bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated Testicular Recurrence of AML in Patients With Chronic GVHD >1 Year Following Allogeneic Stem Cell Transplant
Authors: Dang Brian N. , De Oliveira Satiro , Bowles LaVette , Moore Theodore B.
Published: October 2017

Background:

Patients with chronic graft-versus-host disease (cGVHD) following allogeneic transplant for myeloid leukemias seem to experience a reduced risk of relapse than comparable patients without cGVHD. It is unclear to what extent extramedullary sites are impacted by a graft-versus-leukemia effect.

Design/Method:

Case Series and review of the literature.

Results:

We present 2 cases of pediatric patients with Acute Myelogenous Leukemia who developed isolated testicular relapse more than a year following hematopoietic stem cell transplantation despite having had extensive cGVHD. Both patients were off immunosuppression and cGVHD medications when testicular relapse occurred. At time of relapse, these patients were negative for minimal residual disease in the marrow and the marrow contained all donor cells by engraftment studies. No evidence was found for lymphocyte infiltration into the affected testicle in either patient.

Conclusions:

Although a reduction of marrow relapse can be appreciated in patients with myeloid leukemias and chronic GVHD, this graft-versus-leukemia process may be less robust in extramedullary sites and careful surveillance should be maintained to allow early intervention before overt marrow involvement.
Decisional Informatics for Psychosocial Rehabilitation
Authors: Choi Jimmy , Lysaker Paul H. , Bell Morris D. , Dixon Lisa , Margolies Paul , Gold Matthew , Golden-Roose Elizabeth , Thime Warren , Haber Lawrence C. , Dewberry Michael J. , Stevens Michael , Pearlson Godfrey D. , Fiszdon Joanna M.
Published: October 2017

This study introduces a computerized clinical decision-support tool, the Fluid Outpatient Rehabilitation Treatment (FORT), that incorporates individual and ever-evolving patient needs to guide clinicians in developing and updating treatment decisions in real-time. In this proof-of-concept feasibility pilot, FORT was compared against traditional treatment planning using similar behavioral therapies in 52 adults with severe mental illness attending community-based day treatment. At posttreatment and follow-up, group differences and moderate-to-large effect sizes favoring FORT were detected in social function, work readiness, self-esteem, working memory, processing speed, and mental flexibility. Of participants who identified obtaining a General Education Diploma as their goal, 73% in FORT passed the examination compared with 18% in traditional treatment planning. FORT was also associated with higher agency cost-effectiveness and a better average benefit-cost ratio, even when considering diagnosis, baseline symptoms, and education. Although the comparison groups were not completely equivalent, the findings suggest computerized decision support systems that collaborate with human decision-makers to personalize psychiatric rehabilitation and address critical decisions may have a role in improving treatment effectiveness and efficiency.
Long-term Oncologic Outcome After Laparoscopic Converted or Primary Open Resection for Colorectal Cancer: A Systematic Review of the Literature
Authors: Furnée Edgar J.B. , Allaix Marco E. , Morino Mario
Published: October 2017

Purpose:

The aim of this study was to critically review the current evidence regarding the oncologic outcomes after laparoscopic converted or open resection for colorectal cancer.

Materials and Methods:

A literature search was performed in Pubmed. Study selection and data acquisition were independently performed by 2 reviewers.

Results:

The search strategy yielded a total of 746 articles, resulting in 7 studies eligible for inclusion. A total of 9190 (57 to 8307) patients were included in the open and 238 (17 to 56) in the converted group. In none of the studies, differences were found in disease stage between both groups. There were no significant differences between both groups with regard to overall survival, local recurrence and distant metastasis rate.

Conclusions:

There is currently insufficient evidence that patients who had a laparoscopic resection for colorectal cancer converted to open surgery have a worse oncologic outcome than patients who were primarily treated by an open approach.
Enemy recognition is linked to soldier size in a polymorphic stingless bee
Authors: Grüter Christoph , Segers Francisca H. I. D. , Santos Luana L. G. , Hammel Benedikt , Zimmermann Uwe , Nascimento Fabio S.
Published: October 2017

Many ant and termite colonies are defended by soldiers with powerful mandibles or chemical weaponry. Recently, it was reported that several stingless bee species also have soldiers for colony defence. These soldiers are larger than foragers, but otherwise lack obvious morphological adaptations for defence. Thus, how these soldiers improve colony fitness is not well understood. Robbing is common in stingless bees and we hypothesized that increased body size improves the ability to recognize intruders based on chemosensory cues. We studied the Neotropical species
Tetragonisca angustula
and found that large soldiers were better than small soldiers at recognizing potential intruders. Larger soldiers also had more olfactory pore plates on their antennae, which is likely to increase their chemosensory sensitivity. Our results suggest that improved enemy recognition might select for increased guard size in stingless bees.
Tissue loading and microstructure regulate the deformation of embedded nerve fibres: predictions from single-scale and multiscale simulations
Authors: Zarei Vahhab , Zhang Sijia , Winkelstein Beth A. , Barocas Victor H.
Published: October 2017

Excessive deformation of nerve fibres (axons) in the spinal facet capsular ligaments (FCLs) can be a cause of pain. The axons are embedded in the fibrous extracellular matrix (ECM) of FCLs, so understanding how local fibre organization and micromechanics modulate their mechanical behaviour is essential. We constructed a computational discrete-fibre model of an axon embedded in a collagen fibre network attached to the axon by distinct fibre–axon connections. This model was used to relate the axonal deformation to the fibre alignment and collagen volume concentration of the surrounding network during transverse, axial and shear deformations. Our results showed that fibre alignment affects axonal deformation only during transverse and axial loading, but higher collagen volume concentration results in larger overall axonal strains for all loading cases. Furthermore, axial loading leads to the largest stretch of axonal microtubules and induces the largest forces on axon's surface in most cases. Comparison between this model and a multiscale continuum model for a representative case showed that although both models predicted similar averaged axonal strains, strain was more heterogeneous in the discrete-fibre model.
A dynamically diluted alignment model reveals the impact of cell turnover on the plasticity of tissue polarity patterns
Authors: Hoffmann Karl B. , Voss-Böhme Anja , Rink Jochen C. , Brusch Lutz
Published: October 2017

The polarization of cells and tissues is fundamental for tissue morphogenesis during biological development and regeneration. A deeper understanding of biological polarity pattern formation can be gained from the consideration of pattern reorganization in response to an opposing instructive cue, which we here consider using the example of experimentally inducible body axis inversions in planarian flatworms. We define a dynamically diluted alignment model linking three processes: entrainment of cell polarity by a global signal, local cell–cell coupling aligning polarity among neighbours, and cell turnover replacing polarized cells by initially unpolarized cells. We show that a persistent global orienting signal determines the final mean polarity orientation in this stochastic model. Combining numerical and analytical approaches, we find that neighbour coupling retards polarity pattern reorganization, whereas cell turnover accelerates it. We derive a formula for an effective neighbour coupling strength integrating both effects and find that the time of polarity reorganization depends linearly on this effective parameter and no abrupt transitions are observed. This allows us to determine neighbour coupling strengths from experimental observations. Our model is related to a dynamic 8-Potts model with annealed site-dilution and makes testable predictions regarding the polarization of dynamic systems, such as the planarian epithelium.
Optimal dynamic soaring consists of successive shallow arcs
Authors: Bousquet Gabriel D. , Triantafyllou Michael S. , Slotine Jean-Jacques E.
Published: October 2017

Albatrosses can travel a thousand kilometres daily over the oceans. They extract their propulsive energy from horizontal wind shears with a flight strategy called dynamic soaring. While thermal soaring, exploited by birds of prey and sports gliders, consists of simply remaining in updrafts, extracting energy from horizontal winds necessitates redistributing momentum across the wind shear layer, by means of an intricate and dynamic flight manoeuvre. Dynamic soaring has been described as a sequence of half-turns connecting upwind climbs and downwind dives through the surface shear layer. Here, we investigate the optimal (minimum-wind) flight trajectory, with a combined numerical and analytic methodology. We show that contrary to current thinking, but consistent with GPS recordings of albatrosses, when the shear layer is thin the optimal trajectory is composed of small-angle, large-radius arcs. Essentially, the albatross is a flying sailboat, sequentially acting as sail and keel, and is most efficient when remaining crosswind at all times. Our analysis constitutes a general framework for dynamic soaring and more broadly energy extraction in complex winds. It is geared to improve the characterization of pelagic birds flight dynamics and habitat, and could enable the development of a robotic albatross that could travel with a virtually infinite range.
A 20-year investigation of declining leatherback hatching success: implications of climate variation
Authors: Rafferty Anthony R. , Johnstone Christopher P. , Garner Jeanne A. , Reina Richard D.
Published: October 2017

Unprecedented increases in air temperature and erratic precipitation patterns are predicted throughout the twenty-first century as a result of climate change. A recent global analysis of leatherback turtle hatchling output predicts that the nesting site at Sandy Point National Wildlife Refuge (SPNWR) will experience the most significant regional climate alterations. We aimed to identify how local air temperatures and precipitation patterns influenced within-nest mortality and overall hatchling output at this site between 1990 and 2010. We show that while the greatest mortality occurred during the latest stages of development (stage three), the rate of embryo mortality was highest during the initial stages (stage zero) of development (approx. 3.8 embryos per day per clutch). Increased mortality at stage three was associated with decreased precipitation and increased temperature during this developmental period, whereas precipitation prior to, and during stage zero had the greatest influence on early mortality. There was a significant decline in overall hatching success (falling from 74% to 55%) and emergence rate (calculated from the number of hatchlings that emerged from the nest as a percentage of hatched eggs) which fell from 96% to 91%. However, there was no trend observed in local temperature or precipitation during this timeframe, and neither variable was related to hatching success or emergence rate. In conclusion, our findings suggest that despite influencing within-nest mortality, climatic variability does not account for the overall decline in hatchling output at SPNWR from 1990 to 2010. Further research is therefore needed to elicit the reasons for this decline.
The Electric Honeycomb; an investigation of the Rose window instability
Authors: Niazi Muhammad Shaheer
Published: October 2017

The Rose window instability is a little-explored electrohydrodynamic instability that manifests when a layer of low-conducting oil is placed in an electric field generated by corona discharge in a point-to-plane configuration. Above a critical voltage, the instability starts as a single dimple in the oil layer right below the point electrode and subsequently evolves into a characteristic pattern of polygonal cells. In this study, we experimentally explore governing parameters that guide the instability and document geometric attributes of the characteristic cellular pattern. The driving force for the instability has been attributed to the buildup of charged ions which in turn apply an electric pressure on the oil surface. We confirm the charged surface distribution using thermal imaging and demonstrate that the instability can be locally inhibited by preventing charge buildup under an ion shadow.
Modelling wave-induced sea ice break-up in the marginal ice zone
Authors: Montiel F. , Squire V. A.
Published: October 2017

A model of ice floe break-up under ocean wave forcing in the marginal ice zone (MIZ) is proposed to investigate how floe size distribution (FSD) evolves under repeated wave break-up events. A three-dimensional linear model of ocean wave scattering by a finite array of compliant circular ice floes is coupled to a flexural failure model, which breaks a floe into two floes provided the two-dimensional stress field satisfies a break-up criterion. A closed-feedback loop algorithm is devised, which (i) solves the wave-scattering problem for a given FSD under time-harmonic plane wave forcing, (ii) computes the stress field in all the floes, (iii) fractures the floes satisfying the break-up criterion, and (iv) generates an updated FSD, initializing the geometry for the next iteration of the loop. The FSD after 50 break-up events is unimodal and near normal, or bimodal, suggesting waves alone do not govern the power law observed in some field studies. Multiple scattering is found to enhance break-up for long waves and thin ice, but to reduce break-up for short waves and thick ice. A break-up front marches forward in the latter regime, as wave-induced fracture weakens the ice cover, allowing waves to travel deeper into the MIZ.
The growth of finfish in global open-ocean aquaculture under climate change
Authors: Klinger Dane H. , Levin Simon A. , Watson James R.
Published: October 2017

Aquaculture production is projected to expand from land-based operations to the open ocean as demand for seafood grows and competition increases for inputs to land-based aquaculture, such as freshwater and suitable land. In contrast to land-based production, open-ocean aquaculture is constrained by oceanographic factors, such as current speeds and seawater temperature, which are dynamic in time and space, and cannot easily be controlled. As such, the potential for offshore aquaculture to increase seafood production is tied to the physical state of the oceans. We employ a novel spatial model to estimate the potential of open-ocean finfish aquaculture globally, given physical, biological and technological constraints. Finfish growth potential for three common aquaculture species representing different thermal guilds—Atlantic salmon (
Salmo salar
), gilthead seabream (
Sparus aurata
) and cobia (
Rachycentron canadum
)—is compared across species and regions and with climate change, based on outputs of a high-resolution global climate model. Globally, there are ample areas that are physically suitable for fish growth and potential expansion of the nascent aquaculture industry. The effects of climate change are heterogeneous across species and regions, but areas with existing aquaculture industries are likely to see increases in growth rates. In areas where climate change results in reduced growth rates, adaptation measures, such as selective breeding, can probably offset potential production losses.
Morphological integration in the appendicular skeleton of two domestic taxa: the horse and donkey
Authors: Hanot Pauline , Herrel Anthony , Guintard Claude , Cornette Raphaël
Published: October 2017

Organisms are organized into suites of anatomical structures that typically covary when developmentally or functionally related, and this morphological integration plays a determinant role in evolutionary processes. Artificial selection on domestic species causes strong morphological changes over short time spans, frequently resulting in a wide and exaggerated phenotypic diversity. This raises the question of whether integration constrains the morphological diversification of domestic species and how natural and artificial selection may impact integration patterns. Here, we study the morphological integration in the appendicular skeleton of domestic horses and donkeys, using three-dimensional geometric morphometrics on 75 skeletons. Our results indicate that a strong integration is inherited from developmental mechanisms which interact with functional factors. This strong integration reveals a specialization in the locomotion of domestic equids, partly for running abilities. We show that the integration is stronger in horses than in donkeys, probably because of a greater degree of specialization and predictability of their locomotion. Thus, the constraints imposed by integration are weak enough to allow important morphological changes and the phenotypic diversification of domestic species.
Novel and divergent genes in the evolution of placental mammals
Authors: Dunwell Thomas L. , Paps Jordi , Holland Peter W. H.
Published: October 2017

Analysis of genome sequences within a phylogenetic context can give insight into the mode and tempo of gene and protein evolution, including inference of gene ages. This can reveal whether new genes arose on particular evolutionary lineages and were recruited for new functional roles. Here, we apply MCL clustering with all-versus-all reciprocal BLASTP to identify and phylogenetically date ‘Homology Groups’ among vertebrate proteins. Homology Groups include new genes and highly divergent duplicate genes. Focusing on the origin of the placental mammals within the Eutheria, we identify 357 novel Homology Groups that arose on the stem lineage of Placentalia, 87 of which are deduced to play core roles in mammalian biology as judged by extensive retention in evolution. We find the human homologues of novel eutherian genes are enriched for expression in preimplantation embryo, brain, and testes, and enriched for functions in keratinization, reproductive development, and the immune system.
Chromatin organization by an interplay of loop extrusion and compartmental segregation
Authors: Nuebler Johannes , Fudenberg Geoffrey , Imakaev Maxim , Abdennur Nezar , Mirny Leonid
Published: October 2017

Mammalian chromatin is organized on length scales ranging from individual nucleosomes to chromosomal territories. At intermediate scales two dominant features emerge in interphase: (i) alternating regions (<5Mb) of active and inactive chromatin that spatially segregate into different compartments, and (ii) domains (<1Mb), i.e. regions that preferentially interact internally, which are also termed topologically associating domains (TADs) and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartments are established by a phase separation process according to local chromatin states. Here we use polymer simulations to examine how the two processes, loop extrusion and compartmental segregation, work collectively and potentially interfere in shaping global chromosome organization. Our integrated model faithfully reproduces Hi-C data from previously puzzling experimental observations, where targeting of the TAD-forming machinery led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed hidden, finer compartments, while increased processivity of cohesin led to stronger TADs and reduced compartmentalization, and depletion of the TAD boundary protein, CTCF, weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. This also predicts that interference with chromatin epigenetic states or nuclear volume would affect compartments but not TADs. Our results suggest that chromatin organization on the megabase scale emerges from competition of non-equilibrium active loop extrusion and epigenetically defined compartment structure.
Comparative Transcriptomics of Mango (Mangifera indica L.) Cultivars Provide Insights of Biochemical Pathways Involved in Flavor and Color
Authors: Khan Waqasuddin , Razzak Safina Abdul , Kamran Azim M.
Published: October 2017

Mango is an economically important fruit crop of many tropical and subtropical countries. Recently, leaf and fruit transcriptomes of mango cultivars grown in different geographical regions have characterized. Here, we presented comparative transcriptome analysis of four mango cultivars i.e. cv. Langra, cv. Zill, cv. Shelly and cv. Kent from Pakistan, China, Israel and Mexico respectively. De-novo sequence assembly generated 30,953-85,036 unigenes from RNASeq datasets of mango cultivars. KEGG pathway mapping of mango unigenes identified terpenoids, flavonoids and carotenoids biosynthetic pathways involved in flavor and color. The analysis revealed linalool as major monoterpenoid found in all cultivars studied whereas, monoterpene α-terpineol was specifically found in cv. Shelly. Ditepene gibberellin biosynthesis pathway was found in all cultivars whereas, homoterpene synthase involved in biosynthesis of 4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT; an insect induced diterpene) was found in cv. Kent. Among sesquiterpenes and triterpenes, biosynthetic pathway of Germacrene-D, an antibacterial and anti-insecticidal metabolite was found in cv. Zill and cv. Shelly. Two bioactive triterpenes, lupeol and β-amyrin were found in cv. Langra and cv. Zill. Unigenes involved in biosynthesis of carotenoids, β-carotene and lycopene, were found in cultivars studied. Many unigenes involved in flavonoid biosynthesis were also found. Comparative transcriptomics revealed naringenin (an anti-inflammatory and antioxidant metabolite) as ‘central’ flavanone responsible for biosynthesis of an array of flavonoids. The present study provided insights on genetic resources responsible for flavor and color of mango fruit.
IRF4 haploinsufficiency in a family with Whipple’s disease
Authors: Guérin Antoine , Kerner Gaspard , Marr Nico , Markle Janet G. , Fenollar Florence , Wong Natalie , Boughorbel Sabri , Avery Danielle T. , Ma Cindy S. , Bougarn Salim , Bouaziz Matthieu , Beziat Vivien , Della Mina Erika , Lazarovt Tomi , Worley Lisa , Nguyen Tina , Patin Etienne , Deswarte Caroline , Martinez-Barricarte Rubén , Boucherit Soraya , Ayral Xavier , Edouard Sophie , Boisson-Dupuis Stéphanie , Rattina Vimel , Bigio Benedetta , Vogt Guillaume , Geissmann Frédéric , Quintana-Murci Lluis , Chaussabel Damien , Tangye Stuart G. , Raoult Didier , Abel Laurent , Bustamante Jacinta , Casanova Jean-Laurent
Published: October 2017

The pathogenesis of Whipple’s disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected withTropheryma whipplei(Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant ofIRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rareIRF4alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found thatIRF4had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at theIRF4locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.
Structural Basis for Katanin Self-Assembly
Authors: Nithiananatham Stanley , McNally Francis J. , Al-Bassam Jawdat
Published: October 2017

The reorganization of microtubules in mitosis, meiosis and development requires the microtubule-severing activity of katanin. Katanin is composed of a AAA ATPase subunit and a regulatory subunit. Microtubule severing requires ATP hydrolysis by katanin’s conserved AAA ATPase domains. Whereas other AAA ATPases form stable hexamers, we show that wild-type katanin only forms heterodimers and heterotetramers. Heterododecamers were only observed for an ATP hydrolysis deficient mutant in the presence of ATP, suggesting an auto-inhibition mechanism that prevents oligomerization. X-ray structures of katanin’s AAA ATPase in monomeric nucleotide-free and pseudo-oligomeric ADP-bound states reveal conformational changes in AAA subdomains and N and C-terminal expansion segments that explain this auto-inhibition of assembly. These data lead to a model in which self-inhibited heterodimers bind to a microtubule, then transition into an assembly-competent conformation upon ATP binding. Microtubule-bound heterododecamers then promote tubulin extraction from the microtubule prior to oligomer dissociation.
Classification and Mutation Prediction from Non-Small Cell Lung Cancer Histopathology Images using Deep Learning
Authors: Coudray Nicolas , Moreira Andre L. , Sakellaropoulos Theodore , Fenyö David , Razavian Narges , Tsirigos Aristotelis
Published: October 2017

Visual analysis of histopathology slides of lung cell tissues is one of the main methods used by pathologists to assess the stage, types and sub-types of lung cancers. Adenocarcinoma and squamous cell carcinoma are two most prevalent sub-types of lung cancer, but their distinction can be challenging and time-consuming even for the expert eye. In this study, we trained a deep learning convolutional neural network (CNN) model (inception v3) on histopathology images obtained from The Cancer Genome Atlas (TCGA) to accurately classify whole-slide pathology images into adenocarcinoma, squamous cell carcinoma or normal lung tissue. Our method slightly outperforms a human pathologist, achieving better sensitivity and specificity, with ∼0.97 average Area Under the Curve (AUC) on a held-out population of whole-slide scans. Furthermore, we trained the neural network to predict the ten most commonly mutated genes in lung adenocarcinoma. We found that six of these genes – STK11, EGFR, FAT1, SETBP1, KRAS and TP53 – can be predicted from pathology images with an accuracy ranging from 0.733 to 0.856, as measured by the AUC on the held-out population. These findings suggest that deep learning models can offer both specialists and patients a fast, accurate and inexpensive detection of cancer types or gene mutations, and thus have a significant impact on cancer treatment.
Mitochondrial Methylation Two-Peak Profile Absent in Parkinson’s Disease Patient
Authors: Valente André X. C. N. , Liao Qiwen , Rohkin Guy , Bouça-Machado Raquel , Guedes Leonor Correia , Ferreira Joaquim J. , Lee Simon Ming-Yuen
Published: October 2017

Whole-mitochondrial genome methylation profiles were obtained for mitochondrial DNA (mtDNA) from blood samples of one sporadic Parkinson’s Disease (PD) patient and one healthy control donor, via Whole-Genome Next-Generation Bisulfite Sequencing. Methylation frequency was determined at 836 CpG sites out of the 1146 CpG sites in mtDNA (73% of the total). The control mtDNA methylation profile exhibited a two-peak frequency distribution, with most CpG sites showing either no methylation, or a methylation above 7%. Instead, the sporadic PD mtDNA methylation profile exhibited a generic bell-shaped frequency distribution. The data is suggestive of the bell-shaped methylation profile arising via a degradation towards randomness of the healthy sample two-peak methylation pattern. Overall, this finding provides a possible explanation for the repeated observation of PD-phenotypic characteristics in cybrid cell lines where solely the mtDNA originates from a PD patient. We discuss the finding in terms of the sporadic PD Hematopoietic Origin Theory (HOT).
Comparative analysis of the genomes ofStylophora pistillataandAcropora digitiferaprovides evidence for extensive differences between species of corals
Authors: Voolstra Christian R , Li Yong , Liew Yi Jin , Baumgarten Sebastian , Zoccola Didier , Flot Jean-François , Tambutte Sylvie , Allemand Denis , Aranda Manuel
Published: October 2017

Stony corals form the foundation of coral reef ecosystems. Their phylogeny is characterized by a deep evolutionary divergence that separates corals into a robust and complex clade dating back to at least 245 mya. However, the genomic consequences and clade-specific evolution remain unexplored. In this study we have produced the genome of a robust coral,Stylophora pistillata, and compared it to the available genome of a complex coral,Acropora digitifera. We conducted a fine-scale gene-based analysis focusing on ortholog groups. Among the core set of conserved proteins, we found an emphasis on processes related to the cnidarian-dinoflagellate symbiosis. Similarly, genes associated with the algal symbiosis were also independently expanded in both species, but both corals diverged on the identity of ortholog groups expanded, and we found uneven expansions in genes associated with innate immunity and stress response. Our analyses demonstrate that coral genomes can be surprisingly disparate. Importantly, if the patterns elucidated here are representative of differences between corals from the robust and complex clade, the ability of a coral to respond to climate change may be dependent on its clade association.
The cohesin ring uses its hinge to organize DNA using non-topological as well as topological mechanisms
Authors: Srinivasan Madhusudhan , Scheinost Johanna C. , Petela Naomi J. , Gligoris Thomas G. , Wissler Maria , Ogushi Sugako , Collier James , Voulgaris Menelaos , Kurze Alexander , Chan Kok-Lung , Hu Bin , Costanzo Vincenzo , Nasmyth Kim A.
Published: October 2017

As predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is a perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion in a large variety of mutants. In most cells where cohesin loads onto chromosomes but fails to form cohesion, loading is accompanied by entrapment of individual DNAs. However, cohesin with a hinge domain whose positively charged lumen has been neutralized not only loads onto and translocates along chromatin but also organizes it into chromatid-like threads, despite largely failing to entrap DNAs inside its ring. Thus, cohesin engages chromatin in a non-topological as well as a topological manner. Our finding that hinge mutations, but not fusions between Smc and kleisin subunits, abolish entrapment suggests that DNAs may enter cohesin rings through hinge opening. Lastly, mutation of three highly conserved lysine residues inside the Smc1 moiety of Smc1/3 hinges abolishes all loading without affecting cohesin’s initial recruitment toCENloading sites or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesin’s hinge driven by cycles of ATP hydrolysis.
Profiling and leveraging relatedness in a precision medicine cohort of 92,455 exomes
Authors: Staples Jeffrey , Maxwell Evan K. , Gosalia Nehal , Gonzaga-Jauregui Claudia , Snyder Christopher , Hawes Alicia , Penn John , Ulloa Ricardo , Bai Xiadong , Lopez Alexander E. , Van Hout Cristopher V. , O’Dushlaine Colm , Teslovich Tanya M. , McCarthy Shane E. , Balasubramanian Suganthi , Kirchner H. Lester , Leader Joseph B. , Murray Michael F. , Ledbetter David H. , Shuldiner Alan R. , Yancoupolos George , Dewey Frederick E. , Carey David J. , Overton John D. , Baras Aris , Habegger Lukas , Reid Jeffrey G.
Published: October 2017

Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in-line with expectations given the underlying population and ascertainment approach. For example, we identified ∼66,000 close (first- and second-degree) relationships within DiscovEHR involving 55.6% of study participants. Our simulation results project that >70% of the cohort will be involved in these close relationships as DiscovEHR scales to 250,000 recruited individuals. We reconstructed 12,574 pedigrees using these relationships (including 2,192 nuclear families) and leveraged them for multiple applications. The pedigrees substantially improved the phasing accuracy of 20,947 rare, deleterious compound heterozygous mutations. Reconstructed nuclear families were critical for identifying 3,415de novomutations in ∼1,783 genes. Finally, we demonstrate the segregation of known and suspected disease-causing mutations through reconstructed pedigrees, including a tandem duplication inLDLRcausing familial hypercholesterolemia. In summary, this work highlights the prevalence of cryptic relatedness expected among large healthcare population genomic studies and demonstrates several analyses that are uniquely enabled by large amounts of cryptic relatedness.
Association Analysis and Meta-Analysis of Multi-allelic Variants for Large Scale Sequence Data
Authors: Zhan Xiaowei , Chen Sai , Jiang Yu , Liu Mengzhen , Iacono William G. , Hewitt John K. , Hokanson John E , Krauter Kenneth , Laakso Markku , Li Kevin W. , Lutz Sharon M , McGue Matthew , Pandit Anita , Zajac Gregory JM , Boehnke Michael , Abecasis Goncalo R. , Jiang Bibo , Vrieze Scott I. , Liu Dajiang J.
Published: October 2017

Motivation:

There is great interest to understand the impact of rare variants in human diseases using large sequence datasets. In deep sequences datasets of >10,000 samples, ∼10% of the variant sites are observed to be multi-allelic. Many of the multi-allelic variants have been shown to be functional and disease relevant. Proper analysis of multi-allelic variants is critical to the success of a sequencing study, but existing methods do not properly handle multi-allelic variants and can produce highly misleading association results.

Results:

We propose novel methods to encode multi-allelic sites, conduct single variant and gene-level association analyses, and perform meta-analysis for multi-allelic variants. We evaluated these methods through extensive simulations and the study of a large meta-analysis of ∼18,000 samples on the cigarettes-per-day phenotype. We showed that our joint modeling approach provided an unbiased estimate of genetic effects, greatly improved the power of single variant association tests, and enhanced gene-level tests over existing approaches.

Availability:

Software packages implementing these methods are available at (https://github.com/zhanxw/rvtestshttp://genome.sph.umich.edu/wiki/RareMETAL).

Contact:

xiaowei.zhan@utsouthwestem.edu; dajiang.liu@psu.edu
RES complex is associated with intron definition and required for zebrafish early embryogenesis
Authors: Fernandez Juan P. , Moreno-Mateos Miguel A. , Gohr Andre , Chan Shun Hang , Irimia Manuel , Giraldez Antonio J.
Published: October 2017

Pre-mRNA splicing is a critical step of gene expression in eukaryotes. Transcriptome-wide splicing patterns are complex and primarily regulated by a diverse set of recognition elements and associated RNA-binding proteins. The retention and splicing (RES) complex is formed by three different proteins (Bud13p, Pml1p and Snu17p) and is involved in splicing in yeast. However, the importance of the RES complex for vertebrate splicing, the intronic features associated with its activity, and its role in development are unknown. In this study, we have generated loss-of-function mutants for the three components of the RES complex in zebrafish and showed that they are required during early development. The mutants showed a marked neural phenotype with increased cell death in the brain and a decrease in differentiated neurons. Transcriptomic analysis ofbud13,snip1(pml1) andrbmx2(snu17) mutants revealed a global defect in intron splicing, with strong mis-splicing of a subset of introns. We found these RES-dependent introns were short, rich in GC and flanked by GC depleted exons, all of which are features associated with intron definition. Using these features we developed a predictive model that classifies RES dependent introns. Altogether, our study uncovers the essential role of the RES complex during vertebrate development and provides new insights into its function during splicing.
Networks of genetic similarity reveal non-neutral processes shape strain structure inPlasmodium falciparum
Authors: He Qixin , Pilosof Shai , Tiedje Kathryn E. , Ruybal-Pesántez Shazia , Artzy-Randrup Yael , Baskerville Edward B. , Day Karen P. , Pascual Mercedes
Published: October 2017

Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. InPlasmodium falciparummalaria, thevarmultigene family encoding for the major blood-stage antigenPfEMP1 has evolved enormous genetic diversity through ectopic recombination and mutation. With 50-60vargenes per genome, it is unclear whether immune selection can act as a dominant force in structuringvarrepertoires of local populations. The combinatorial complexity of thevarsystem remains beyond the reach of existing strain theory, and previous evidence for non-random structure cannot demonstrate immune selection without comparison to neutral models. We develop two neutral models that encompass malaria epidemiology but exclude competitive interactions between parasites. These models, combined with networks of genetic similarity, reveal non-neutral strain structure in both simulated systems and an extensively sampled population in Ghana. The unique population structure we identify underlies the large transmission reservoir characteristic of highly endemic regions in Africa.
A feed-forward relay between Bicoid and Orthodenticle regulates the timing of embryonic patterning inDrosophila
Authors: Datta Rhea R. , Ling Jia , Kurland Jesse , Ren Xiaotong , Xu Zhe , Yucel Gozde , Moore Jackie , Shokri Leila , Baker Isabel , Bishop Timothy , Struffi Paolo , Levina Rimma , Bulyk Martha L. , Johnston Robert J. , Small Stephen
Published: October 2017

The K50 homeodomain (K50HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. InDrosophila melanogaster, another K50HD protein, Bicoid (Bcd), has evolved to replace Otd’s ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes includingotd. Otd and Bcd bind similar DNA sequencesin vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd, and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd, and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd, and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development.
The 3D characteristics of post-traumatic syringomyelia in a rat model: a propagation-based synchrotron radiation microtomography study
Authors: Liao Shenghui , Ni Shuangfei , Cao Yong , Yin Xianzhen , Wu Tianding , Lu Hongbin , Hu Jianzhong , Wu Hao , Lang Ye
Published: October 2017

Many published literature sources have described the histopathological characteristics of post-traumatic syringomyelia (PTS). However, three-dimensional (3D) visualization studies of PTS have been limited due to the lack of reliable 3D imaging techniques. In this study, the imaging efficiency of propagation-based synchrotron radiation microtomography (PB-SRµCT) was determined to detect the 3D morphology of the cavity and surrounding microvasculature network in a rat model of PTS. The rat model of PTS was established using the infinite horizon impactor to produce spinal cord injury (SCI), followed by a subarachnoid injection of kaolin to produce arachnoiditis. PB-SRµCT imaging and histological examination, as well as fluorescence staining, were conducted on the animals at the tenth week after SCI. The 3D morphology of the cystic cavity was vividly visualized using PB-SRµCT imaging. The quantitative parameters analyzed by PB-SRµCT, including the lesion and spared spinal cord tissue area, the minimum and maximum diameters in the cystic cavity, and cavity volume, were largely consistent with the results of the histological assessment. Moreover, the 3D morphology of the cavity and surrounding angioarchitecture could be simultaneously detected on the PB-SRµCT images. This study demonstrated that high-resolution PB-SRµCT could be used for the 3D visualization of trauma-induced spinal cord cavities and provides valuable quantitative data for cavity characterization. PB-SRµCT could be used as a reliable imaging technique and offers a novel platform for tracking cavity formation and morphological changes in an experimental animal model of PTS.
The effect of self-consistent potentials on EXAFS analysis
Authors: Ravel B. , Newville M. , Kas J. J. , Rehr J. J.
Published: October 2017

A theory program intended for use with extended X-ray-absorption fine structure (EXAFS) spectroscopy and based on the popularFEFF8is presented. It provides an application programming interface designed to make it easy to integrate high-quality theory into EXAFS analysis software. This new code is then used to examine the impact of self-consistent scattering potentials on EXAFS data analysis by methodical testing of theoretical fitting standards against a curated suite of measured EXAFS data. For each data set, the results of a fit are compared using a well characterized structural model and theoretical fitting standards computed both with and without self-consistent potentials. It is demonstrated that the use of self-consistent potentials has scant impact on the results of the EXAFS analysis.
Anger following provocation in individuals with psychopathic traits
Authors: Steuerwald Brian L. , Brown Allison R. , Mneimne Malek , Kosson David
Published: October 2017

Purpose

The purpose of this paper is to test the attenuated-anger and heightened-anger hypotheses of psychopathy by assessing the physiological, behavioral, and subjective measures of anger in individuals with and without psychopathic traits.

Design/methodology/approach

In all, 62 male college students were assigned to one of three groups based on evidence of elevated affective-interpersonal (Factor 1) and antisocial lifestyle (Factor 2) traits associated with psychopathy (the IF1+F2 group), evidence of only Factor 2 traits (the F2 only group), or based on the absence of psychopathic traits (the control group), using Gough’s (1957) Socialization scale and a modified, interview only form of Hare’s (1991) Psychopathy Checklist-Revised. To induce anger, participants received unjust criticism about their performance on a computer-based affective lexical decision task and were denied a performance bonus they had reason to expect.

Findings

Following provocation, the three groups displayed similar increases in blood pressure, pulse, and self-reported anger. The control and IF1+F2 groups also displayed similar retaliation toward the confederate. However, the IF1+F2 group displayed smaller increases on two of three measures of facial muscle activity associated with anger.

Originality/value

This study is one of the first to assess anger responsiveness in individuals with psychopathic traits using a powerful anger induction and using physiological, behavioral, and subjective indices of anger. It is also the first to assess both the attenuated-anger and the heightened-anger hypotheses of psychopathy. The findings appear largely inconsistent with both perspectives.
Understanding researchers’ intention to publish in open access journals
Authors: Moksness Lars , Olsen Svein Ottar
Published: October 2017

Purpose

The purpose of this paper is to understand how attitudes, norms (injunctive and descriptive) and perceived behavioral control (PBC) (capacity and autonomy) influence the intention to publish open access (OA), and how personal innovativeness in information technology affects attitude and PBC.

Design/methodology/approach

This study employs an integrated and extended theory of planned behavior (TPB) framework within a cross-sectional survey design. The sample consists of researchers at a Norwegian university, and data are collected digitally via e-mail invitation and analyzed using structural equation modeling.

Findings

This study determines that attitude is the strongest predictor of the intention to publish OA, followed by injunctive and descriptive social norms, and PBC capacity and autonomy. All factors positively influence intention apart from PBC autonomy, which has a negative effect.

Research limitations/implications

Potential limitations include: a relatively small sample size, self-reported data and employing intention, not behavior, as the ultimate dependent variable.

Practical implications

This research contributes with a deeper understanding of what drives the intention to publish OA research articles, and how innovativeness affects attitudes and PBC autonomy. Support is found for an extended TPB model with decomposed normative and PBC components. This knowledge is essential in creating an impetus for systematic research on OA publishing behavior.

Originality/value

Theory-driven research into understanding OA publishing behavior is rare. Decomposing the normative and PBC constructs is uncommon in TPB research, and a novel approach in OA research. Personal innovativeness has not been explored previously in relation to OA publishing.