bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the performance of real-time epidemic forecasts: A case study of Ebola in the Western Area Region of Sierra Leone, 2014–15
Authors: Funk Sebastian , Camacho Anton , Kucharski Adam J. , Lowe Rachel , Eggo Rosalind M. , Edmunds W. John
Published: August 2017

Real-time forecasts based on mathematical models can inform critical decision-making during infectious disease outbreaks. Yet, epidemic forecasts are rarely evaluated during or after the event, and there is little guidance on the best metrics for assessment. Here, we propose an evaluation approach that disentangles different components of forecasting ability using metrics that separately assess the calibration, sharpness and unbiasedness of forecasts. This makes it possible to assess not just how close a forecast was to reality but also how well uncertainty has been quantified. We used this approach to analyse the performance of weekly forecasts we generated in real time in Western Area, Sierra Leone, during the 2013–16 Ebola epidemic in West Africa. We investigated a range of forecast model variants based on the model fits generated at the time with a semi-mechanistic model, and found that good probabilistic calibration was achievable at short time horizons of one or two weeks ahead but models were increasingly inaccurate at longer forecasting horizons. This suggests that forecasts may have been of good enough quality to inform decision making requiring predictions a few weeks ahead of time but not longer, reflecting the high level of uncertainty in the processes driving the trajectory of the epidemic. Comparing forecasts based on the semi-mechanistic model to simpler null models showed that the best semi-mechanistic model variant performed better than the null models with respect to probabilistic calibration, and that this would have been identified from the earliest stages of the outbreak. As forecasts become a routine part of the toolkit in public health, standards for evaluation of performance will be important for assessing quality and improving credibility of mathematical models, and for elucidating difficulties and trade-offs when aiming to make the most useful and reliable forecasts.
Mosaic Turner syndrome shows reduced phenotypic penetrance in an adult population study compared to clinically ascertained cases
Authors: Tuke Marcus A. , Ruth Katherine S. , Wood Andrew R. , Beaumont Robin N. , Tyrrell Jessica , Jones Samuel E. , Yaghootkar Hanieh , Turner Claire L.S. , Donohoe Mollie E. , Brooke Antonia M. , Collinson Morag N. , Freathy Rachel M. , Weedon Michael N. , Frayling Timothy M. , Murray Anna
Published: August 2017

Women with X chromosome aneuploidy such as 45,X (Turner syndrome) or 47,XXX (Triple X syndrome) present with characteristics including differences in stature, increased cardiovascular disease risk and primary ovarian insufficiency. Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the phenotypic penetrance is overestimated. Studies of prenatally ascertained X chromosome aneuploidy cases have limited follow-up data and so the long-term consequences into adulthood are often not reported. We aimed to characterise the prevalence and phenotypic consequences of X chromosome aneuploidy in a large population of women over 40 years of age. We detected 30 women with 45,X, 186 with mosaic 45,X/46,XX and 110 with 47,XXX among 244,848 UK Biobank women, using SNP array data. The prevalence of non-mosaic 45,X (1/8,162) and 47,XXX (1/2,226) was lower than expected, but was higher for mosaic 45,X/46,XX (1/1,316). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognised Turner syndrome phenotype, including a 17.2cm shorter stature (SD = 5.72cm;P= 1.5 × 10−53) and 16/30 did not report an age at menarche. The phenotype of women with 47,XXX included taller stature (5.3cm; SD = 5.52cm;P= 5.8 × 10−20), earlier menopause age (5.12 years; SD = 5.1 years;P= 1.2 x 10−14) and a lower fluid intelligence score (24%; SD = 29.7%;P= 3.7 × 10−8). In contrast, the characteristics of women with mosaic 45,X/46,XX were much less pronounced than expected. Women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. In conclusion, the availability of data from 244,848 women allowed us to assess the phenotypic penetrance of traits associated with X chromosome aneuploidy in an adult population setting. Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.

Funding

None
Human occipital bone sexual dimorphism in an Archiac period archaeological population
Authors: Hoover Dr. Kara C.
Published: August 2017

PREPRINT NOTES

This paper was submitted for publication theInternational Journal of Osteoarchaeologyin August of 2003. The paper was rejected roughly a year later due to scope and collection issues. I revisited the paper in 2007 with an eye to updating and resubmitting with additional data but the project was triaged from the publication pipeline due to the work involved relative to other projects more relevant to my research interests at the time. The current preprint paper contains updated references on occipital bone sexual dimorphism—all limited to the condylar region rather than the full suite of variation in the region.

I am posting this to the preprint server to contribute the findings to the larger scientific community in the hopes that I might have time to revisit the paper as a student project. A more rigorous study would need to expand the sample either to a study collection that has remains with known sex (either verified via molecular sexing techniques or using a modern study collection) or additional comparative collections from hunter-gatherer populations. If a student is interested in taking up the topic and assuming lead authorship on a co-authored paper, I’d be happy to collaborate and see this piece through the publication pipeline.

This paper presents the results of a comprehensive study of sexual dimorphism in the human occipital region of the skull using the remains of 39 prehistoric adults from the prehistoric Windover (6,000-8,000 BP). The results of a discriminant analysis classified 64% of the individuals correctly (using osteologically identified sex). Sexual dimorphism in this population may not be prevalent due to environmental stress.
GIVE: toward portable genome browsers for personal websites
Authors: Cao Xiaoyi , Yan Zhangming , Wu Qiuyang , Zheng Alvin , Zhong Sheng
Published: August 2017

Growing popularity and diversity of genomic data demands portable and versatile genome browsers. Here, we present an open source programming library, called GIVE that facilitates creation of personalized genome browsers without requiring a system administrator. By inserting HTML tags, one can add to a personal webpage interactive visualization of multiple types of genomics data, including genome annotation, “linear” quantitative data (wiggle), and genome interaction data. GIVE includes a graphical interface called HUG (HTML Universal Generator) that automatically generates HTML code for displaying user chosen data, which can be copy-pasted into user’s personal website or saved and shared with collaborators. The simplicity of use was enabled by encapsulation of novel data communication and visualization technologies, including new data structures, a memory management method, and a double layer display method. GIVE is available at:http://www.givengine.org/.
LIM Protein Ajuba associates with the RPA complex through direct and cell cycle-dependent interaction with the RPA70 subunit
Authors: Fowler Sandy , Maguin Pascal , Kalan Sampada , Loayza Diego
Published: August 2017

DNA damage response pathways are essential for genome stability and cell survival. Specifically, the ATR kinase is activated by DNA replication stress. An early event in this activation is the recruitment and phosphorylation of RPA, a single stranded DNA binding complex composed of three subunits, RPA70,RPA32 and RPA14. We have previously shown that the LIM protein Ajuba associates with RPA, and that depletion of Ajuba leads to potent activation of ATR. In this study, we show evidence that the Ajuba-RPA interaction occurs through direct protein contact with RPA70, and that their association is cell cycle-regulated and is reduced upon DNA replication stress. We propose a model in which Ajuba negatively regulates the ATR pathway by directly interacting with RPA70, thereby preventing an inappropriate ATR activation. Our results provide a framework to understand the mechanism of regulation of ATR in human cells, which is important to prevent cellular transformation and tumorigenesis.
Map-based cloning of the genePm21that confers broad spectrum resistance to wheat powdery mildew
Authors: He Huagang , Zhu Shanying , Ji Yaoyong , Jiang Zhengning , Zhao Renhui , Bie Tongde
Published: August 2017

Common wheat (Triticum aestivumL.) is one of the most important cereal crops. Wheat powdery mildew caused byBlumeria graminisf. sp.tritici(Bgt) is a continuing threat to wheat production. ThePm21gene, originating fromDasypyrum villosum, confers high resistance to all knownBgtraces and has been widely applied in wheat breeding in China. In this research, we identifyPm21as a typical coiled-coil, nucleotide-binding site, leucine-rich repeat gene by an integrated strategy of resistance gene analog (RGA)-based cloning via comparative genomics, physical and genetic mapping, BSMV-induced gene silencing (BSMV-VIGS), large-scale mutagenesis and genetic transformation.
Withdrawal-induced escalated oxycodone self-administration is mediated by kappa opioid receptor function
Authors: Nguyen Jacques D. , Kirson Dean , Steinman Michael Q. , Patel Reesha , Khom Sophia , Varodayan Florence P. , Hedges David M. , Oleata Christopher S. , Grant Yanabel , Roberto Marisa , Taffe Michael A.
Published: August 2017

Background:

Prescription opioid addiction is a significant health problem characterized by compulsive drug seeking, withdrawal and chronic relapse. We investigated the neurobiological consequences of escalation of prescription opioid use using extended access to intravenous oxycodone self-administration in rats.

Methods:

Male Wistar rats acquired oxycodone self-administration (0.15 mg/kg/infusion, i.v.) in 1h or 12h access sessions. Electrophysiological and immunohistochemical studies investigated the effects of oxycodone self-administration on kappa opioid receptor (KOR) regulation of GABAergic signaling and dynorphin expression in the central nucleus of the amygdala (CeA).

Results:

Rats given 12h access to oxycodone for 5 sessions/week (LgA) escalated their responding more than rats given 1h oxycodone (ShA) or 12h saline access. Slowed escalation of responding was found in rats given 12h access for 7 sessions/week (LgA-7day) or rats pretreated with the KOR antagonist nor-binaltorphamine dihydrochloride (norBNI) before LgA (norBNI+LgA). The KOR agonist U-50488 decreased GABA release in CeA neurons of all groups except LgA. norBNI increased GABA release in control group neurons, suggesting tonic KOR activity. This activity was abolished in ShA, norBNI+LgA, and LgA-7day rat neurons, consistent with decreased CeA dynorphin immunoreactivity observed in LgA-7day rats. However, norBNI effects were reversed (decreased CeA GABA release) in LgA rat neurons.

Conclusions:

The experience of intermittent extended withdrawal periods accelerates the escalation of oxycodone self-administration and causes greater dysregulation of CeA KOR-mediated GABAergic signaling. A KOR agonist/antagonist switch effect seen with other drugs of abuse was absent, which suggests that oxycodone-induced neuroadaptations may be distinct from those resulting from other drugs of abuse.
Dynamics of corticospinal motor control during overground and treadmill walking in humans
Authors: Roeder Luisa , Boonstra Tjeerd W , Smith Simon S , Kerr Graham K
Published: August 2017

Increasing evidence suggests cortical involvement in the control of human gait. However, the nature of corticospinal interactions remains poorly understood. We performed time-frequency analysis of electrophysiological activity acquired during treadmill and overground walking in 22 healthy, young adults. Participants walked at their preferred speed (4.2, SD 0.4 km h−1), which was matched across both gait conditions. Event-related power, corticomuscular coherence (CMC) and inter-trial coherence (ITC) were assessed for EEG from bilateral sensorimotor cortices and EMG from the bilateral tibialis anterior (TA) muscles. Cortical power, CMC and ITC at theta, alpha, beta and gamma frequencies (4-45 Hz) increased during the double support phase of the gait cycle for both overground and treadmill walking. High beta (21-30 Hz) CMC and ITC of EMG was significantly increased during overground compared to treadmill walking, as well as EEG power in theta band (4-7 Hz). The phase spectra revealed positive time lags at alpha, beta and gamma frequencies, indicating that the EEG response preceded the EMG response. The parallel increases in power, CMC and ITC during double support suggest evoked responses at spinal and cortical populations rather than a modulation of ongoing corticospinal oscillatory interactions. The evoked responses are not consistent with the idea of synchronization of ongoing corticospinal oscillations, but instead suggest coordinated cortical and spinal inputs during the double support phase. Frequency-band dependent differences in power, CMC and ITC between overground and treadmill walking suggest differing neural control for the two gait modalities, emphasizing the task-dependent nature of neural processes during human walking.

New & Noteworthy

We investigated cortical and spinal activity during overground and treadmill walking in healthy adults. Parallel increases in power, CMC and ITC during double support suggest evoked responses at spinal and cortical populations rather than a modulation of ongoing corticospinal oscillatory interactions. These findings identify neurophysiological mechanisms that are important for understanding cortical control of human gait in health and disease.
GIC: A computational method for predicting the essentiality of long noncoding lncRNAs
Authors: Zeng Pan , Chen Ji , Zhou Yuan , Yang Jichun , Cui Qinghua
Published: August 2017

Measuring the essentiality of genes is critically important in biology and medicine. Some bioinformatic methods have been developed for this issue but none of them can be applied to long noncoding RNAs (lncRNAs), one big class of biological molecules. Here we developed a computational method, GIC (Gene Importance Calculator), which can predict the essentiality of both protein-coding genes and lncRNAs based on RNA sequence information. For identifying the essentiality of protein-coding genes, GIC is competitive with well-established computational scores. More important, GIC showed a high performance for predicting the essentiality of lncRNAs. In an independent mouse lncRNA dataset, GIC achieved an exciting performance (AUC=0.918). In contrast, the traditional computational methods are not applicable to lncRNAs. As a public web server, GIC is freely available at http://www.cuilab.cn/gic/.
SFMetaDB: A Comprehensive Annotation of Mouse RNA Splicing Factor RNA-Seq Datasets
Authors: Li Jin , Tseng Ching-San , Federico Antonio , Ivankovic Franjo , Huang Yi-Shuian , Ciccodicola Alfredo , Swanson Maurice S. , Yu Peng
Published: August 2017

Although the number of RNA-Seq datasets deposited publicly has increased over the past few years, incomplete annotation of the associated metadata limits their potential use. Because of the importance of RNA splicing in diseases and biological processes, we constructed a database called SFMetaDB by curating datasets related with RNA splicing factors. Our effort focused on the RNA-Seq datasets in which splicing factors were knocked-down, knocked-out or over-expressed, leading to 75 datasets corresponding to 56 splicing factors. These datasets can be used in differential alternative splicing analysis for the identification of the potential targets of these splicing factors and other functional studies. Surprisingly, only ∼15% of all the splicing factors have been studied by loss- or gain-of-function experiments using RNA-Seq. In particular, splicing factors with domains from a few dominant Pfam domain families have not been studied. This suggests a significant gap that needs to be addressed to fully elucidate the splicing regulatory landscape. Indeed, there are already mouse models available for ∼20 of the unstudied splicing factors, and it can be a fruitful research direction to study these splicing factors in vitro and in vivo using RNA-Seq.

Database URL

http://sfmetadb.ece.tamu.edu/
The small non-coding vault RNA1-1 acts as a riboregulator of autophagy
Authors: Horos Rastislav , Alleaume Anne-Marie , Kleinendorst Roos , Tarafder Abul K. , Schwarzl Thomas , Zielonka Elisabeth M. , Adak Asli , Castello Alfredo , Huber Wolfgang , Sachse Carsten , Hentze Matthias W.
Published: August 2017

Vault RNAs (vtRNA) are small, 88-100nt non-coding RNAs found in many eukaryotes. Although they have been linked to drug resistance, apoptosis and nuclear transport, their function remains unclear. Here we show that a human vtRNA, RNA1-1, specifically binds to the autophagy receptor sequestosome-1/p62. Antisense-mediated depletion of vault RNA1-1 augments, whereas increased vault RNA1-1 expression restricts, autophagic flux in a p62-dependent manner. Bulk autophagy induced by starvation reduces the levels of vault RNA1-1 and the fraction of RNA-bound p62. These findings show that RNAs can act as riboregulators of biological processes by interacting with proteins, and assign a function to a vault RNA.
Community-based benchmarking improves spike rate inference from two-photon calcium imaging data
Authors: Berens Philipp , Freeman Jeremy , Deneux Thomas , Chenkov Nicolay , McColgan Thomas , Speiser Artur , Macke Jakob H. , Turaga Srinivas , Mineault Patrick , Rupprecht Peter , Gerhard Stephan , Friedrich Rainer W. , Friedrich Johannes , Paninski Liam , Pachitariu Marius , Harris Kenneth D. , Bolte Ben , Machado Timothy A. , Ringach Dario , Stone Jasmine , Rogerson Luke E. , Sofroniew Nicolas J , Reimer Jacob , Froudarakis Emmanouil , Euler Thomas , Roman-Roson Miroslav , Theis Lucas , Tolias Andreas S. , Bethge Matthias
Published: August 2017

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike trains from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.
microRNA tissue atlas of the malaria mosquitoAnopheles gambiae
Authors: Lampe Lena , Levashina Elena A.
Published: August 2017

Anopheles gambiaemosquitoes transmit the human malaria parasitePlasmodium falciparum, which causes the majority of fatal malaria cases worldwide. The hematophagous life style defines the mosquito reproductive biology and is exploited byP. falciparumfor its own sexual reproduction and transmission. The two main phases of the mosquito reproductive cycle, pre-vitellogenic (PV) and post-blood meal (PBM) shape its capacity to transmit malaria. Transition between these phases is tightly coordinated to ensure homeostasis between mosquito tissues and successful reproduction. One layer of control is provided by microRNAs, well known regulators of blood meal digestion and egg development inAedesmosquitoes. Here, we report a global overview of tissue-specific miRNA expression during the PV and PBM phases and identify miRNAs regulated during PV to PBM transition. The observed coordinated changes in the expression levels of a set of miRNAs in the energy-storing tissues suggest a role in the regulation of blood meal-induced metabolic changes.
The RS Domain of Human CFIm68 Plays a Key Role in Selection Between Alternative Sites of Pre-mRNA Cleavage and Polyadenylation
Authors: Hardy Jessica G. , Tellier Michael , Murphy Shona , Norbury Chris J.
Published: August 2017

Many eukaryotic protein-coding genes give rise to alternative mRNA isoforms with identical protein-coding capacities but which differ in the extents of their 3´ untranslated regions (3´UTRs), due to the usage of alternative sites of pre-mRNA cleavage and polyadenylation. By governing the presence of regulatory 3´UTR sequences, this type of alternative polyadenylation (APA) can significantly influence the stability, localisation and translation efficiency of mRNA. Though a variety of molecular mechanisms for APA have been proposed, previous studies have identified a pivotal role for the multi-subunit cleavage factor I (CFIm) in this process in mammals. Here we show that, in line with previous reports, depletion of the CFIm 68 kDa subunit (CFIm68) by CRISPR/Cas9-mediated gene disruption in HEK293 cells leads to a shift towards the use of promoter-proximal poly(A) sites. Using these cells as the basis for a complementation assay, we show that CFIm68 lacking its arginine/serine-rich (RS) domain retains the ability to form a nuclear complex with other CFIm subunits, but selectively lacks the capacity to restore polyadenylation at promoter-distal sites. In addition, nanoparticle-mediated analysis indicates that the RS domain is extensively phosphorylated in vivo. Overall, these results suggest that the CFIm68 RS domain makes a key regulatory contribution to APA.
Expression of lamina proteins Lamin Dm0 and Kugelkern suppresses stem cell proliferation
Authors: Petrovsky Roman , Großhans Jörg
Published: August 2017

The nuclear lamina is involved in numerous cellular functions, such as gene expression, nuclear organization, nuclear stability, and cell proliferation. The mechanism underlying the involvement of lamina is often not clear, especially in physiological contexts. Here we investigate how the farnesylated lamina proteins Lamin Dm0 and Kugelkern are linked to proliferation control of intestinal stem cells (ISCs) in adultDrosophilaflies by loss-of-function and gain-of-function experiments. We found that ISCs mutant for Lamin Dm0 or Kugelkern proliferate, whereas overexpression of Lamin Dm0 or Kugelkern strongly suppressed proliferation. The anti-proliferative activity is, at least in part, due to suppression of Jak/Stat but not Delta/Notch signalling. Lamin Dm0 expression suppresses Jak/Stat signalling by normalization of about 50% of the Stat target genes in ISCs.

Author summary

The nuclear lamina is a protein meshwork that lies beneath the inner side of the nuclear membrane and interacts with nuclear pores, chromatin and the cytoskeleton. Changes in proteins of the nuclear lamina cause a wide range of diseases which are often not well understood. It is hypothesized that impairment of stem cell function, as a result of lamina changes, might play a key role in some of those diseases. Here we use the well characterizedDrosophilamidgut as a system to investigate the role of lamina proteins Lamin Dm0 and Kugelkern on stem cell proliferation.
Bioinformatics analysis for L polymerase homology of arenaviruses
Authors: Alrashedi Hasan , Jones Ian , Mulley Geraldine , Neuman Benjamin W
Published: August 2017

Many pathogenic viruses can transmit between humans and animals as zoonotic infectious often to cause dangerous disease with obvious clinical signs, sometimes globally. However, these outbreaks are generally only dealt with seriously when the viruses concerned have been confirmed and classified as zoonotic. Arenavirus haemorrhagic fever viruses can cause epidemics in some areas of the world. To assess the potential of similar viruses to become zoonotic in the future, bioinformatics of relatively conserved virus proteins, such as the L polymerase of arenaviruses, can be used to identify homology with viruses that might give future outbreaks. In this paper, new and archival metazoan transcriptome sequence data was used as a resource to identify similar sequences to known arenavirus sequences for the purpose of risk prediction. In essence, bioinformatics was utilized to provide a better understanding of the potential evolution and natural history of uncharacterized virus sequences in the GenBank database. Several matches were identified which, along with a reasoned approach to their phyla, was used to provide a likelihood score of their zoonotic potential.
A gut pathobiont synergizes with the microbiota to instigate inflammatory disease marked by immunoreactivity against other symbionts but not itself
Authors: Gomes-Neto João Carlos , Kittana Hatem , Mantz Sara , Segura Munoz Rafael R. , Schmaltz Robert J. , Bindels Laure B. , Clarke Jennifer , Hostetter Jesse M. , Benson Andrew K. , Walter Jens , Ramer-Tait Amanda E.
Published: August 2017

Inflammatory bowel diseases (IBD) are likely driven by aberrant immune responses directed against the resident microbiota. Although IBD is commonly associated with a dysbiotic microbiota enriched in putative pathobionts, the etiological agents of IBD remain unknown. Using a pathobiont-induced intestinal inflammation model and a defined bacterial community, we provide new insights into the immune-microbiota interactions during disease. In our model system, the pathobiontHelicobacter bilisinstigates disease following sub-pathological dextran sulfate sodium treatment. We show thatH. biliscauses mild inflammation in mono-associated mice, but severe disease in the presence of a microbiota, demonstrating synergy between the pathobiont and microbiota in exacerbating pathology. Remarkably, inflammation depends on the presence ofH. bilis, but is marked by a predominant Th17 response against specific members of the microbiota and not the pathobiont, even upon the removal of the most immune-dominant taxa. Neither increases in pathobiont burden nor unique changes in immune-targeted microbiota member abundances are observed during disease. Collectively, our findings demonstrate that a pathobiont instigates inflammation without being the primary target of a Th17 response or by altering the microbiota community structure. Moreover, our findings point toward monitoring pathobiont-induced changes in microbiota immune targeting as a new concept in IBD diagnotics.
LhrandHmrare required for sister chromatid detachment during anaphase but not for centromere function
Authors: Blum Jacob A. , Bonaccorsi Silvia , Marzullo Marta , Palumbo Valeria , Yamashita Yukiko M. , Barbash Daniel A. , Gatti Maurizio
Published: August 2017

Crosses betweenDrosophila melanogasterfemales andDrosophila simulansmales produce hybrid sons that die at the larval stage. This hybrid lethality is suppressed by loss-of-function mutations in theD. melanogaster Hybrid male rescue(Hmr) or in theD. simulans Lethal hybrid rescue(Lhr)genes. Previous studies have shown that Hmr and Lhr interact with heterochromatin proteins and suppress expression of transposable elements withinD. melanogaster. It also has been proposed that Hmr and Lhr function at the centromere. We examined mitotic divisions in larval brains fromHmrandLhrsingle mutants andHmr; Lhrdouble mutants inD. melanogaster. In none of the mutants did we observe defects in metaphase chromosome alignment or hyperploid cells, which are hallmarks of centromere or kinetochore dysfunction. In addition, we found that Hmr-HA and Lhr-HA do not localize to centromeres either during interphase or mitotic division. However, all mutants displayed anaphase bridges and chromosome aberrations resulting from the breakage of these bridges, predominantly at the euchromatin-heterochromatin junction. The few dividing cells present in hybrid males showed irregularly condensed chromosomes with fuzzy and often closely apposed sister chromatids. Despite this defect in condensation, chromosomes in hybrids managed to align on the metaphase plate and undergo anaphase. We conclude that there is no evidence for a centromeric function of Hmr and Lhr withinD. melanogasternor for a centromere defect causing hybrid lethality. Instead we find thatHmrandLhrare required inD. melanogasterfor detachment of sister chromatids during anaphase.
Predictive coding over the lifespan: Increased reliance on perceptual priors in older adults – a magnetoencephalography and dynamic causal modelling study
Authors: Chan Jason S. , Wibral Michael , Wollstadt Patricia , Stawowsky Cerisa , Brandl Mareike , Helbling Saskia , Naumer Marcus , Kaiser Jochen
Published: August 2017

Aging is accompanied by unisensory decline; but to compensate for this, two complementary strategies are potentially relied upon increasingly: first, older adults integrate more information from different sensory organs. Second, according to predictive coding (PC) we form ‘templates’ (internal models or ‘priors’) of the environment through our experiences. It is through increased life experience that older adults may rely more on these templates compared to younger adults. Multisensory integration and predictive coding would be effective strategies for the perception of near-threshold stimuli, but they come at the cost of integrating irrelevant information. Their role can be studied in multisensory illusions because these require the integration of different sensory information, as well as an internal model of the world that can take precedence over sensory input. Here, we elicited a classic multisensory illusion, the sound-induced flash illusion, in younger (mean: 27 yrs) and older (mean: 67 yrs) adult participants while recording the magnetoencephalogram. Older adults perceived more illusions than younger adults. Older adults had increased pre-stimulus beta(β)-band activity compared to younger adults as predicted by microcircuit theories of predictive coding, which suggest priors and predictions are linked to β-band activity. In line with our hypothesis, transfer entropy analysis and dynamic causal models of pre-stimulus MEG data revealed a stronger illusion-related modulation of cross-modal connectivity from auditory to visual cortices in older compared to younger adults. We interpret this as the neural correlate of increased reliance on a cross-modal predictive template in older adults that is leading to the illusory percept.
npInv: accurate detection and genotyping of inversions mediated by non-allelic homologous recombination using long read sub-alignment
Authors: Shao Haojing , Ganesamoorthy Devika , Duarte Tania , Cao Minh Duc , Hoggart Clive , Coin Lachlan J.M.
Published: August 2017

Detection of genomic inversions remains challenging. Many existing methods primarily target inversions with a non repetitive breakpoint, leaving inverted repeat (IR) mediated non-allelic homologous recombination (NAHR) inversions largely unexplored. We present npInv, a novel tool specifically for detecting and genotyping NAHR inversion using long read sub-alignment of long read sequencing data. We use npInv to generate a whole-genome inversion map for NA12878 consisting of 30 NAHR inversions (of which 15 are novel), including all previously known NAHR mediated inversions in NA12878 with flanking IR less than 7kb. Our genotyping accuracy on this dataset was 94%. We used PCR to confirm presence of two of these novel NAHR inversions. We show that there is a near linear relationship between the length of flanking IR and the size of the NAHR inversion.
Evolutionary history of New World monkeys revealed by molecular and fossil data
Authors: Silvestro Daniele , Tejedor Marcelo F. , Serrano-Serrano Martha L. , Loiseau Oriane , Rossier Victor , Rolland Jonathan , Zizka Alexander , Antonelli Alexandre , Salamin Nicolas
Published: August 2017

New World monkeys (parvorder Platyrrhini) are one of the most diverse groups of primates, occupying today a wide range of ecosystems in the American tropics and exhibiting large variations in ecology, morphology, and behavior. Although the relationships among the almost 200 living species are relatively well understood, we lack robust estimates of the timing of origin, the ancestral morphology, and the evolution of the distribution of the clade. Here we integrate paleontological and molecular evidence to investigate the evolutionary dynamics of extinct and extant platyrrhines. We develop an analytical framework to infer ancestral states, the evolution of body mass, and changes in latitudinal ranges through time. Our results show that extant platyrrhines originated some 5–10 million years earlier than previously assumed, likely dating back to the Middle Eocene (∼ 43 million years ago, Ma). The estimated ancestral platyrrhine was strikingly small – weighing ∼ 0.4 kg, as compared to the largest modern species over 10 kg – matching the size of their presumed Eocene North African ancestors. Small-sized callitrichines (marmosets and tamarins) retained a small body mass throughout their evolutionary history, thus challenging the hypothesis of phyletic dwarfism as an explanation to their adaptive traits. In contrast, a rapid change in body mass range took place as the three families diverged between the Late Oligocene and the Early Miocene. That period also marks a peak in diversity of fossil platyrrhines and is associated with their widest latitudinal range, expanding as far to the South as Patagonia. This geographic expansion is temporally coincident with a significant increase in platyrrhine population size inferred from genomic data, and with warm and humid climatic conditions linked to the Miocene Climatic Optimum and the lower elevation of the Andes. These results unveil the early evolution of an iconic group of monkeys and showcase the advantages of integrating fossil and molecular data for estimating evolutionary rates and trends.
CHIC: a short read aligner for pan-genomic references
Authors: Valenzuela Daniel , Mäkinen Veli
Published: August 2017

Recently the topic of computational pan-genomics has gained increasing attention, and particularly the problem of moving from a single-reference paradigm to a pan-genomic one. Perhaps the simplest way to represent a pan-genome is to represent it as a set of sequences. While indexing highly repetitive collections has been intensively studied in the computer science community, the research has focused on efficient indexing and exact pattern patching, making most solutions not yet suitable to be used in bioinformatic analysis pipelines.

Results:

We present CHIC, a short-read aligner that indexes very large and repetitive references using a hybrid technique that combines Lempel-Ziv compression with Burrows-Wheeler read aligners.

Availability:

Our tool is open source and available online athttps://gitlab.com/dvalenzu/CHIC
Regulatory divergence of flowering time genes in the allopolyploidBrassica napus
Authors: Marc Jones D. , Wells Rachel , Pullen Nick , Trick Martin , Irwin Judith A. , Morris Richard J.
Published: August 2017

Polyploidy is a recurrent feature of eukaryotic evolution and has been linked to increases in complexity, adaptive radiation and speciation. Within angiosperms, such events occur repeatedly in many plant lineages. We investigated the role of duplicated genes in the regulation of flowering inBrassica napus. This relatively young allotetraploid represents a snapshot of evolution and artificial selection in progress. In line with the gene balance hypothesis, we find preferential retention of expressed flowering time genes relative to the whole genome. Furthermore, gene expression dynamics across development reveal diverged regulation of many flowering time gene copies. This finding supports the concept of responsive backup circuits being key for the retention of duplicated genes. A case study ofBnaTFL1reveals differences in cis-regulatory elements downstream of these genes that could explain this divergence. Such differences in the regulatory dynamics of duplicated genes highlight the challenges for translating gene networks from model to more complex polyploid crop species.
Genomic relationships reveal significant dominance effects for growth in hybridEucalyptus
Authors: Tan Biyue , Grattapaglia Dario , Wu Harry X. , Ingvarsson Pär K.
Published: August 2017

Non-additive genetic effects can be effectively exploited in control-pollinated families with the availability of genome-wide markers. We used 41,304 SNP markers and compared pedigreevs.marker-based genetic models by analysing height, diameter, basic density and pulp yield for 338Eucalyptus urophyllaxE.grandiscontrol-pollinated families represented by 949 informative individuals. We evaluated models accounting for additive, dominance, and first-order epistatic interactions (additive by additive, dominance by dominance, and additive by dominance). We showed that the models can capture a large proportion of the genetic variance from dominance and epistasis for growth traits as those components are typically not independent. We also show that we could partition genetic variances more precisely when using relationship matrices derived from markers compared to using only pedigree information. In addition, phenotypic prediction accuracies were only slightly increased by including dominance effects for growth traits since estimates of non-additive variances yielded rather high standard errors. This novel result improves our current understanding of the architecture of quantitative traits and recommends accounting for dominance variance when developing genomic selection strategies in hybridEucalyptus.
Oxytocin Signaling in the Medial Amygdala is required for Sex Discrimination of Social Cues
Authors: Yao Shenqin , Bergan Joseph , Lanjuin Anne , Dulac Catherine
Published: August 2017

The neural control of social behaviors in rodents requires the encoding of pheromonal cues by the vomeronasal system. Here we show that the typical preference of male mice for females is eliminated in mutants lacking oxytocin, a neuropeptide modulating social behaviors in many species. Ablation of the oxytocin receptor in aromatase expressing neurons of the medial amygdala (MeA) fully recapitulates the elimination of female preference in males. Further, single unit recording in the MeA uncovered significant changes in the sensory representation of conspecific cues in the absence of oxytocin signaling. Finally, acute manipulation of oxytocin signaling in adults is sufficient to alter social interaction preferences in males as well as responses of MeA neurons to chemosensory cues. These results uncover the critical role of oxytocin signaling in a molecularly defined neuronal population in order to modulate the behavioral and physiological responses of male mice to females on a moment-to-moment basis.
Biofilm formation and toxin production provide a fitness advantage in mixed colonies of natural yeast isolates
Authors: Deschaine Bernadette M. , Heysel Angela R. , Lenhart Adam , Murphy Helen A.
Published: August 2017

Microbes exist in complex communities and can engage in social interactions ranging from cooperation to warfare. Biofilms are structured, cooperative microbial communities; they are pervasive and ancient, representing the first fossilized life. Like all cooperative communities, biofilms are susceptible to invasion by selfish individuals who benefit from cooperation, but do not contribute. The ubiquity of biofilms therefore poses a challenge to evolutionary theory. One hypothesis for biofilm stability is spatial structure: patches of related cooperative cells are able to outcompete unrelated cells. These dynamics have been explored computationally and in bacterial systems; however, their relevance to eukaryotic microbes remains an open question. Here, we investigate the interactions of environmental yeast isolates with different social phenotypes. Our results show that biofilm strains spatially exclude non-biofilm strains, and that biofilm spatial structure confers a consistent and robust fitness advantage in direct competition. We also find that biofilms protect against killer toxin, a warfare phenotype. During biofilm formation, cells are susceptible to toxin from nearby competitors; however, increased spatial use by biofilms provides an escape from toxin-producers. Our results suggest that yeast biofilms represent a competitive strategy, and that principles elucidated for the evolution and stability of bacterial biofilms may apply to eukaryotes.
Systemic HIV-1 Infection Produces a Unique Glial Footprint in Humanized Mouse Brains
Authors: Li Weizhe , Gorantla Santhi , Gendelman Howard E. , Poluektova Larisa Y.
Published: August 2017

Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are hindered by the availability of relevant small-animal models. To overcome this hindrance, a mouse model reconstituted with humanized brain and immune systems was created. Newborn NOD/SCID/IL2Rγc-/-mice of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC yielded an anatomical symmetrical glia (human astrocyte and oligodendrocyte) repopulation of the mouse brain. The human glia were observed in periventricular areas, white matter tracts, the olfactory bulb and brain stem. HIV-1 infection of these dual humanized mice led to meningeal and perivascular human leukocyte infiltration into brain. The species-specific viral-neuroimmune interactions in the infected animals were identified by deep RNA sequencing. In the corpus callosum and hippocampus overlapping human-specific transcriptional alterations were seen for interferon type 1 and 2 signaling pathways (STAT1, 2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1)in infected animals. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAGandZNF488) were downregulated. The data sets were confirmed by real-time PCR. The viral defense signaling patterns observed in these mice parallels the neuroimmune communication networks present in the HIV-1 infected human brain. In this manner, the new mouse model can facilitate discovery of therapeutics, viral eradication targets for virus induced nervous system diseases, and simplify HIVCure research approaches.

Summary Statement

We created mice with both a humanized brain and an immune system. The animals were used to investigate glial responses to HIV-1 infection. At a transcriptional level we defined the interactions between human glia and immune cells in the presence of the systemic HIV-1 infection. Noticeably, altered transcriptional changes were human specific. At five weeks after viral infection humanized mouse brain displayed potent interferon-mediated antiviral innate immune responses and alteration of neuronal progenitors differentiation and myelination. This model can be used to tests both diagnostic and therapeutic interventions for cure HIV-associated brain impairment.
Pathogen-Host Analysis Tool (PHAT): an Integrative Platform to Analyze Pathogen-Host Relationships in Next-Generation Sequencing Data
Authors: Gibb Christopher M. , Jackson Robert , Mohammed Sabah , Fiaidhi Jinan , Zehbe Ingeborg
Published: August 2017

The Pathogen-Host Analysis Tool (PHAT) is an application for processing and analyzing next-generation sequencing (NGS) data as it relates to relationships between pathogen and host organisms. Unlike custom scripts and tedious pipeline programming, PHAT provides an integrative platform encompassing raw and aligned sequence and reference file input, quality control (QC) reporting, alignment and variant calling, linear and circular alignment viewing, and graphical and tabular output. This novel tool aims to be user-friendly for life scientists studying diverse pathogen-host relationships.

Availability and Implementation

The project is publicly available on GitHub (https://github.com/chgibb/PHAT) and includes convenient installers, as well as portable and source versions, for both Windows and Linux (Debian and RedHat). Up-to-date documentation for PHAT, including user guides and development notes, can be found athttps://chgibb.github.io/PHATDocs/. We encourage users and developers to provide feedback (error reporting, suggestions, and comments) using GitHub Issues.

Contact

Lead software developer:chris.gibb@outlook.com
Extraordinary Self-Sacrifice
Authors: Krupp D.B.
Published: August 2017

Theories of self-sacrifice ordinarily assume that actors will have larger fitness effects on recipients than on themselves. There are, however, conditions in which actors can pay costs that exceed the altruistic benefits they provide or the spiteful costs they impose. In a spatially structured population, I show that such “extraordinary” self-sacrifice evolves when actors use information about kinship and dispersal to maximize inclusive fitness. The result can be described by a simple rule: extraordinary self-sacrifice evolves when the actor’s neighbors are kin and the recipient’s neighbors are not.
Recurring infection with ecologically distinct human papillomavirus (HPV) types explains high prevalence and diversity
Authors: Ranjeva Sylvia , Baskerville Edward B. , Dukic Vanja , Villa Luisa , Lazcano-Ponce Eduardo , Giuliano Anna , Dwyer Greg , Cobey Sarah
Published: August 2017

The high prevalence of human papillomavirus (HPV), the most common sexually transmitted infection, arises from the coexistence of over 200 genetically distinct types. Accurately predicting the impact of vaccines that target multiple types requires understanding the factors that determine HPV diversity. The diversity of many pathogens is driven by type-specific or “homologous” immunity, which promotes the spread of variants to which hosts have little immunity. To test for homologous immunity and to identify mechanisms determining HPV transmission, we fitted nonlinear mechanistic models to longitudinal data on genital infections in unvaccinated men. Our results provide no evidence for homologous immunity, instead showing that infection with one HPV type strongly increases the risk of infection with that type for years afterwards. For HPV16, the type responsible for most HPV-related cancers, an initial infection increases the one-year probability of reinfection by 20-fold, and the probability of reinfection remains 14-fold higher two years later. This increased risk occurs in both sexually active and celibate men, suggesting that it arises from auto-inoculation, episodic reactivation of latent virus, or both. Overall our results show that high HPV prevalence and diversity can be explained by a combination of a lack of homologous immunity, frequent reinfections, weak competition between types, and variation in type fitness between host subpopulations. Due to the high risk of reinfection, vaccinating boys that have not yet been exposed may be crucial to reduce prevalence, but our results suggest that there may also be large benefits from vaccinating previously infected individuals.