bluuebunny/crossref_metadata_2025 huggingface dataset:
Infection With Chlamydia trachomatis Increases the Risk of High-grade Anal Intraepithelial Neoplasia in People Living With Human Immunodeficiency Virus
Authors: Masiá Mar , Fernández-González Marta , García José A , Padilla Sergio , García-Payá Elena , Gutiérrez Ana , Ortiz de la Tabla Victoria , García-Abellán Javier , Agulló Vanesa , Gutiérrez Félix
Published: July 2019

Background

We aimed to assess the relationship between sexually transmitted infections (STIs)—including a large panel of human papillomavirus (HPV) genotypes—and high-grade anal intraepithelial neoplasia (HGAIN) in men who have sex with men (MSM) who were living with human immunodeficiency virus (HIV).

Methods

In a prospective study in an HIV cohort, participants underwent high-resolution anoscopy (HRA) for anorectal swabs collection to investigate STIs and for anal biopsy. Multiplex real-time polymerase chain reactions were performed, detecting several STIs and 28 HPV genotypes. Univariate and multivariate generalized linear models were used to analyze the relationships of variables of interest with HGAIN.

Results

There were 145 participants included; in 49, 2 HRAs were performed. Ureaplasma urealyticum (UU) was detected in 25 (17.2%) participants, Chlamydia trachomatis (CT) in 13 (9.0%), Mycoplasma genitalium (MG) in 4 (2.8%), HPV16 in 38 (26.2%), HPV52 in 29 (20%), and HPV53 and HPV42 in 28 (19.3%) participants each. There were 35 (24.1%) subjects diagnosed with HGAIN. In the univariate analysis, HGAIN was associated with CT, UU, MG, HPV16, HPV53, HPV68, and HPV70, and significant interactions were found between CT and HPV16 (odds ratio [OR] 31.0 95% confidence interval [CI] 4.3–221.7) and between UU and HPV16 (OR 8.8, 95% CI 2.1–37.5). In the adjusted model, CT, HPV16, HPV53, HPV70, the CD4+/CD8+ ratio, and the interaction between CT and HPV16 remained independent predictors of HGAIN. HPV16, HPV53, and HPV70 persisted in the second HRA in all the participants with recurrent HGAIN.

Conclusions

Coinfection with CT may potentiate the oncogenic capability of HPV16 and increase the risk of HGAIN in people with HIV. HPV53 and HPV70 should be considered among the genotypes associated with HGAIN.
Genome-Wide Single-Nucleotide Polymorphism Data Unveil Admixture of Chinese Indigenous Chicken Breeds with Commercial Breeds
Authors: Nie Changsheng , Almeida Pedro , Jia Yaxiong , Bao Haigang , Ning Zhonghua , Qu Lujiang
Published: June 2019

The conservation and development of chicken have received considerable attention, but the admixture history of chicken breeds, especially Chinese indigenous breeds, has been poorly demonstrated. In this study, we aimed to evaluate the genetic diversity and population structure of eight chicken breeds (including conserved chicken breeds) from different geographic origin and to identify admixture within these breeds using a 600-K single-nucleotide polymorphism panel for genotyping. Using the genotype of 580,961 single-nucleotide polymorphism markers scored in 1,200 animals, we evaluated the genetic diversity (heterozygosity and proportion of polymorphic markers), linkage disequilibrium decay, population structure (principal component analysis and neighbor-joining tree), genetic differentiation (FST and genetic distance), and migration events (TreeMix and f-statistics) of the eight domesticated chicken breeds. The results of population analytical methods revealed patterns of hybridization that occurred after divergence in Tibetan chicken. We argue that chicken migration and admixture, followed by trade, have been important forces in shaping the genomic variation in modern Chinese chicken. Moreover, isolation by distance might play a critical role in shaping the genomic variation within Eurasia continent chicken breeds. Moreover, genetic information provided in this study is valuable resources for production applications (genomic prediction, and breeding strategy) and scientific research (genetic basis detection, studying evolution, or domestication).
Sex Differences in Depression as a Risk Factor for Alzheimer’s Disease: A Systematic Review
Authors: Underwood Emily A , Davidson Heather P , Azam Amber B , Tierney Mary C
Published: June 2019

Background and Objectives

Depression is an important risk factor for Alzheimer’s disease (AD) but little is known about the mechanisms of this association. Given sex differences in both AD and depression, we sought to conduct a systematic review and meta-analysis to examine whether there are sex differences in their association, as this may improve understanding of underlying mechanisms.

Research Design and Methods

MEDLINE, PsycINFO, and Cochrane Reviews were searched for observational studies including both sexes and examining the association between history of depression and AD.

Results

Forty studies, including 62,729 women and 47,342 men, were identified. Meta-analysis was not possible because only 3 studies provided sufficient data. Seven studies provided information about the influence of sex for a qualitative synthesis. Two found an association in men only, 2 in women only, and 3 reported no sex differences. The 2 studies finding an association in women only were unique in that they had the shortest follow-up periods, and were the only clinic-based studies.

Discussion and Implications

The findings of our systematic review show that there are important methodological differences among the few studies providing data on the influence of sex on depression as a risk factor for AD. Had all 40 studies provided sex-segregated data, these methodological differences and their impact on sex effects could have been examined quantitatively. We encourage researchers to report these data, as well as potential moderating factors, so that the role of sex differences can be better understood.
Seismic activity during the 2013–2015 intereruptive phase at Lascar volcano, Chile
Authors: Gaete Ayleen , Cesca Simone , Franco Luis , San Martin Juan , Cartes Cristian , Walter Thomas R
Published: June 2019

In addition to enabling the physical processes of volcanic systems to be better understood, seismology has been also used to infer the complexity of magma pathways and plumbing systems in steep-sided andesitic and stratovolcanoes. However, in these volcanic environments, the application of seismic location methods is particularly challenging and systematic comparisons of common methods are lacking. Furthermore, little is known about the characteristic seismicity and deep structure of Lascar volcano, one of the most historically active volcanoes in northern Chile known to produce VEI-4 eruptions. To better understand the inner processes and deep structure of Lascar, the local broad-band seismic monitoring network was densified during a temporal installation in 2014–2015. Herein, we focus on the local seismicity during the 2014–2015 unrest episode, during which we recorded numerous seismic events mainly classified as long-period (LP) type, but also denote volcano-tectonic (VT) activity. Specifically, a long-lasting phase of LP activity is observed over a period of ∼14 months that starts in tandem with a pulse of VT activity. The LP rate and amplitude are modulated over time; they are lower in the initial phase, rise during the intermediate period from October 2014 to July 2015, and finally slowly decay while approaching the eruption time. The location of LPs is challenging due to the typical lack of clear seismic onsets. We thus encompass this problem by comparing a broad range of different standard and novel location techniques to map the source region of LPs by fitting the amplitude decay, polarization patterns, coherence of characteristic functions and cross-correlation differential times. As a result, we principally constrain LP locations within the first 5 km depth below the summit extending downward along a narrow, conduit-like path. We identify different regions of complexity: VTs dominate at depth, both VTs and LPs cluster in an intermediate depth region (down to 1.5 km), suggesting a change in the plumbing system geometry, and LPs dominate the shallowest region. Based on these results, we infer the presence of a subvertical conduit extending down to a depth of ∼5 km, and a region of path divergence, possibly accommodating a magma plumbing system, at a depth of ∼3 km beneath the volcano summit. Identifying the locations of complexities in the magma pathways at Lascar may help identify future unrest. The results are compared with independent observations, demonstrating the strength of the location method used herein that will be tested at volcanoes elsewhere.
Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling
Authors: Pilato Celeste M , Park Jae Hong , Kong Lingling , d’Ydewalle Constantin , Valdivia David , Chen Karen S , Griswold-Prenner Irene , Sumner Charlotte J
Published: June 2019

A pathological hallmark of spinal muscular atrophy (SMA) is severe motor neuron (MN) loss, which results in muscle weakness and often infantile or childhood mortality. Although it is well established that deficient expression of survival motor neuron (SMN) protein causes SMA, the molecular pathways that execute MN cell death are poorly defined. The c-Jun NH2-terminal kinases (JNKs) are stress-activated kinases with multiple substrates including c-Jun, which can be activated during neuronal injury and neurodegenerative disease leading to neuronal apoptosis. Recently, increased JNK-c-Jun signaling was reported in SMA raising the possibility that JNK inhibitors could be a novel treatment for this disease. We examined JNK-c-Jun activity in SMA mouse and human cultured cells and tissues. Anisomycin treatment of human SMA fibroblasts and sciatic nerve ligation in SMA mice provoked robust phosphorylated-c-Jun (p-c-Jun) expression indicating that SMN-deficiency does not prevent activation of the stress-induced JNK-c-Jun signaling pathway. Despite retained capacity to activate JNK-c-Jun, we observed no basal increase of p-c-Jun levels in SMA compared to control cultured cells, human or mouse spinal cord tissues, or mouse MNs during the period of MN loss in severe SMA model mice. In both controls and SMA, ~50% of α-MN nuclei express p-c-Jun with decreasing expression during the early postnatal period. Together these studies reveal no evidence of stress-activated JNK-c-Jun signaling in MNs of SMA mice or human tissues, but do highlight the important role of JNK-c-Jun activity during normal MN development raising caution about JNK antagonism in this pediatric neuromuscular disease.
Sponge Behavior and the Chemical Basis of Responses: A Post-Genomic View
Authors: Leys Sally P , Mah Jasmine L , McGill Paul R , Hamonic Laura , De Leo Fabio C , Kahn Amanda S
Published: June 2019

Sponges perceive and respond to a range of stimuli. How they do this is still difficult to pin down despite now having transcriptomes and genomes of an array of species. Here we evaluate the current understanding of sponge behavior and present new observations on sponge activity in situ. We also explore biosynthesis pathways available to sponges from data in genomes/transcriptomes of sponges and other non-bilaterians with a focus on exploring the role of chemical signaling pathways mediating sponge behavior and how such chemical signal pathways may have evolved. Sponge larvae respond to light but opsins are not used, nor is there a common photoreceptor molecule or mechanism used across sponge groups. Other cues are gravity and chemicals. In situ recordings of behavior show that both shallow and deep-water sponges move a lot over minutes and hours, and correlation of behavior with temperature, pressure, oxygen, and water movement suggests that at least one sponge responds to changes in atmospheric pressure. The sensors for these cues as far as we know are individual cells and, except in the case of electrical signaling in Hexactinellida, these most likely act as independent effectors, generating a whole-body reaction by the global reach of the stimulus to all parts of the animal. We found no evidence for use of conventional neurotransmitters such as serotonin and dopamine. Intriguingly, some chemicals synthesized by symbiont microbes could mean other more complex signaling occurs, but how that interplay might happen is not understood. Our review suggests chemical signaling pathways found in sponges do not reflect loss of a more complex set.
Scenario-based analyses evaluate potential outcomes of proposed regulatory changes in recreational fishery
Authors: Thomas Alyssa S , Milfont Taciano L , Gavin Michael C
Published: June 2019

Understanding current and predicting future behaviour of fishers is fundamental to designing effective management strategies. The management of most recreational fisheries requires releasing fish not meeting size or daily limits, and assuming the majority survive. In the Marlborough Sounds, New Zealand, a maximum size limit imposed on the blue cod (Parapercis colias) fishery aimed to achieve a more balanced sex ratio for this hermaphroditic species. We tested three alternative size limit scenarios (current, increased, and no maximum size) in a study with recreational fishers (N = 420) to investigate whether regulation change would influence their intentions to discard fish and fishing satisfaction. Increasing or eliminating the maximum size led to lower discard intentions and greater fishing satisfaction, suggesting strategies to achieve both management goals (e.g. more large fish) and increased fisher satisfaction (potentially increasing compliance). More broadly, the results demonstrate the benefits of using scenarios to evaluate potential regulatory changes prior to implementation.
Attaining sustainable high-rise office buildings in warm-summer-cold-winter climates: a case study on Frankfurt
Authors: Hong Yuanda , Deng Wu , Ezeh Collins I , Peng Zhen
Published: June 2019

Attaining sustainability in high-rise office buildings necessitates determining the major elements and their associating impacts on the energy performance of this building typology. This study investigates the impact of architectural and engineering features on the energy performance of high-rise office buildings within a warm-summer-cold-winter climate. A rectangular building plan form with a 1:1.44 plan ratio, vertical split core position and central atrium presented the best building performance. The plan form, core position and atrium effect accounted for 59, 30 and 11%, respectively, of an estimated 20.6% building energy savings. Furthermore, exploiting passive strategies founded on the climate and building features as defined by `PassivHaus’ standards further reduced the building energy usage.
Legitimation Strategies in International Hierarchies
Authors: MacKay Joseph
Published: June 2019

How do hierarchical cores or metropoles legitimate their influence or rule? How do their approaches to legitimation inform resistance? This theory note rethinks how legitimation operates in hierarchies, with a focus on variation in cores’ legitimation strategies. I argue that varying claims to hierarchical legitimacy shape both action at the core and resistance at the periphery. I develop a four-part typology of legitimation strategies, differentiated along two axes. On the first, cores may be universalist, recognizing no legitimate equals, or competitive, recognizing other cores as peer rivals. On the second, they may chiefly innovate legitimacy claims internally, drawing them from their own political traditions, or externally, borrowing the claims of others. These strategies shape available options for revisionism by rivals and resistance by hierarchical subordinates. I illustrate with historical examples.
Accuracy in the Application of Statistical Matching Methods for Continuous Variables Using Auxiliary Data
Authors: Van Delden Arnout , Du Chatinier Bart J , Scholtus Sander
Published: June 2019

Statistical matching is a technique to combine variables in two or more nonoverlapping samples that are drawn from the same population. In the current study, the unobserved joint distribution between two target variables in nonoverlapping samples is estimated using a parametric model. A classical assumption to estimate this joint distribution is that the target variables are independent given the background variables observed in both samples. A problem with the use of this conditional independence assumption is that the estimated joint distribution may be severely biased when the assumption does not hold, which in general will be unacceptable for official statistics. Here, we explored to what extent the accuracy can be improved by the use of two types of auxiliary information: the use of a common administrative variable and the use of a small additional sample from a similar population. This additional sample is included by using the partial correlation of the target variables given the background variables or by using an EM algorithm. In total, four different approaches were compared to estimate the joint distribution of the target variables. Starting with empirical data, we show how the accuracy of the joint distribution is affected by the use of administrative data and by the size of the additional sample included via a partial correlation and through an EM algorithm. The study further shows how this accuracy depends on the strength of the relations among the target and auxiliary variables. We found that including a common administrative variable does not always improve the accuracy of the results. We further found that the EM algorithm nearly always yielded the most accurate results; this effect is largest when the explained variance of the separate target variables by the common background variables is not large.
Effect of turbulent reacceleration on electrons produced by dark matter annihilation in the Coma cluster
Authors: Marchegiani P
Published: June 2019

In this paper, we study the effect of reacceleration provided by turbulences on electrons produced by dark matter (DM) annihilation in the Coma cluster. We use a simplified phenomenological model to describe the effect of the turbulences, and explore a limited subset of three possible DM models for neutralino particles with different mass and annihilation channel. We find that, for values of the annihilation cross-section of the order of the upper limits found with Fermi–LAT measurements in astrophysical objects, and for conservative values of the boosting factor due to DM substructures, the reacceleration due to turbulences can enhance the radio emission produced by DM-originated electrons up to the level of the observed flux of the radio halo in Coma, for moderate reacceleration intensity in relatively short times. Therefore, we conclude that, even if it is not possible to distinguish between the fits obtained in this paper because of the scattering present in the radio flux data, the electrons produced by DM annihilation can be possible seed electrons for the reacceleration, as well as secondary electrons of hadronic origin. A possible discriminant between these two classes of models is the flux produced in the gamma ray band, which in the case of DM-originated electrons should be more than two orders of magnitude smaller than the present Fermi–LAT upper limits, whereas in the hadronic case the expected gamma ray flux should be close to the value of present upper limits.
Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging
Authors: Lee Jong-Hyuk , Demarest Tyler G , Babbar Mansi , Kim Edward W , Okur Mustafa N , De Supriyo , Croteau Deborah L , Bohr Vilhelm A
Published: June 2019

Cockayne syndrome is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) is persistently activated by unrepaired DNA damage and consumes and depletes cellular nicotinamide adenine dinucleotide, which leads to mitochondrial dysfunction. Here, the distribution of poly (ADP ribose) (PAR) was determined in CSB-deficient cells using ADPr-ChAP (ADP ribose-chromatin affinity purification), and the results show striking enrichment of PAR at transcription start sites, depletion of heterochromatin and downregulation of H3K9me3-specific methyltransferases SUV39H1 and SETDB1. Induced-expression of SETDB1 in CSB-deficient cells downregulated PAR and normalized mitochondrial function. The results suggest that defects in CSB are strongly associated with loss of heterochromatin, downregulation of SETDB1, increased PAR in highly-transcribed regions, and mitochondrial dysfunction.
RNA polymerase II plays an active role in the formation of gene loops through the Rpb4 subunit
Authors: Allepuz-Fuster Paula , O’Brien Michael J , González-Polo Noelia , Pereira Bianca , Dhoondia Zuzer , Ansari Athar , Calvo Olga
Published: June 2019

Gene loops are formed by the interaction of initiation and termination factors occupying the distal ends of a gene during transcription. RNAPII is believed to affect gene looping indirectly owing to its essential role in transcription. The results presented here, however, demonstrate a direct role of RNAPII in gene looping through the Rpb4 subunit. 3C analysis revealed that gene looping is abolished in the rpb4Δ mutant. In contrast to the other looping-defective mutants, rpb4Δ cells do not exhibit a transcription termination defect. RPB4 overexpression, however, rescued the transcription termination and gene looping defect of sua7-1, a mutant of TFIIB. Furthermore, RPB4 overexpression rescued the ssu72-2 gene looping defect, while SSU72 overexpression restored the formation of gene loops in rpb4Δ cells. Interestingly, the interaction of TFIIB with Ssu72 is compromised in rpb4Δ cells. These results suggest that the TFIIB–Ssu72 interaction, which is critical for gene loop formation, is facilitated by Rpb4. We propose that Rpb4 is promoting the transfer of RNAPII from the terminator to the promoter for reinitiation of transcription through TFIIB–Ssu72 mediated gene looping.
Using Transcriptome to Discover a Novel Melatonin-Induced Sodic Alkaline Stress Resistant Pathway in Solanum lycopersicum L.
Authors: Yan Yanyan , Jing Xin , Tang Huimeng , Li Xiaotong , Gong Biao , Shi Qinghua
Published: June 2019

Melatonin plays important roles in multiple stress responses. However, the downstream signaling pathway and molecular mechanism are unclear until now. Here, we not only revealed the transcriptional control of melatonin-induced sodic alkaline stress tolerance, but also described a screen for key downstream transcriptional factors of melatonin through transcriptome analysis. The melatonin-induced transcriptional network of hormone, transcriptional factors and functional genes has been established under both control and stress conditions. Among these, six candidates of transcriptional factors have been identified via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Using the virus-induced gene silencing approach, we confirmed that DREB1α and IAA3 were key downstream transcriptional factors of melatonin-induced sodic alkaline stress tolerance at the genetic level. The transcriptions of DREB1α and IAA3 could be activated by melatonin or sodic alkaline treatment. Interestingly, we found that DREB1α could directly upregulate the expression of IAA3 by binding to its promoters. Moreover, several physiological processes of Na+ detoxification, dehydration resistance, high pH buffering and reactive oxygen species scavenging were confirmed to depend or partly depend on DREB1α and IAA3 pathway in melatonin-induced stress tolerance. Taken together, this study suggested that DREB1α and IAA3 are positive resistant modulators, and provided a direct link among melatonin, DREB1α and IAA3 in the sodic alkaline stress tolerance activating in tomato plants.
Source Strength Modulates Fruit Set by Starch Turnover and Export of Both Sucrose and Amino Acids in Pepper
Authors: de ï¿½vila Silva Lucas , Condori-Apfata Jorge A , Costa Paulo Mafra de Almeida , Martino Pedro Brandï¿½o , Tavares Ana C Azevedo , Marcelino Mariana Marques , Raimundi Sï¿½bata C Januï¿½rio , Picoli Edgard A de Toledo , Araï¿½jo Wagner L , Zsï¿½gï¿½n Agustin , Sulpice Ronan , Nunes-Nesi Adriano
Published: June 2019

Fruit set is an important yield-related parameter, which varies drastically due to genetic and environmental factors. Here, two commercial cultivars of Capsicum chinense (Biquinho and Habanero) were evaluated in response to light intensity (unshaded and shaded) and N supply (deficiency and sufficiency) to understand the role of source strength on fruit set at the metabolic level. We assessed the metabolic balance of primary metabolites in source leaves during the flowering period. Furthermore, we investigated the metabolic balance of the same metabolites in flowers to gain more insights into their influence on fruit set. Genotype and N supply had a strong effect on fruit set and the levels of primary metabolites, whereas light intensity had a moderate effect. Higher fruit set was mainly related to the export of both sucrose and amino acids from source leaves to flowers. Additionally, starch turnover in source leaves, but not in flowers, had a central role on the sucrose supply to sink organs at night. In flowers, our results not only confirmed the role of the daily supply of carbohydrates on fruit set but also indicated a potential role of the balance of amino acids and malate.
Nanobody stability engineering by employing the ΔTm shift; a comparison with apparent rate constants of heat-induced aggregation
Authors: Kunz Patrick , Ortale Aurelio , Mücke Norbert , Zinner Katinka , Hoheisel Jörg D
Published: June 2019

The antigen-binding domains of camelid heavy-chain antibodies, also called nanobodies, gained strong attention because of their unique functional and biophysical properties. They gave rise to an entire spectrum of applications in biotechnology, research and medicine. Despite several reports about reversibly refolding nanobodies, protein aggregation plays a major role in nanobody thermoresistance, asking for strategies to engineer their refolding behavior. Here, we use measurements of nanobody aggregation kinetics to validate structural features in the nanobody fold that are suppressing heat-induced nanobody aggregation. Furthermore, the kinetic measurements yielded a detailed insight into the concept of the ΔTm shift, a metric for protein aggregation propensities obtained from differential scanning fluorimetry measurements. By relating the equilibrium measurements of the ΔTm shift to the kinetic measurements of heat-induced nanobody aggregation, a distinct relationship could be identified that allows a prediction of nanobody aggregation rates from a simple equilibrium measurement of ΔTm.
QuantTB – A method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data
Authors: Anyansi Christine , Keo Arlin , Walker Bruce , Straub Timothy J. , Manson Abigail L. , Earl Ashlee M. , Abeel Thomas
Published: June 2019

Background

Mixed infections of Mycobacterium tuberculosis, and antibiotic heteroresistance, continue to complicate tuberculosis (TB) diagnosis and treatment. Detection of mixed infections has been limited to molecular genotyping techniques, which lack the sensitivity and resolution to accurately estimate the multiplicity of TB infections. In contrast, whole genome sequencing offers sensitive views of the genetic differences between strains of M. tuberculosis within a sample. Although metagenomic tools exist to classify strains in a metagenomic sample, most tools have been developed for more divergent species, and therefore cannot provide the sensitivity required to disentangle strains within closely related bacterial species such as M. tuberculosis.

Here we present QuantTB, a method to identify and quantify individual M. tuberculosis strains in whole genome sequencing data. QuantTB uses SNP markers to determine the combination of strains that best explain the allelic variation observed in a sample. QuantTB outputs a list of identified strains, their corresponding relative abundances, as well as a list of drugs for which resistance-conferring mutations (or heteroresistance) has been predicted within the sample.

Results

We show that QuantTB has a high degree of resolution, and is capable of differentiating communities differing by less than 25 SNPs and identifying strains down to 1× coverage. Using simulated data, we found QuantTB outperformed other metagenomic strain identification tools at detecting strains and quantifying strain multiplicity. In a real-world scenario, using a dataset of paired clinical isolates from a study of patients with either reinfections or relapses, we found that QuantTB could detect mixed infections and reinfections at rates concordant with a manually curated approach.

Conclusion

QuantTB can determine infection multiplicity, identify hetero-resistance patterns, enable differentiation between relapse and re-infection, and clarify transmission events across seemingly unrelated patients – even in low-coverage (1x) samples. QuantTB outperforms existing tools and promises to serve as a valuable resource for both clinicians and researchers working with clinical TB samples.
Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer
Authors: Langdon Ryan , Richmond Rebecca , Elliott Hannah R. , Dudding Tom , Kazmi Nabila , Penfold Chris , Ingarfield Kate , Ho Karen , Bretherick Andrew , Haley Chris , Zeng Yanni , Walker Rosie M , Pawlita Michael , Waterboer Tim , Ring Sue , Gaunt Tom , Smith George Davey , Suderman Matthew , Thomas Steve , Ness Andy , Relton Caroline
Published: June 2019

Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conduct epigenome-wide association studies (EWAS) of these factors and ∼3-year survival using Illumina Methylation EPIC blood DNA methylation profiles from 409 individuals in the Head and Neck 5000 (HN5000) study. CpG site associations below our multiple-testing threshold (PBonferroni< 0.05) with both a prognostic factor and with survival were observed in four gene regions:SPEG(smoking),GFI1(smoking),PPT2(smoking), andKHD3CL(alcohol consumption). These were further analysed using 2-step Mendelian randomization to assess whether methylation may be a causal mediator of cancer survival. Evidence for mediation was observed only in theSPEGgene region, showing an association with decreased survival (mortality HR: 1.28, 95% CI: 1.14 to 1.43,P:2.12×10−05). Replication in data from independent datasets, and from HN5000 participants with longer follow-up times is needed to confirm these findings.
Evaluation of deep-learning-based lncRNA identification tools
Authors: Yang Cheng , Zhou Man , Xie Haoling , Zhu Huaiqiu
Published: June 2019

Long non-coding RNAs (lncRNAs, length above 200 nt) exert crucial biological roles and have been implicated in cancers1,2. To characterize newly discovered transcripts, one major issue is to distinguish lncRNAs from mRNAs. Since experimental methods are time-consuming and costly, computational methods are preferred for large-scale lncRNA identification. In a recent study, Amin et al.3 evaluated three deep-learning-based lncRNA identification tools (i.e., lncRNAnet4, LncADeep5, and lncFinder6) and concluded “The LncADeep PR (precision recall) curve is just above the no-skill model and LncADeep showed poor overall performance”. This surprising conclusion is based on the authors’ use of a non-default setting of LncADeep. Actually, LncADeep has two models, one for full-length transcripts, and the other for transcripts including partial-length. Being aware of the difficulty of assembling full-length transcripts from RNA-seq dataset, LncADeep’s default model is for transcripts including partial-length. However, according to the results posted on Amin et al.’s website, the authors used LncADeep with full-length model, while they claimed to use the default setting of LncADeep, to identify lncRNAs from GENCODE dataset, which is composed of full- and partial-length transcripts. Thus, in their evaluation, the performance of LncADeep was underestimated. In this correspondence, we have tested LncADeep’s default setting (i.e., model for transcripts including partial-length) on the datasets used in Amin et al.3, and LncADeep achieved overall the best performance compared with the other tools’ results reported by Amin et al.
Proteomic studies of the Arabidopsis TRAPP complexes reveal conserved organization and a novel plant-specific component with a role in plant development
Authors: Garcia Veder J. , Xu Shou-Ling , Ravikumar Raksha , Wang Wenfei , Elliott Liam , Fesenko Mary , Altmann Melina , Falter-Braun Pascal , Moore Ian , Assaad Farhah F. , Wang Zhi-Yong
Published: June 2019

How the membrane trafficking system spatially organizes intracellular activities and intercellular signaling networks is not well understood in plants. The Transport Protein Particle (TRAPP) complexes are known to play key roles in selective delivery of membrane vesicles to various subcellular compartments in yeast and animals, but remain to be fully characterized in plants. Here we interrogate the TRAPP complexes in Arabidopsis using quantitative proteomic approaches. TRS33 is a component shared by all TRAPP complexes in yeast and animals, and the Arabidopsis AtTRS33 is essential for the subcellular dynamics of other TRAPP components. Affinity purification of AtTRS33 followed by quantitative mass spectrometry identified fourteen interacting proteins; these include not only thirteen homologs of all known TRAPP components in yeast and mammals but also a novel protein we named TRAPP-interacting plant protein (TRIPP), which is conserved in multi-cellular photosynthetic organisms. Proteomic and molecular analyses showed that TRIPP specifically associates with the TRAPPII complexin vivoand directly interacts with the TRAPPII-specific subunits but not the subunits shared with TRAPPIII. TRIPP co-localizes with a subset of TRS33 compartments, and its localization is disrupted in thetrs33mutant. Loss-of-functiontrippmutation caused growth and reproductive development defects, including partial photomorphogenesis in the dark. Our study demonstrates that plants possess at least two distinct TRAPP complexes similar to metazoan, and identifies TRIPP as a novel plant-specific component of the TRAPPII complex with important functions in plant growth and development.
H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
Authors: Cai Yichao , Zhang Ying , Loh Yan Ping , Tng Jia Qi , Lim Mei Chee , Cao Zhendong , Raju Anandhkumar , Lieberman-Aiden Erez , Li Shang , Manikandan Lakshmanan , Tergaonkar Vinay , Tucker-Kellogg Greg , Fullwood Melissa Jane
Published: June 2019

Gene repression and silencers are poorly understood. We reasoned that H3K27me3-rich regions (MRRs) of the genome defined from clusters of H3K27me3 peaks may be used to identify silencers that can regulate gene expression via proximity or looping. MRRs were associated with chromatin interactions and interact preferentially with each other. MRR component removal at interaction anchors by CRISPR led to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. The MRR knockout cells also showed changes in phenotype associated with cell identity, and altered xenograft tumor growth. MRR-associated genes and long-range chromatin interactions were susceptible to H3K27me3 depletion. Our results characterized H3K27me3-rich regions and their mechanisms of functioning via looping.
Hotspot prioritizations show sensitivity to data type
Authors: Norman Kari EA , White Ethan P
Published: June 2019

Prioritizing regions for conservation is essential for effectively allocating limited conservation resources. One of the most common approaches to prioritization is identifying regions with the highest biodiversity, or hotspots, typically using global range map data. Range maps are readily available at large scales for an array of taxa, but are also known to differ from local-scale survey data in the same regions. We examined how prioritizations may differ between range map and survey data using the North American Breeding Bird survey (BBS) and BirdLife International range maps as a case study. Hotspot prioritizations were generated for species richness and the richness of rare species at two scales.

Total species richness patterns differed substantially between data types with at most a 41% overlap in identified hotspots. Some regions had few or no hotspots for one data type and a significant number for the other. Hotspots for rare species were more similar across the data types with 44% overlap at the larger scale. Future efforts to prioritize areas for conservation should consider differences between local-scale survey data and range maps, match data to the scale of interest, and develop methods to better downscale range map-based prioritizations to the scale of conservation decisions.
The whale shark genome reveals patterns of vertebrate gene family evolution
Authors: Tan Milton , Redmond Anthony K. , Dooley Helen , Nozu Ryo , Sato Keiichi , Kuraku Shigehiro , Koren Sergey , Phillippy Adam M. , Dove Alistair D.M. , Read Timothy D.
Published: June 2019

Chondrichthyes (cartilaginous fishes) are fundamental for understanding vertebrate evolution, yet their genomes are understudied. We report long-read sequencing of the whale shark genome to generate the best gapless chondrichthyan genome assembly yet with higher contig contiguity than all other cartilaginous fish genomes, and studied vertebrate genomic evolution of ancestral gene families, immunity, and gigantism. We found a major increase in gene families at the origin of gnathostomes (jawed vertebrates) independent of their genome duplication. We studied vertebrate pathogen recognition receptors (PRRs), which are key in initiating innate immune defense, and found diverse patterns of gene family evolution, demonstrating that adaptive immunity in gnathostomes did not fully displace germline-encoded PRR innovation. We also discovered a new Toll-like receptor (TLR29) and three NOD1 copies in the whale shark. We found chondrichthyan and giant vertebrate genomes had decreased substitution rates compared to other vertebrates, but gene family expansion rates varied among vertebrate giants, suggesting substitution and expansion rates of gene families are decoupled in vertebrate genomes. Finally, we found gene families that shifted in expansion rate in vertebrate giants were enriched for human cancer-related genes, consistent with gigantism requiring adaptations to suppress cancer.
Diagnostic optical sequencing
Authors: Korshoj Lee E. , Nagpal Prashant
Published: June 2019

Advances in precision medicine require high-throughput, inexpensive, point-of-care diagnostic methods with multi-omics capability for detecting a wide range of biomolecules and their molecular variants. Optical techniques have offered many promising advances towards such diagnostics. However, the inability to squeeze light with several hundred-nanometer wavelengths into angstrom-scale volume for single nucleotide measurements has hindered further progress. Recently, a block optical sequencing (BOS) method has been shown for determining relative nucleobase content in DNA k-mer blocks with Raman spectroscopy, and a block optical content scoring (BOCS) algorithm was developed for robust content-based genetic biomarker database searching. Here, we performed BOS measurements on positively-charged silver nanoparticles to achieve 93.3% accuracy for predicting nucleobase content in DNA k-mer blocks (where k=10), as well as measurements on RNA and chemically-modified nucleobases for extensions to transcriptomic and epigenetic studies. Our high-accuracy BOS measurements were then used with BOCS to correctly identify a β-lactamase gene from the MEGARes antibiotic resistance database and confirm the Pseudomonas aeruginosa pathogen of origin from <12 content measurements (<15% coverage) of the gene. These results prove the integration of BOS/BOCS as a diagnostic optical sequencing platform. With the versatile range of available plasmonic substrates offering simple data acquisition, varying resolution (single-molecule to ensemble), and multiplexing, this optical sequencing platform has potential as the rapid, cost-effective method needed for broad-spectrum biomarker detection.
α2δ-2 protein controls structure and function at the cerebellar climbing fiber synapse
Authors: Beeson Kathleen A. , Beeson Ryne , Westbrook Gary L. , Schnell Eric
Published: June 2019

α2δ proteins (Cacna2d1-4) are auxiliary subunits of voltage-dependent calcium channels that also drive synapse formation and maturation. Because cerebellar Purkinje cells (PCs) only express one isoform of this family, α2δ-2 (Cacna2d2), we used PCs as a model system to examine roles of α2δ in excitatory synaptic function in a Cacna2d2 knockout mouse. Whole-cell recordings of PCs from acute cerebellar slices revealed altered climbing fiber (CF)-evoked complex spike generation, as well as increased amplitude and faster decay of CF-evoked excitatory postsynaptic currents (EPSCs). CF terminals in the KO were localized more proximally on PC dendrites, as indicated by VGLUT2+ immunoreactive puncta, and computational modeling demonstrated that the increased EPSC amplitude can be partly attributed to the more proximal location of CF terminals. In addition, CFs in KO mice exhibited increased multivesicular transmission, corresponding to greater sustained responses during repetitive stimulation, despite a reduction in the measured probability of release. Electron microscopy demonstrated that mutant CF terminals had twice as many vesicle release sites, providing a morphologic explanation for the enhanced glutamate release. Though KO CFs evoked larger amplitude EPSCs, the charge transfer was the same as wildtype as a result of increased glutamate re-uptake, producing faster decay kinetics. Together, the larger, faster EPSCs in the KO explain the altered complex spike responses, which degrade information transfer from PCs and likely contribute to ataxia in Cacna2d2 KO mice. Our results also illustrate the multidimensional synaptic roles of α2δ proteins.

Significance Statement

α2δ proteins (Cacna2d1-4) regulate synaptic transmission and synaptogenesis, but co-expression of multiple α2δ isoforms has obscured a clear understanding of how various α2δ proteins control synaptic function. We focused on roles of the α2δ-2 protein (Cacna2d2), whose deletion causes cerebellar ataxia and epilepsy in mice and humans. Because cerebellar Purkinje cells only expresses this single isoform, we studied excitatory climbing fiber synaptic function onto Purkinje cells in Cacna2d2 knockout mice. Using optical and electrophysiological analysis, we provide a detailed description of the changes in Purkinje cells lacking α2δ-2, and provide a comprehensive mechanistic explanation for how functional synaptic phenotypes contribute to the altered cerebellar output.
Molecular tuning of the axonal mitochondrial Ca2+ uniporter ensures metabolic flexibility of neurotransmission
Authors: Ashrafi Ghazaleh , de Juan-Sanz Jaime , Farrell Ryan , Ryan Timothy A
Published: June 2019

The brain is a vulnerable metabolic organ and must adapt to different fuel conditions to sustain function. Nerve terminals are a locus of this vulnerability but how they regulate ATP synthesis as fuel conditions vary is unknown. We show that synapses can switch from glycolytic to oxidative metabolism, but to do so, they rely on activity-driven presynaptic mitochondrial Ca2+ uptake to accelerate ATP production. We demonstrate that while in non-neuronal cells mitochondrial Ca2+ uptake requires elevated extramitochondrial Ca2+, axonal mitochondria readily take up Ca2+ in response to small changes in Ca2+. We identified the brain-specific protein MICU3 as a critical driver of this tuning of Ca2+ sensitivity. Ablation of MICU3 renders axonal mitochondria similar to non-neuronal mitochondria, prevents acceleration of local ATP synthesis, and impairs presynaptic function under oxidative conditions. Thus, presynaptic mitochondria rely on MICU3 to facilitate mitochondrial Ca2+ uptake during activity and achieve metabolic flexibility.
IBD analysis of Australian amyotrophic lateral sclerosis SOD1-mutation carriers identifies five founder events and links sporadic cases to existing ALS families
Authors: Henden Lyndal , Twine Natalie A. , Szul Piotr , McCann Emily P. , Nicholson Garth A. , Rowe Dominic B. , Kiernan Matthew C. , Bauer Denis C. , Blair Ian P. , Williams Kelly L.
Published: June 2019

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by the loss of upper and lower motor neurons resulting in paralysis and eventual death. Approximately 10% of ALS cases have a family history of disease, while the remaining cases present as apparently sporadic. Heritability studies suggest a significant genetic component to sporadic ALS, and although most sporadic cases have an unknown genetic etiology, some familial ALS mutations have also been found in sporadic cases. This suggests that some sporadic cases may be unrecognised familial cases with reduced disease penetrance. Identifying a familial basis of disease in apparently sporadic ALS cases has significant genetic counselling implications for immediate relatives. A powerful strategy to uncover a familial link is identity-by-descent (IBD) analysis which detects genomic regions that have been inherited from a common ancestor. We performed IBD analysis on 90 Australian familial ALS cases from 25 families and three sporadic ALS cases, each of whom carried one of three SOD1 mutations (p.I114T, p.V149G and p.E101G). We identified five unique haplotypes that carry these mutations in our cohort, indicative of five founder events. This included two different haplotypes that carry SOD1 p.I114T, where one haplotype was present in one sporadic case and 20 families, while the second haplotype was found in the remaining two sporadic cases and one family, thus linking these familial and sporadic cases. Furthermore, we linked two families that carry SOD1 p.V149G and found that SOD1 p.E101G arose independently in each family that carries this mutation.