bluuebunny/crossref_metadata_2025 huggingface dataset:
Illuminating the Anthropocene: Ecopoetic Explorers at the Edge of the Naturecultures Abyss
Authors: Quetchenbach Bernard
Published: March 2019

This essay-review considers three recent ecocritical texts that examine the environmental imagination at work in contemporary North American experimental ecopoetry. Compensating for decades of ecocritical neglect, the scholars represented by these volumes turn their attention to experimental poetry of the late twentieth and early twenty-first centuries. Special attention is focused on the work of poets attempting to synthesize art and science, and to develop poetics as a means to forge and communicate new links between species. Striving to incorporate environmental systems into poetic structures, contemporary ecopoets promote a crucial role and an ambitious agenda for the genre. Spurred by the Anthropocene imperative to reconfigure relationships between human and nonhuman, civilization and planet, nature and culture, experimental ecopoets create art that is both playful and urgent, but often difficult and obscure. The criticism gathered in these texts provides timely and much-needed theory and context illuminating a vibrant and important movement, or series of related movements, meant to equip both poetry and human culture for coping with the challenges posed by Anthropocene conditions and necessities.
Gasotransmitters in pregnancy: from conception to uterine involution†
Authors: Guerra Damian D , Hurt K Joseph
Published: March 2019

Gasotransmitters are endogenous small gaseous messengers exemplified by nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S or sulfide). Gasotransmitters are implicated in myriad physiologic functions including many aspects of reproduction. Our objective was to comprehensively review basic mechanisms and functions of gasotransmitters during pregnancy from conception to uterine involution and highlight future research opportunities. We searched PubMed and Web of Science databases using combinations of keywords nitric oxide, carbon monoxide, sulfide, placenta, uterus, labor, and pregnancy. We included English language publications on human and animal studies from any date through August 2018 and retained basic and translational articles with relevant original findings. All gasotransmitters activate cGMP signaling. NO and sulfide also covalently modify target protein cysteines. Protein kinases and ion channels transduce gasotransmitter signals, and co-expressed gasotransmitters can be synergistic or antagonistic depending on cell type. Gasotransmitters influence tubal transit, placentation, cervical remodeling, and myometrial contractility. NO, CO, and sulfide dilate resistance vessels, suppress inflammation, and relax myometrium to promote uterine quiescence and normal placentation. Cervical remodeling and rupture of fetal membranes coincide with enhanced oxidation and altered gasotransmitter metabolism. Mechanisms mediating cellular and organismal changes in pregnancy due to gasotransmitters are largely unknown. Altered gasotransmitter signaling has been reported for preeclampsia, intrauterine growth restriction, premature rupture of membranes, and preterm labor. However, in most cases specific molecular changes are not yet characterized. Nonclassical signaling pathways and the crosstalk among gasotransmitters are emerging investigation topics.
Risk of Malignant Cancers in Inflammatory Bowel Disease
Authors: Loo Simone Y , Vutcovici Maria , Bitton Alain , Lakatos Peter L , Azoulay Laurent , Suissa Samy , Brassard Paul
Published: March 2019

Objectives

To explore the trends and the predictors of incident malignant cancer among patients with inflammatory bowel disease [IBD].

Methods

We identified a cohort of all patients with incident IBD in Quebec, Canada, from 1998 to 2015, using provincial administrative health-care databases [RAMQ and Med-Echo]. Annual incidence rates [IRs] of cancer were calculated using Poisson regression and were compared with those of the Quebec population using standardized incidence ratios [SIRs ]. Temporal trends in these rates were evaluated by fitting generalized linear models. Conditional logistic regression was used to estimate odds ratios [ORs] for predictors associated with cancer development.

Results

The cohort included 35 985 patients with IBD, of which 2275 developed cancers over a mean follow-up of 8 years (IR 785.6 per 100 000 persons per year; 95% confidence interval [CI] 754.0–818.5). The rate of colorectal cancer decreased significantly from 1998 to 2015 [p < 0.05 for linear trend], but the incidence remained higher than expected, compared with the Quebec population [SIR 1.39; 95% CI 1.19–1.60]. Rates of extraintestinal cancers increased non-significantly over time [p = 0.11 for linear trend]. In the IBD cohort, chronic kidney disease [OR 1.29; 95% CI 1.17–1.43], respiratory diseases [OR 1.07; 95% CI 1.02–1.12], and diabetes mellitus [OR 1.06; 95% CI 1.01–1.11] were associated with an increase in the incidence of cancer.

Conclusions

The decreasing rates of colorectal cancer suggest improved management and care in IBD. Further studies are needed to explore the impact of comorbid conditions on the risk of cancer in IBD.
Disparities in treatment of diabetes and hypertension among groups of foreign origin and the general Finnish population
Authors: Etchi Daniel T , Lilja Eero , Koponen Päivikki , Laatikainen Tiina
Published: March 2019

Background

Migrants from low-income countries are more predisposed to diabetes and cardiovascular risks than host European natives, but how treatment targets are met in migrant patients is unclear. We examined health service use and treatment of diabetes and hypertension among selected migrant groups and the general Finnish population and compared prevalence of cardiovascular risk factors between patients and non-patients.

Methods

Cross-sectional data from randomly sampled 30- to 64-year-old participants (387 Russian, 198 Somali and 343 Kurdish origin migrants) of the Migrant Health and Wellbeing Survey (2010–2012) were used. Health 2011 survey data (n = 1086) were used as a comparison group.

Results

Compared with the general population, diabetes-related doctor/nurse visits were more frequent among Russian and Somali, but not the Kurdish group. Use of prescribed antidiabetic and antihypertensive drugs were significantly lower among Russians (78%/56%) and Kurdish (68%/58%), but not in Somalis (85%/62%) compared with the general population (96%/78%). Obesity, elevated blood pressure and elevated glucose levels were more prevalent in patients than non-patients, and over 60% of patients and over 70% of non-patients had elevated plasma low density lipoprotein cholesterol. Differences in cardiovascular disease (CVD) risk profiles between patients and non-patients were not associated with socio-economic factors.

Conclusions

This study indicates disparities in prevalence and management of diabetes and hypertension and their associated risk factors among ethnic groups. Diabetes, CVD risks and treatment outcomes in patients were sub-optimal, especially among foreign origin groups. Comprehensive health promotion strategies are needed to improve cardiometabolic health in vulnerable populations.
Recombinant dermatan sulfate is a potent activator of heparin cofactor II-dependent inhibition of thrombin
Authors: Tykesson Emil , Maccarana Marco , Thorsson Hanna , Liu Jian , Malmström Anders , Ellervik Ulf , Westergren-Thorsson Gunilla
Published: March 2019

The glycosaminoglycan dermatan sulfate (DS) is a well-known activator of heparin cofactor II-dependent inactivation of thrombin. In contrast to heparin, dermatan sulfate has never been prepared recombinantly from material of non-animal origin. Here we report on the enzymatic synthesis of structurally well-defined DS with high anticoagulant activity. Using a microbial K4 polysaccharide and the recombinant enzymes DS-epimerase 1, dermatan 4-O-sulfotransferase 1, uronyl 2-O-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase, several new glycostructures have been prepared, such as a homogenously sulfated IdoA-GalNAc-4S polymer and its 2-O-, 6-O- and 2,6-O-sulfated derivatives. Importantly, the recombinant highly 2,4-O-sulfated DS inhibits thrombin via heparin cofactor II, approximately 20 times better than heparin, enabling manipulation of vascular and extravascular coagulation. The potential of this method can be extended to preparation of specific structures that are of importance for binding and activation of cytokines, and control of inflammation and metastasis, involving extravasation and migration.
Legislating for universal access to medicines: a rights-based cross-national comparison of UHC laws in 16 countries
Authors: Perehudoff S Katrina , Alexandrov Nikita V , Hogerzeil Hans V
Published: March 2019

Universal health coverage (UHC) aims to ensure that all people have access to health services including essential medicines without risking financial hardship. Yet, in many low- and middle-income countries (LMICs) inadequate UHC fails to ensure universal access to medicines and protect the poor and vulnerable against catastrophic spending in the event of illness. A human rights approach to essential medicines in national UHC legislation could remedy these inequities. This study identifies and compares legal texts from national UHC legislation that promote universal access to medicines in the legislation of 16 mostly LMICs: Algeria, Chile, Colombia, Ghana, Indonesia, Jordan, Mexico, Morocco, Nigeria, Philippines, Rwanda, South Africa, Tanzania, Turkey, Tunisia and Uruguay. The assessment tool was developed based on WHO’s policy guidelines for essential medicines and international human rights law; it consists of 12 principles in three domains: legal rights and obligations, good governance, and technical implementation. Relevant legislation was identified, mapped, collected and independently assessed by multi-disciplinary, multi-lingual teams. Legal rights and State obligations toward medicines are frequently codified in UHC law, while most good governance principles are less common. Some technical implementation principles are frequently embedded in national UHC law (i.e. pooled user contributions and financial coverage for the vulnerable), while others are infrequent (i.e. sufficient government financing) to almost absent (i.e. seeking international assistance and cooperation). Generally, upper-middle and high-income countries tended to embed explicit rights and obligations with clear boundaries, and universal mechanisms for accountability and redress in domestic law while less affluent countries took different approaches. This research presents national law makers with both a checklist and a wish list for legal reform for access to medicines, as well as examples of legal texts. It may support goal 7 of the WHO Medicines & Health Products Strategic Programme 2016–30 to develop model legislation for medicines reimbursement.
Visual Networks As a Means of Representing Collocational Information in Electronic Dictionaries
Authors: Torner Sergi , Arias-Badia Blanca
Published: March 2019

The digital turn in lexicography has paved the way to new techniques for presenting information in dictionaries. This paper explores the potential of collocational networks (Phillips 1983, Williams 1998) as key lexicographical tools to represent information about lexical combinatorics. Collocational networks, which had initially been used as a means of identifying collocations in large corpora, must now be rethought in order to assist non-expert dictionary users in text production by allowing them to find the exact collocates they are looking for, as well as by offering the grammatical information needed to use collocations accurately. We advocate improving networks by incorporating information visualization techniques (Ware 2008, Pham 2012). Specifically, we suggest a number of measures which may be taken to both simplify access to the information provided by raw output from corpora —much of which may be noise for the dictionary user— and to enrich such collocational data by means of visually-explained relevant grammatical information.
Topological Types of Algebraic Stacks
Authors: Chough Chang-Yeon
Published: March 2019

The main goal of this paper is to set a foundation for homotopy theory of algebraic stacks under model category theory and to show how it can be applied in various contexts. It not only generalizes the étale homotopy theory to algebraic stacks but also provides more suitable framework for the homotopy theory in a broader context. Also, a new result that the profinite completion of pro-simplicial sets admits a right adjoint is provided and integrated with the foundational work to generalize Artin–Mazur’s comparison theorem from schemes to algebraic stacks in a formal way.
A review of measurement practice in studies of clinical decision support systems 1998–2017
Authors: Scott Philip J , Brown Angela W , Adedeji Taiwo , Wyatt Jeremy C , Georgiou Andrew , Eisenstein Eric L , Friedman Charles P
Published: March 2019

Objective

To assess measurement practice in clinical decision support evaluation studies.

Materials and Methods

We identified empirical studies evaluating clinical decision support systems published from 1998 to 2017. We reviewed titles, abstracts, and full paper contents for evidence of attention to measurement validity, reliability, or reuse. We used Friedman and Wyatt’s typology to categorize the studies.

Results

There were 391 studies that met the inclusion criteria. Study types in this cohort were primarily field user effect studies (n = 210) or problem impact studies (n = 150). Of those, 280 studies (72%) had no evidence of attention to measurement methodology, and 111 (28%) had some evidence with 33 (8%) offering validity evidence; 45 (12%) offering reliability evidence; and 61 (16%) reporting measurement artefact reuse.

Discussion

Only 5 studies offered validity assessment within the study. Valid measures were predominantly observed in problem impact studies with the majority of measures being clinical or patient reported outcomes with validity measured elsewhere.

Conclusion

Measurement methodology is frequently ignored in empirical studies of clinical decision support systems and particularly so in field user effect studies. Authors may in fact be attending to measurement considerations and not reporting this or employing methods of unknown validity and reliability in their studies. In the latter case, reported study results may be biased and effect sizes misleading. We argue that replication studies to strengthen the evidence base require greater attention to measurement practice in health informatics research.
Applying machine learning to predict real-world individual treatment effects: insights from a virtual patient cohort
Authors: Fang Gang , Annis Izabela E , Elston-Lafata Jennifer , Cykert Samuel
Published: March 2019

Objective

We aimed to investigate bias in applying machine learning to predict real-world individual treatment effects.

Materials and Methods

Using a virtual patient cohort, we simulated real-world healthcare data and applied random forest and gradient boosting classifiers to develop prediction models. Treatment effect was estimated as the difference between the predicted outcomes of a treatment and a control. We evaluated the impact of predictors (ie, treatment predictors [X1], confounders [X2], treatment effects modifiers [X3], and other outcome risk factors [X4]) with known effects on treatment and outcome using real-world data, and outcome imbalance on predicting individual outcome. Using counterfactuals, we evaluated percentage of patients with biased predicted individual treatment effects

Results

The X4 had relatively more impact on model performance than X2 and X3 did. No effects were observed from X1. Moderate-to-severe outcome imbalance had a significantly negative impact on model performance, particularly among subgroups in which an outcome occurred. Bias in predicting individual treatment effects was significant and persisted even when the models had a 100% accuracy in predicting health outcome.

Discussion

Inadequate inclusion of the X2, X3, and X4 and moderate-to-severe outcome imbalance may affect model performance in predicting individual outcome and subsequently bias in predicting individual treatment effects. Machine learning models with all features and high performance for predicting individual outcome still yielded biased individual treatment effects.

Conclusions

Direct application of machine learning might not adequately address bias in predicting individual treatment effects. Further method development is needed to advance machine learning to support individualized treatment selection.
Persistence of a Geographically-Stable Hybrid Zone in Puerto Rican Dwarf Geckos
Authors: Pinto Brendan J , Titus-McQuillan James , Daza Juan D , Gamble Tony
Published: March 2019

Determining the mechanisms that create and maintain biodiversity is a central question in ecology and evolution. Speciation is the process that creates biodiversity. Speciation is mediated by incompatibilities that lead to reproductive isolation between divergent populations and these incompatibilities can be observed in hybrid zones. Gecko lizards are a speciose clade possessing an impressive diversity of behavioral and morphological traits. In geckos, however, our understanding of the speciation process is negligible. To address this gap, we used genetic sequence data (both mitochondrial and nuclear markers) to revisit a putative hybrid zone between Sphaerodactylus nicholsi and Sphaerodactylus townsendi in Puerto Rico, initially described in 1984. First, we addressed discrepancies in the literature on the validity of both species. Second, we sampled a 10-km-wide transect across the putative hybrid zone and tested explicit predictions about its dynamics using cline models. Third, we investigated potential causes for the hybrid zone using species distribution modeling and simulations; namely, whether unique climatic variables within the hybrid zone might elicit selection for intermediate phenotypes. We find strong support for the species-level status of each species and no evidence of movement, or unique climatic variables near the hybrid zone. We suggest that this narrow hybrid zone is geographically stable and is maintained by a combination of dispersal and selection. Thus, this work has identified an extant model system within geckos that that can be used for future investigations detailing genetic mechanisms of reproductive isolation in an understudied vertebrate group.
Isotopic evidence for volatile replenishment of the Moon during the Late Accretion
Authors: Lin Yanhao , van Westrenen Wim
Published: March 2019

The traditional view of a dry, volatile-poor Moon has been challenged by the identification of water and other volatiles in lunar samples, but the volatile budget delivery time(s), source(s) and temporal evolution remain poorly constrained. Here we show that hydrogen and chlorine isotopic ratios in lunar apatite changed significantly during the Late Accretion (LA, 4.1–3.8 billion years ago). During this period, deuterium/hydrogen ratios in the Moon changed from initial carbonaceous-chondrite-like values to values consistent with an influx of ordinary-chondrite-like material and pre-LA elevated δ37Cl values drop towards lower chondrite-like values. Inferred pre-LA lunar interior water contents are significantly lower than pristine values suggesting degassing, followed by an increase during the LA. These trends are consistent with dynamic models of solar-system evolution, suggesting that the Moon's (and Earth's) initial volatiles were replenished ∼0.5 Ga after their formation, with their final budgets reflecting a mixture of sources and delivery times.
Exoscope-Guided (VITOM 3D) Single-Stage Removal of Supratentorial Cavernous Angioma and Hemangioblastoma: 3-Dimensional Operative Video
Authors: Angileri Filippo Flavio , Esposito Felice , Scibilia Antonino , Priola Stefano Maria , Raffa Giovanni , Germanò Antonino
Published: March 2019

This video shows an exoscope-guided single-stage resection with 3-dimensional technology of a supratentorial cavernoma and a supratentorial hemangioblastoma during the same surgical procedure. The patient is a 42-yr-old man with a history of generalized tonico-clonic seizures. Contrast-enhanced magnetic resonance (MR) revealed the presence of a left frontal cavernoma and a left T1 non-enhancing hypointese temporal lesion (hemangioblastoma). The operation was carried out in the lateral position with the sole use of a 3D-exoscope (VITOM-3D, Karl Storz GmbH&Co, Tuttlingen, Germany). The operating room set-up included the surgeons standing at the head of the patients with the operating and navigator screens in the front of them and the exoscope arm entering from the left side.

As recently highlighted, the 3D-exoscope carries several advantages: (1) it allows neurosurgeons to operate in a confortable and stable position; (2) it is less space-occupying in comparison to the microscope; (3) the optics and 3D-screen offer an optimal stereoscopic view in comparison to the 2D-exoscope, important for both surgical and training purposes; (4) although sharing with the endoscope, the image quality and confortable surgeon's position, there is no conflict between the surgical instruments and the scope in the surgical field.

The adopted strategy enabled a complete resection of both lesions. The postoperative course was uneventful and the patient was seizure-free; the antiepileptic drugs were discontinued 3 mo after surgery.

The 3D-exoscope represents a promising surgical tool, which may become part of the neurosurgical armamentarium. Nevertheless, the conceivable capability to improve neurosurgical results will have to be explored.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

The patient has consented to the submission of the surgical video for submission to the journal.
Diversity and evolution of the parotoid macrogland in true toads (Anura: Bufonidae)
Authors: O´donohoe M E Ailin , Luna María Celeste , Regueira Eleonora , Brunetti Andres E , Basso Nestor G , Lynch John D , Pereyra Martín O , Hermida Gladys N
Published: March 2019

Skin glands in amphibians are either distributed throughout the skin or aggregated in multiglandular structures such as the parotoids typical of most species of Bufonidae. Although many early divergent and derived bufonids lack a discrete parotoid in the postorbital–supratympanic (PoSt) region, they have a great macroscopic diversity in the skin morphology of this region. To understand the origin and evolution of this diversity, in particular of the parotoids, we describe the histomorphology of the skin of the PoSt and dorsal regions in 17 species of bufonids, with or without external evident parotoid, and compare it with previously published descriptions. The survey results in 27 characters that were optimized on a phylogenetic hypothesis of Bufonidae. Our results reveal that the PoSt region has a noteworthy morphological diversity of types of glands, spatial organization and differences in the secretion products. Some morphological characters represent putative synapomorphies of internal clades of Bufonidae and are related to the progressive differentiation towards defined structures (macroglands, parotoids). These morphological results, along with published information on the toxicity of the skin secretions and defensive behaviours in some representative species, allow us to infer possible relationships between these features.
An Analytic Platform for the Rapid and Reproducible Annotation of Ventilator Waveform Data
Authors: Rehm Gregory B. , Kuhn Brooks T. , Lieng Monica K. , Cortes-Puch Irene , Nguyen Jimmy , Guo Edward C. , Delplanque Jean-Pierre , Anderson Nicholas R. , Adams Jason Y.
Published: March 2019

Algorithmic classifiers are crucial components of clinical decision support (CDS) systems needed to advance healthcare delivery. Robust CDS systems must be derived and validated via creation of multi-reviewer adjudicated gold standard datasets. Manual annotation of physiologic data such as mechanical ventilator waveform data (VWD) can be time-consuming, and lacks methodological consistency in dataset development. To address these issues, we have created a system for annotating and adjudicating VWD called the Annotation PipeLine (APL) to optimize VWD annotation by expert reviewers. APL combines visual assessment of waveform characteristics with metadata display, enabling inclusion of quantitative thresholds into annotation decisions by reviewers. APL also includes specific features for resolving multi-reviewer disagreements and generating gold standard data sets. APL’s unique combination of methods and open source framework may accelerate the creation of CDS algorithms for ventilator management, and may serve as a model for future research into physiologic waveform annotation systems.
Repositioning septins within the core particle
Authors: Mendonça Deborah C. , Macedo Joci N. , Itri Rosangela , Guimaraes Samuel L. , Barroso da Silva Fernando L. , Cassago Alexandre , Garratt Richard C. , Portugal Rodrigo , Araujo Ana P. U.
Published: March 2019

Septins are GTP binding proteins considered to be a novel component of the cytoskeleton. They polymerize into filaments based on hetero-oligomeric core particles which, in humans, are either hexamers or octamers composed of two copies each of either three or four different septins from the 13 available. Not all combinations are possible as it is believed that these must obey substitution rules which determine that different septins must be derived from four distinct and well-established sub-groups. Here, we have purified and characterized one such combinations, SEPT5-SEPT6-SEPT7, and used TEM to derive the first structural information concerning its assembly. The full complex was purified using an affinity tag attached to only one of its components (SEPT7) and was able to bind to and perturb lipid bilayers. Although the complex assembled into elongated hexameric particles, the position of SEPT5 was incompatible with that predicted by the reported structure of SEPT2-SEPT6-SEPT7 based on the substitution rules. MBP-fusion constructs for SEPT5 and SEPT2 and immuno-staining clearly show that these septins occupy the terminal positions of the SEPT5-SEPT6-SEPT7 and SEPT2-SEPT6-SEPT7 hexamers, respectively. In so doing they expose a so-called NC interface which we show to be more susceptible to perturbation at high salt concentrations. Our results show that the true structure of the hexamer is inverted with respect to that described previously and, as such, is more compatible with that reported for yeast. Taken together, our results suggest that the mechanisms involved in spontaneous self-assembly of septin core particles and their filaments deserve further reflection.
Impact of pterygium on the ocular surface and meibomian glands
Authors: Wanzeler Ana Cláudia Viana , Barbosa Italo Antunes França , Duarte Bruna , Barbosa Eduardo Buzolin , Borges Daniel Almeida , Alves Monica
Published: March 2019

Purpose

To analyze how ocular surface parameters correlate to pterygium and investigate the possible impact on tear film and meibomian glands.

Methods

we investigated objective parameters of the ocular surface such as conjunctival hyperemia, tear film stability and volume, meibomian gland dysfunction, dry eye disease, corneal topography comparing healthy individuals and correlating with the pterygium clinical presentation.

Results

A total of 83 patients were included. Corneal astigmatism induction was 2.65 ± 2.52 D (0.4-11.8). The impact of pterygium on the ocular surface parameters compared to matched controls was seen in: conjunctival hyperemia (control 1.55±0.39/pterygium 2.14±0.69; p=0.0001), tear meniscus height (control 0.24±0.05 mm/pterygium 0.36±0.14mm; p 0.0002), meiboscore lower eyelid (control 0.29±0.64/pterygium 1.38±0.95; p 0.0001) and meiboscore upper eyelid (control 0.53±0.62/pterygium 0.98±0.75; p=0.0083). We found a high number of pterygium patients (88%) presented meibomian gland alterations. Interestingly, meibomian gland loss was coincident to the localization of the pterygium in 54% of the upper and 77% lower lids.

Conclusion

Pterygium greatly impacts on ocular surface by inducing direct alterations in the pattern of meibomian glands besides corneal irregularities, conjunctival hyperemia and lacrimal film alterations, inducing significant symptoms and potential signs of dysfunction.
GCNA interacts with Spartan and Topoisomerase II to regulate genome stability
Authors: Davis Gregory M. , Dokshin Gregoriy A. , Sawle Ashley D. , Eldridge Matthew D. , Romer Katherine A. , Gourley Taylin E. , Molesworth Luke W. , Tatnell Hannah R. , Ozturk Ahmet R. , de Rooij Dirk G. , Hannon Gregory J. , Page David C. , Mello Craig C. , Carmell Michelle A.
Published: March 2019

GCNA proteins are expressed across eukarya in pluripotent cells and have conserved functions in fertility. GCNA homologs Spartan/DVC-1 and Wss1 resolve DNA-protein crosslinks (DPCs), including Topoisomerase-DNA adducts, during DNA replication. We show that GCNA and Topoisomerase 2 (Top2) physically interact and colocalize on condensed chromosomes during mitosis, when Spartan is not present. We show thatC. elegans gcna-1mutants are sensitive to Top2 poison and accumulate mutations consistent with low fidelity repair of DNA damage, leading to loss of fitness and fertility over generations. We also demonstrate that mouse GCNA interacts with TOP2, andGcna-mutant mice exhibit abnormalities consistent with the inability to process DPCs, including chromatin condensation and crossover defects. Together, our findings provide evidence that GCNA maintains genomic integrity by processing Top2 DPCs in the germline and early embryo, where the genome is challenged with an increased DPC burden.
Extreme rainfall drives early onset cyanobacterial bloom
Authors: Larsen Megan L. , Baulch Helen M. , Schiff Sherry L. , Simon Dana F. , Sauvé Sébastien , Venkiteswaran Jason J.
Published: March 2019

The increasing prevalence of cyanobacteria-dominated harmful algal blooms is strongly associated with nutrient loading and changing climatic patterns. Changes to precipitation frequency and intensity, as predicted by current climate models, are likely to affect bloom development and composition through changes in nutrient fluxes and water column mixing. However, few studies have directly documented the effects of extreme precipitation events on cyanobacterial composition, biomass, and toxin production.

We tracked changes in a eutrophic reservoir following an extreme precipitation event, describing an atypically early toxin-producing cyanobacterial bloom, successional progression of the phytoplankton community, toxins, and geochemistry.

An increase in bioavailable phosphorus by more than 27-fold in surface waters preceded notable increases in Aphanizomenon flos-aquae throughout the reservoir approximately 2 weeks post flood and ~5 weeks before blooms typically occur. Anabaenopeptin-A and three microcystin congeners (microcystin-LR, -YR, and -RR) were detected at varying levels across sites during the bloom period, which lasted between 3 and 5 weeks.

Synthesis and applications: These findings suggest extreme rainfall can trigger early cyanobacterial bloom initiation, effectively elongating the bloom season period of potential toxicity. However, effects will vary depending on factors including the timing of rainfall and reservoir physical structure. In contrast to the effects of early season extreme rainfall, a mid-summer runoff event appeared to help mitigate the bloom in some areas of the reservoir by increasing flushing.
Brain Age Prediction: Cortical and Subcortical Shape Covariation in the Developing Human Brain
Authors: Zhao Yihong , Klein Arno , Castellanos F. Xavier , Milham Michael P.
Published: March 2019

Cortical development is characterized by distinct spatial and temporal patterns of maturational changes across various cortical shape measures. There is a growing interest in summarizing complex developmental patterns into a single index, which can be used to characterize an individual’s brain age. We conducted this study with two primary aims. First, we sought to quantify covariation patterns for a variety of cortical shape measures, including cortical thickness, gray matter volume, surface area, mean curvature, and travel depth, as well as white matter volume, and subcortical gray matter volume. We examined these measures in a sample of 869 participants aged 5-18 from the Healthy Brain Network (HBN) neurodevelopmental cohort using the Joint and Individual Variation Explained (Lock et al., 2013) method. We validated our results in an independent dataset from the Nathan Kline Institute - Rockland Sample (NKI-RS; N=210) and found remarkable consistency for some covariation patterns. Second, we assessed whether covariation patterns in the brain can be used to accurately predict a person’s chronological age. Using ridge regression, we showed that covariation patterns can predict chronological age with high accuracy, reflected by our ability to cross-validate our model in an independent sample with a correlation coefficient of 0.84 between chronologic and predicted age. These covariation patterns also predicted sex with high accuracy (AUC=0.85), and explained a substantial portion of variation in full scale intelligence quotient (R2=0.10). In summary, we found significant covariation across different cortical shape measures and subcortical gray matter volumes. In addition, each shape measure exhibited distinct covariations that could not be accounted for by other shape measures. These covariation patterns accurately predicted chronological age, sex and general cognitive ability. In a subset of NKI-RS, test-retest (<1 month apart, N=120) and longitudinal scans (1.22 ± 0.29 years apart, N=77) were available, allowing us to demonstrate high reliability for the prediction models obtained and the ability to detect subtle differences in the longitudinal scan interval among participants (median and median absolute deviation of absolute differences between predicted age difference and real age difference = 0.53 ± 0.47 years, r=0.24, p-value=0.04).
Mapping Lung Cancer Epithelial-Mesenchymal Transition States and Trajectories with Single-Cell Resolution
Authors: Karacosta Loukia G. , Anchang Benedict , Ignatiadis Nikolaos , Kimmey Samuel C. , Benson Jalen A. , Shrager Joseph B. , Tibshirani Robert , Bendall Sean C. , Plevritis Sylvia K.
Published: March 2019

Elucidating a continuum of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in clinical samples promises new insights in cancer progression and drug response. Using mass cytometry time-course analysis, we resolve lung cancer EMT states through TGFβ-treatment and identify through TGFβ-withdrawal, an MET state previously unrealized. We demonstrate significant differences between EMT and MET trajectories using a novel computational tool (TRACER) for reconstructing trajectories between cell states. Additionally, we construct a lung cancer reference map of EMT and MET states referred to as the EMT-MET STAte MaP (STAMP). Using a neural net algorithm, we project clinical samples onto the EMT-MET STAMP to characterize their phenotypic profile with single-cell resolution in terms of ourin vitroEMT-MET analysis. In summary, we provide a framework that can be extended to phenotypically characterize clinical samples in the context ofin vitrostudies showing differential EMT-MET traits related to metastasis and drug sensitivity.
Identification of bacteria involved in the decomposition of lignocellulosic biomass treated with cow rumen fluid by metagenomic analysis
Authors: Lee Chol Gyu , Baba Yasunori , Asano Ryoki , Fukuda Yasuhiro , Tada Chika , Nakai Yutaka
Published: March 2019

Previously, pretreatment of plant biomass using rumen fluid systems was developed to decompose cell wall. However, microbes which involved in plant cell wall decomposition in this system have not been identified, because the conditions of this system are different from the in situ rumen environment. We investigated the bacteria involved in the decomposition of cellulose and hemicellulose in a waste paper with the rumen pretreatment system using shotgun metagenomic analysis with next generation sequencing. After pretreatment of waste paper, about a half of the cellulose and hemicellulose content was decomposed. Genes encoding for cellulase and hemicellulase were mainly found to belonging to Ruminococcus, Clostridium, and Exiguobacterium. This study shows that Clostridium and Exiguobacterium, which have not been identified as predominant genus involved in cellulose and hemicellulose decomposition, might be categorized as the main fibrolytic bacteria in this system.
Interkinetic nuclear migration in the zebra1sh retina as a diffusive process
Authors: Azizi Afnan , Herrmann Anne , Wan Yinan , Buse Salvador J. R. P. , Keller Philipp J. , Goldstein Raymond E. , Harris William A.
Published: March 2019

A major hallmark of neural development is the oscillatory movement of nuclei between the apical and basal surfaces of the neuroepithelium during the process of interkinetic nuclear migration (IKNM). Here, we employ long-term, rapid lightsheet and two-photon imaging of Zebrafish retinas in vivo during early development to uncover the physical processes that govern the behavior of nuclei during IKNM. These images allow the capture of reliable tracks of nuclear movements and division during early retinogenesis for many tightly packed nuclei. These tracks are then used to create and test a theory of retinal IKNM as a diffusive process across a nuclear concentration gradient generated by the addition of new nuclei at the apical surface. The analysis reveals the role of nuclear packing at the apical surface on the migration dynamics of nuclei, provides a robust quantitative explanation for the distribution of nuclei across the retina, and may have implications for stochastic fate choice in this system.
A weak Foxp3 hypomorph enhances spontaneous and therapeutic immune surveillance of cancer in mice
Authors: Almeida-Santos José , Bergman Marie-Louise , Cabral Inês Amendoeira , Correia Vasco , Caramalho Íris , Demengeot Jocelyne
Published: March 2019

It is well established that therapeutic impairment of Foxp3+regulatory T cells (Treg) in mice and humans favors immune rejection of solid tumors. Less explored are the genetic associations between Foxp3 allelic variants and tumor incidence, only sporadically reported in human studies. In this work, we tested and demonstrate that Foxp3fGFP, an allele classified as hypomorphic in Th1 inflammatory contexts but not affecting health at steady state, confers increased anti-tumor immunity. Our conclusions stem out of the analysis of three tumor models of different tissue origin, in two murine genetic backgrounds. When compared to wild type animals, mice carrying the Foxp3fGFPallele spontaneously delay, reduce or prevent primary tumor growth, decrease metastasis growth and potentiate the response to anti-CTLA4 monotherapy. These findings suggest that allelic variance at the Foxp3 locus may have significant impact on cancer incidence and/or the success of cancer-immunotherapies in humans.
Effect of Saudi and Egyptian pomegranate polyphenols in regulating the activity of PON1, PON2 and lipid profile for preventing coronary heart disease
Authors: BinMowyna Mona Nasser , Binobead Manal Abdulaziz , Al Badr Nawal Abdullah , AlSedairy Sahar Abdulaziz , Rahim Elredh Islam Abdul , Al-Qahtani Wedad Saeed
Published: March 2019

Saudi and Egyptian pomegranate juice (APJ and EPJ) contains potent polyphenols antioxidants which were found to reduce serum and macrophage oxidative stress. The protective effects of APJ and EPJ against atherogenicity were evaluated by feeding mice with hypercholesterolemic diet supplemented with PJ. PJ consumption reduced mice serum Triglycerides (TG), Total cholesterol (TC) and (low density lipoprotein (LDL-c) and increase in the High-density lipoprotein (HDL-c) compared with mouse with control diet or atherogenic diet. The risk ratio and atherogenic index were significantly lower in either APJ or EPJ supplemented group. Paraoxonase 1 (PON1) which remains associated with HDL showed significant increase in the activity in mice supplemented with PJ compared to mice with atherogenic diet (AD). PJ consumption significantly reduced lipid peroxidation and increased glutathione levels. The reduction in lipid peroxidation varied from 57 to 76%. PJ supplementation reduced peritoneal macrophages (MPM) mediated oxidation of LDL by 68 to 82% and decreased mouse peritoneal macrophages (MPM) Ox-LDL uptake by 31 to 48%. A significant up regulation of macrophage PON2 activity was induced by PJ reducing the macrophage oxidative stress. In conclusion, PJ consumption resulted in anti-oxidative and antiatherogenic effects on serum and macrophages which could prevent atherosclerosis and coronary heart diseases.
Generation of a white-albino phenotype from cobalt blue and yellow-albino trouts: inheritance pattern and chromatophores analysis
Authors: Hattori Ricardo Shohei , Yoshinaga Tulio Teruo , Butzge Arno Juliano , Hattori-Ihara Shoko , Tsukamoto Ricardo Yasuichi , Takahashi Neuza Sumico , Tabata Yara Aiko
Published: March 2019

Albinism is the most common color variation described in fish and is characterized by a white or yellow phenotype according to the species. In rainbow troutOncorhynchus mykiss, aside from yellow-albino phenotypes, cobalt blue variants with autosomal, recessive inheritance have also been reported. In this study, we investigated the inheritance pattern and chromatophores distribution/abundance of cobalt blue trouts obtained from a local fish farm. Based on crosses with wild-type and dominant yellow-albino lines, we could infer that cobalt blue are dominant over wild-type and co-dominant in relation to yellow-albino phenotype, resulting in a fourth phenotype: the white-albino. Analysis of chromatophores revealed that cobalt blue trouts present melanophores, as the wild-type, and a reduced number of xanthophores. As regards to the white-albino phenotype, they were not only devoid of melanophores but also presented a reduced number of xanthophores. Cobalt blue and white-albino trouts also presented a more elongated body shape and, most remarkably, a smaller pituitary gland compared to wild-type and yellow-albino, suggesting that the allele for blue color is somehow linked with this abnormal pituitary phenotype. These phenotypes represent interesting models for research on body pigmentation in salmonids and on the mechanisms behind endocrine control of color patterning.
Long-lasting effects of proanthocyanidins in rat prevent cafeteria diet effects by limiting adipose tissue accrual
Authors: Ardevol Anna , Gines Iris , GIL-CARDOSO Katherine , Serrano Joan , CASANOVA-MARTI Angela , Lobato Maria , Terra Ximena , Blay MTeresa , Pinent Montserrat
Published: March 2019

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe the molecular targets and the duration of the effects. We treated rats with 500 mg GSPE/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on cafeteria diet, we used RT-PCR to measure the mRNA of the key energy metabolism enzymes from liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. Liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, fatty oxidation (Oxct1 and Cpt1b mRNA) was increased in muscle. However, after seventeen weeks, there was a completely different gene expression pattern. As conclusion, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle
Reduced chromatin accessibility underlies gene expression differences in homologous chromosome arms of hexaploid wheat and diploidAegilops tauschii
Authors: Lu Fu-Hao , McKenzie Neil , Gardiner Laura-Jayne , Luo Ming-Cheng , Hall Anthony , Bevan Michael W
Published: March 2019

Polyploidy has been centrally important in driving the evolution of plants, and leads to alterations in gene expression that are thought to underlie the emergence of new traits. Despite the common occurrence of these global patterns of altered gene expression in polyploids, the mechanisms involved are not well understood. Using a precise framework of highly conserved syntenic genes on hexaploid wheat chromosome 3DL and its progenitor 3L chromosome arm of diploidAegilops tauschii, we show that 70% of these genes exhibited proportionally reduced gene expression, in which expression in the hexaploid context of the 3DL genes was approximately 40% of the levels observed in diploidAe. tauschii.Many genes showing elevated expression during later stages of grain development in wheat compared toAe. tauschii.Gene sequence and methylation differences accounted for only a few cases of differences in gene expression. In contrast, large scale patterns of reduced chromatin accessibility of genes in the hexaploid chromosome arm compared to its diploid progenitor were correlated with observed overall reduction in gene expression and differential gene expression. Therefore, that an overall reduction in accessible chromatin underlies the major differences in gene expression that results from polyploidization.
Leishmania majordegrades murine CXCL1 – an immune evasion strategy
Authors: Yorek Matthew S. , Poudel Barun , Mazgaeen Lalita , Pope R. Marshall , Wilson Mary E. , Gurung Prajwal
Published: March 2019

Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year and more than 1 billion people at risk of contracting this disease in endemic areas. The innate immune system plays a central role in controllingL. majorinfection by initiating a signaling cascade that results in production of pro-inflammatory cytokines and recruitment of both innate and adaptive immune cells. Upon infection withL. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils to the site of infection. Herein, we report thatL. majorspecifically targets murine CXCL1 for degradation. The degradation of CXCL1 is not dependent on host factors asL. majorcan directly degrade recombinant CXCL1 in a cell-free system. Using mass spectrometry, we discovered that theL. majorprotease cleaves at the C-terminal end of murine CXCL1. Finally, our data suggest thatL. majormetalloproteases are involved in the direct cleavage and degradation of CXCL1, and a synthetic peptide spanning the CXCL1 cleavage site can be used to inhibitL. majormetalloprotease activity. In conclusion, our study has identified an immune evasion strategy employed byL. majorto evade innate immune responses in mice, likely reservoirs in the endemic areas, and further highlights that targeting theseL. majormetalloproteases may be important in controlling infection within the reservoir population and transmittance of the disease.

Authors’ summary

Our study discovered a highly specific role forL. majormetalloprotease in cleaving and degrading murine CXCL1. Indeed,L. majormetalloprotease did not cleave murine CXCL2 or human CXCL1, CXCL2 and CXCL8. CXCL1 is a critical chemokine required for neutrophil recruitment to the site of infection; thus, we propose that this metalloprotease may have evolved to evade immune responses specifically in the murine host. We have further identified that the C-terminal end on CXCL1 is targeted for cleavage by theL. majormetalloprotease. Finally, this cleavage site information was used to design peptides that are able to inhibit CXCL1 degradation byL. major. Our study highlights an immune evasion strategy utilized byL. majorto establish infection within a murine host.