strongly increased statistical linkage between ancestral populations that is consistent with negative epistatic selection shaping genomic ancestry combinations during the course of hybridization. This study provides a detailed, experimentally tractable example that genomes of natural populations are mosaics reflecting different evolutionary histories. Exploiting genome-wide heterogeneity in the history of ancestral recombination and lineage-specific mutations sheds new light on the population history of S. pombe and highlights the importance of hybridization as a creative force in generating biodiversity.
Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model
Authors: Phillips Ryan S. , John Tibin T. , Koizumi Hidehiko , Molkov Yaroslav I. , Smith Jeffrey C.
Published: September 2018

An autorhythmic population of excitatory neurons in the brainstem pre-Bötzinger complex is a critical component of the mammalian respiratory oscillator. Two intrinsic neuronal biophysical mechanisms—a persistent sodium current (INaP) and a calcium-activated non-selective cationic current (ICAN)—were proposed to individually or in combination generate cellular-and circuit-level oscillations, but their roles are debated without resolution. We re-examined these roles with a new computational model of an excitatory population with randomly distributed INaP and ICAN conductances and synaptic connections. This model robustly reproduces experimental data showing contrary to previous hypotheses, rhythm generation is independent of ICAN activation, which instead determines population activity amplitude. The novel insight is that this occurs when ICAN is primarily activated by neuronal calcium fluxes driven by synaptic mechanisms. Rhythm depends critically on INaP in a subpopulation forming the rhythmogenic kernel. The model explains how the rhythm and amplitude of respiratory oscillations involve distinct biophysical mechanisms.
Disease networks and their contribution to disease understanding and drug repurposing: Evolution of the concept, techniques and data sources
Authors: García del Valle Eduardo P. , García Gerardo Lagunes , Santamaría Lucía Prieto , Zanin Massimiliano , Ruiz Ernestina Menasalvas , Rodríguez-González Alejandro
Published: September 2018

Over a decade ago, a new discipline called network medicine emerged as an approach to understand human diseases from a network theory point-of-view. Disease networks proved to be an intuitive and powerful way to reveal hidden connections among apparently unconnected biomedical entities such as diseases, physiological processes, signaling pathways, and genes. One of the fields that has benefited most from this improvement is the identification of new opportunities for the use of old drugs, known as drug repurposing. The importance of drug repurposing lies in the high costs and the prolonged time from target selection to regulatory approval of traditional drug development. In this document we analyze the evolution of disease network concept during the last decade and apply a data science pipeline approach to evaluate their functional units. As a result of this analysis, we obtain a list of the most commonly used functional units and the challenges that remain to be solved. This information can be very valuable for the generation of new prediction models based on disease networks.
Reconciling high-throughput gene essentiality data with metabolic network reconstructions
Authors: Blazier Anna S. , Papin Jason A.
Published: September 2018

The identification of genes essential for bacterial growth and survival represents a promising strategy for the discovery of antimicrobial targets. Essential genes can be identified on a genome-scale using transposon mutagenesis approaches; however, variability between screens and challenges with interpretation of essentiality data hinder the identification of both condition-independent and condition-dependent essential genes. To illustrate the scope of these challenges, we perform a large-scale comparison of multiple published Pseudomonas aeruginosa gene essentiality datasets, revealing substantial differences between the screens. We then contextualize essentiality using genome-scale metabolic network reconstructions and demonstrate the utility of this approach in providing functional explanations for essentiality and reconciling differences between screens. Genome-scale metabolic network reconstructions also enable a high-throughput, quantitative analysis to assess the impact of media conditions on the identification of condition-independent essential genes. Our computational model-driven analysis provides mechanistic insight into essentiality and contributes novel insights for design of future gene essentiality screens and the identification of core metabolic processes.

Author Summary

With the rise of antibiotic resistance, there is a growing need to discover new therapeutic targets to treat bacterial infections. One attractive strategy is to target genes that are essential for growth and survival. Essential genes can be identified with transposon mutagenesis approaches; however, variability between screens and challenges with interpretation of essentiality data hinder the identification and analysis of essential genes. We performed a large-scale comparison of multiple gene essentiality screens of the microbial pathogen Pseudomonas aeruginosa. We implemented a computational model-driven approach to provide functional explanations for essentiality and reconcile differences between screens. The integration of computational modeling with high-throughput experimental screens may enable the identification of drug targets with high-confidence and provide greater understanding for the development of novel therapeutic strategies.
Quantification of Structural Brain Connectivity via a Conductance Model
Authors: Frau-Pascual Aina , Fogarty Morgan , Fischl Bruce , Yendiki Anastasia , Aganj Iman ,   †for the Alzheimer’s Disease Neuroimaging Initiativey
Published: September 2018

Abstaract

Connectomics has proved promising in quantifying and understanding the effects of development, aging and an array of diseases on the brain. In this work, we propose a new structural connectivity measure from diffusion MRI that allows us to incorporate direct brain connections, as well as indirect ones that would not be otherwise accounted for by standard techniques and that may be key for the better understanding of function from structure. From our experiments on the Human Connectome Project dataset, we find that our measure of structural connectivity better correlates with functional connectivity than streamline tractography does, meaning that it provides new structural information related to function. Through additional experiments on the ADNI-2 dataset, we demonstrate the ability of this new measure to better discriminate different stages of Alzheimer’s disease. Our findings suggest that this measure is useful in the study of the normal brain structure, and for quantifying the effects of disease on the brain structure.
Social insect colony size is correlated with rates of substitution and DNA repair gene evolution
Authors: Rubin Benjamin E. R.
Published: September 2018

Larger numbers of germline cell divisions can increase the number of mutations inherited by offspring. Therefore, in systems where the number of offspring is dependent on the number of germline cell divisions, a higher overall rate of molecular evolution may be expected. Here I examine whether colony size in social insects, which varies from tens to millions, influences molecular evolutionary rates by analyzing several recently collected datasets. First, I find that colony size is negatively correlated with GC-content across 115 ant genera, indicative of a positive relationship between substitution rate and colony size. Second, genome-wide rates of molecular evolution are positively correlated with colony size in three clades of social insects including eight species in the ant genusPseudomyrmex, seven fungus-growing ants, and 11 bee species. The additional germline cell divisions necessary to maintain large colony sizes might lead to mutation accumulation in the germlines of queens of these species, a process similar to that which occurs in aging human males. I also find intensified constraint on DNA repair genes in species with large colonies, suggesting that the additional mutations that occur in these taxa increase selective pressure for improved replication fidelity. Colony size, a fundamental facet of eusociality, plays a previously unappreciated role in genome evolution.
Plantarflexor fiber length and tendon slack length are the strongest determinates of simulated single-leg heel raise function
Authors: Baxter Josh R. , Hast Daniel C. , Hast Michael W.
Published: September 2018

Achilles tendon ruptures lead to reduced ankle function and often limits recreational activity. Single-leg heel raises are often used clinically to characterize patient function. However, it is unclear how the structure of the Achilles tendon and plantarflexor muscles affects single-leg heel raise function. Therefore, the purpose of this study was to develop a musculoskeletal model in order to simulate the effects of muscle-tendon unit (MTU) parameters on peak plantarflexion during this clinically-relevant task. The ankle joint was plantarflexed by two MTUs that represented the soleus and gastrocnemius muscles. The optimal fiber length, maximal muscle force, muscle pennation, tendon stiffness, and resting ankle angle – a surrogate measure of tendon slack length – were iteratively adjusted to test the combined effects of each of these MTU parameters. Single-leg heel raises were simulated by maximally exciting the two plantarflexor MTUs for each model configuration (N = 161,051 simulations). Optimal muscle fiber and tendon slack lengths had the greatest effect on peak plantarflexion during simulated single-leg heel raises. Simulations that were unable to produce at least 30 degrees of plantarflexion had muscle fibers that were shorter than healthy muscle and longer tendon slack lengths. These findings highlight the importance of preserving muscle fascicle and tendon length following Achilles tendon injuries.

Fundingno funding has been provided for this research

Acknowledgementsthe Authors have no acknowledgements

Conflict of interestthe Authors have no conflicts of interest that are relevant to this work
Photocage-initiated time-resolved solution X-ray scattering investigation of protein dimerization
Authors: Josts Inokentijs , Niebling Stephan , Gao Yunyun , Levantino Matteo , Tidow Henning , Monteiro Diana
Published: September 2018

This work demonstrates a new method for investigating time-resolved structural changes in protein conformation and oligomerization via photocage-initiated time-resolved X-ray solution scattering by observing the ATP-driven dimerization of the MsbA nucleotide-binding domain. Photocaged small molecules allow the observation of single-turnover reactions of non-naturally photoactivatable proteins. The kinetics of the reaction can be derived from changes in X-ray scattering associated with ATP-binding and subsequent dimerization. This method can be expanded to any small-molecule-driven protein reaction with conformational changes traceable by X-ray scattering where the small molecule can be photocaged.