bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between the ionizing continuum and the variable C iv broad absorption line in multi-epoch observations of SDSS J141007.74+541203.3
Authors: Huang Hong-Yan , Pan Cai-Juan , Lu Wei-Jian , Qin Yi-Ping , Lin Ying-Ru , Huang Wei-Rong , Zhou Yu-Tao , Yao Min , Nong Wei-Jing , Lu Mei-Mei , Yao Zhi-Kao , Han Qing-Lin
Published: May 2019

Correlations between the variations of quasar absorption lines and the ionizing continuum have been confirmed recently in systematic studies. However, no convincing individual case is reported. We present a statistical analysis of the variable C iv broad absorption line (BAL) in the quasar SDSS J141007.74+541203.3, which has been observed with 44 epochs by the Sloan Digital Sky Survey Data Release 14. Grier et al. have concluded that the most likely cause of the variability of the BAL in SDSS J141007.74+541203.3 is a rapid response to changes in the incident ionizing continuum. In this paper, we confirm the anticorrelation between the equivalent width of BALs and the flux of the continuum based on the spectra of this quasar, which show significant variations. This serves as further independent evidence for the conclusions of Grier et al.
The political economy of carbon pricing: a panel analysis
Authors: Dolphin Geoffroy , Pollitt Michael G , Newbery David M
Published: May 2019

In virtually all jurisdictions that explicitly price carbon, its average (emissions-weighted) price remains low. Our analysis focuses on the political economy of its introduction as well as its stringency in an international panel of national and North American subnational jurisdictions. Results suggest that political economy factors primarily affected the former and that policy stringency is a highly persistent process. This has two important policy implications. First, successful passage of carbon pricing legislation will either come with contemporaneous compensation of incumbent, CO2-intensive, sectors or occur after their relative weakening. Second, if political economy constraints continue to prevail, climate change mitigation strategies will require multiple instruments.
Photosynthetic Responses to High Temperature and Strong Light Suggest Potential Post-flowering Drought Tolerance of Sorghum Japanese Landrace Takakibi
Authors: Ohnishi Norikazu , Wacera W. Fiona , Sakamoto Wataru
Published: May 2019

Sorghum [Sorghum bicolor (L.) Moench] is a C4 crop known to be adaptable to harsh environments such as those under high temperature and water deficit. In this study, we focused on a Japanese sorghum landrace Takakibi (NOG) and employed chlorophyll fluorescence measurements to assess its response to environmental stress. Comparison of photosynthetic rate evaluated using two parameters (effective quantum yield and electron transfer rate) indicated that NOG showed less activity than BTx623 in the pre-flowering stage, which was consistent with the higher susceptibility of NOG seedlings to drought than BTx623. The observed differences in photosynthetic activity between the two cultivars were detectable without drought conditions on days with high temperature and strong light. Interestingly, the photosynthetic activity of NOG leaves in stress conditions increased soon after heading, and the trend was similar to that in BTx642, a well-characterized post-flowering drought-tolerant cultivar. In contrast, BTx623 showed a gradual decline in photosynthetic rate. Thus, we inferred that Japanese Takakibi has the potential to show pre-flowering drought susceptibility and post-flowering drought tolerance, through which it adapts to local climates with high temperature and strong light at harvest.
Gender differences in cardiovascular risk of patients with rheumatoid arthritis
Authors: Adawi M , Gurovich B , Firas S , Watad A , Bragazzi N l , Amital H , Sirchan R , Blum A
Published: May 2019

Background

Rheumatoid Arthritis (RA) is a chronic inflammatory disease, affecting women more than men, with a more aggressive course in women.

Design

A prospective study that recruited 58 patients (46 women aged 56 ± 12 years) with active long-standing RA disease (>12 months). Our goals were to measure their endothelial function, part of the cardiovascular risk assessment.

Methods

The Brachial Artery method measured endothelial function (the flow mediated percent change [FMD percentage] of the brachial artery diameter). A senior Rheumatologist clinically evaluated all subjects. Mann Whitney rank sum test estimated gender differences among the RA patients.

Results

Median FMD% change for men was −6.07%, while median FMD% change for women was 0.44% (Z = 2.38, P = 0.01). Baseline Brachial artery diameter was larger in men (Z = 2.52, P = 0.01); however, tender joints count and BMI were greater in women (Z=−2.24, P = 0.01; Z=−3.99, P = 0.001), respectively.

Conclusions

Women with RA have significantly better endothelial function than men with RA. It means that even though RA is 3-fold more prevalent in women, women are more protected from atherosclerotic coronary artery disease and cardiac events.
EFFECTIVE DOSES DUE TO OUTDOOR AND INDOOR RADON AT A MEDITERRANEAN SITE
Authors: Kikaj Dafina , Vaupotič Janja
Published: May 2019

A year-long continuous measurement of the radon activity concentration in the outdoor air at a Mediterranean site has shown a range of 2–144 Bq m−3 and annual mean of 18 ± 14 Bq m−3. Seasonal means were: 15 ± 10 Bq m−3 in winter, 15 ± 12 Bq m−3 in spring, 22 ± 19 Bq m−3 in summer and 17 ± 12 Bq m−3 in autumn. In summer, the average radon activity concentration in the daytime (6–22 h) was 15.2 Bq m−3 and in the night-time (22–6 h) 33.4 Bq m−3. The annual effective dose was 1.83 mSv, with 1.66 mSv from indoor and 0.17 mSv (9%) from outdoor radon. The related doses for the summertime were (mSv): 0.29, 0.24 and 0.05 (18%).
Missing pieces of the retention puzzle
Authors: Whitney-Dumais Tammy , Hyrkäs Kristiina
Published: May 2019

Identifying pragmatic aspects for succession planning needs
To Mitigate The Lnt Model’s Unintended Consequences—A Proposed Stopping Point For As Low As Reasonably Achievable
Authors: Abelquist Eric W.
Published: May 2019

While the debate over the linear no-threshold model continues, there’s a relatively straightforward step that can be taken to mitigate the unintended consequences of the linear no-threshold model and the application of the as low as reasonably achievable principle—enact a stopping point for as low as reasonably achievable. The National Council on Radiation Protection and Measurements defined the negligible individual dose in 1993 as having a value of 0.01 mSv y−1. Radiation safety professionals overwhelmingly agree that applying the as low as reasonably achievable principle at very low doses, such as those consistent with background radiation levels, is not improving radiation safety of the public or radiation workers. To the contrary, this practice has significant financial and social consequences, and it severely inhibits public communication of radiation risks. To move forward, the National Council on Radiation Protection and Measurements should increase the negligible individual dose to a more practical value of 0.1 mSv y−1—the new as low as reasonably achievable stopping point. While radiation research in radiation biology and epidemiology are needed to better understand low-dose health effects below 100 mSv, in the meantime we should apply what we know—i.e., that radiation protection should not include trying to protect people from radiation doses that are consistent with variations in background radiation.
Getting to the End Zone With Medicare for All
Authors: Atkins Carl D.
Published: May 2019

Incremental reform is an option put forward to bridge the gap between the advances made by the Affordable Care Act and Medicare for All. Starting with the premise that the barriers to enactment of Medicare for All are less than they appear, this article discusses some specific concerns about Medicare for All and how a well-implemented plan can overcome them. Regarding the bills in Congress as blueprints on which to build a foundation for a well-implemented plan, concerns about utilization, costs, funding, workforce changes, and political objections are all found to be manageable.
A Tribute to Rob Restuccia and Thoughts About How We Continue to Move Forward Toward the Promise of Universal Entitlement
Authors: Master Robert
Published: May 2019

Rob Restuccia defined how health care justice and equity is advanced through his pioneering work that led to the passage of the Affordable Care Act (ACA). The evolution of the ACA is unfinished but the roadmap is clear. Next steps include a public option, the unshackling of government's ability to purchase pharmaceuticals and expansion to the entire nation. Through his life's work, Rob Restuccia has taught us how we will get there.
Risk Factors for Rapid Progression From Acute Recurrent to Chronic Pancreatitis in Children
Authors: Liu Quin Y. , Abu‐El‐Haija Maisam , Husain Sohail Z. , Barth Bradley , Bellin Melena , Fishman Douglas S. , Freedman Steven D. , Gariepy Cheryl E. , Giefer Matthew J. , Gonska Tanja , Heyman Melvin B. , Himes Ryan , Lin Tom K. , Maqbool Asim , Mascarenhas Maria , McFerron Brian A. , Morinville Veronique D. , Nathan Jaimie D. , Ooi Chee Y. , Perito Emily R. , Pohl John F. , Rhee Sue , Schwarzenberg Sarah J. , Shah Uzma , Troendle David , Werlin Steven L. , Wilschanski Michael , Zimmerman M. Bridget , Lowe Mark E. , Uc Aliye
Published: May 2019

Objective:

The aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.

Study Design:

Data were collected from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohort. Kaplan‐Meier curves were constructed to calculate duration of progression from initial attack of acute pancreatitis (AP) to CP. Log‐rank test was used to compare survival (nonprogression) probability distribution between groups. Cox proportional hazard regression models were fitted to obtain hazard ratio (with 95% confidence interval [CI]) of progression for each risk variable.

Results:

Of 442 children, 251 had ARP and 191 had CP. The median time of progression from initial attack of AP to CP was 3.79 years. The progression was faster in those ages 6 years or older at the first episode of AP compared to those younger than 6 years (median time to CP: 2.91 vs 4.92 years; P = 0.01). Children with pathogenic PRSS1 variants progressed more rapidly to CP compared to children without PRSS1 variants (median time to CP: 2.52 vs 4.48 years; P = 0.003). Within 6 years after the initial AP attack, cumulative proportion with exocrine pancreatic insufficiency was 18.0% (95% CI: 12.4%, 25.6%); diabetes mellitus was 7.7% (95% CI: 4.2%, 14.1%).

Conclusions:

Children with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.
Predictive Value of Abnormal Findings on Covered Transjugular Intrahepatic Portosystemic Shunt Baseline Doppler Sonography
Authors: Habibollahi Peiman , Shamchi Sara Pourhassan , D'souza Julia , Weber Charles N. , Langer Jill E. , Nadolski Gregory J. , Chauhan Anil
Published: May 2019

Doppler ultrasound (DUS) is frequently performed as a screening and diagnostic modality to evaluate the transjugular intrahepatic portosystemic shunt (TIPS) for short- and intermediate-term complications of the procedure. However, the clinical significance of initial frequently observed abnormalities in flow velocities, gradient, and direction in patients with covered TIPS is less studied. A retrospective study was performed between January 2005 and December 2014, and all patients undergoing covered TIPS procedure for the management of portal hypertension were included. Abnormal DUS findings were defined as intrashunt peak systolic velocities (PSVs) less than 90 or greater than 190 cm/s, intrashunt gradient greater than 50 cm/s, and abnormal flow direction in the main, right, and/or left portal veins. A total of 283 patients with adequate clinical follow-up and baseline TIPS DUS were included in the study. Median follow-up was 18.2 months. During the follow-up period, portal hypertension symptoms recurred in 83 patients who underwent TIPS angiography and/or revision. Of the 83, 57 had an elevated portosystemic gradient (>12 mm Hg) requiring angioplasty/stenting. With regard to baseline ultrasound, low PSVs were present in 88 patients (31.1%), high PSVs in 44 patients (15.5%), and elevated gradient in 98 patients (34.6%). The rate of developing TIPS stenosis in the future was not higher in patients with abnormal DUS parameters. For example, 26 (19.7%) of 132 patients with abnormal TIPS velocities developed stenosis compared with 31 (20.5%) of 151 patients with normal velocities (P= 0.9). Based on these results, abnormal DUS findings observed on baseline TIPS ultrasound examination have low predictive value for future covered TIPS dysfunction and failure.
Phosphatidylinositol Cycle Disruption is Central to Atypical Hemolytic-Uremic Syndrome Caused by Diacylglycerol Kinase Epsilon Deficiency
Authors: So Vincent , Wu Jing , Traynor-Kaplan Alexis , Choy Christopher , Epand Richard , Botelho Roberto , Lemaire Mathieu
Published: May 2019

Background

Loss-of-function mutations in diacylglycerol kinase epsilon (DGKE) cause a rare form of atypical hemolytic-uremic syndrome (aHUS) for which there is no treatment besides kidney transplantation. Highly expressed in kidney endothelial cells, DGKE is a lipid kinase that phosphorylates diacylglycerol (DAG) to phosphatic acid (PA). Specifically, DGKE’s preferred substrate is 38:4-DAG, that is DAG containing stearic acid (18:0) and arachidonic acid (20:4). DAG is produced when phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is cleaved by phospholipase C (PLC). A better understanding of how DGKE deficiency impacts the endothelial lipid landscape is critical to developing a treatment for this condition.

Methods

We used orthogonal methods to compare the lipid levels in two novel models of DGKE deficiency to their respective controls: an immortalized human umbilical vein endothelial cell (iHUVEC) engineered with CRISPR/Cas9 and a blood outgrowth endothelial cell (BOEC) from an affected patient. Methods included mass spectrometry lipidomics, radiolabeling of phosphoinositides with [3H]myo-inositol, and live-tracking of a transfected fluorescent PtdIns(4,5)P2 biosensor.

Results

Unexpectedly, mass spectrometry lipidomics data revealed that high 38:4-DAG was not observed in the two DGKE-deficient models. Instead, a reduction in 38:4-PtdIns(4,5)P2 was the major abnormality.These results were confirmed with the other two methods in DGKE-deficient iHUVEC.

Conclusion

Reduced 38:4-PtdIns(4,5)P2—but not increased 38:4-DAG—is likely to be key to the pro-thrombotic phenotype exhibited by patients with DGKE aHUS.

TRANSLATIONAL STATEMENT

Mutations in DGKE cause a severe renal thrombotic microangiopathy that affects young children and leads to end-stage renal disease before adulthood. DGKE preferentially phosphorylates diacylglycerol to its corresponding phosphatidic acid (PA), which is then used to synthesize PtdIns(4,5)P2 via the phosphatidylinositol cycle. Understanding the disease pathophysiology is necessary to develop a treatment to prevent this outcome. This paper describes how we applied mass spectrometry lipidomics to two novel models of DGKE deficiency to investigate how this defect impacts the levels of diacylglycerol, PA and related phosphoinositides in endothelia. Unexpectedly, our data show that the critical abnormality caused by DGKE deficiency is not high diacylglycerol, but rather low PtdIns(4,5)P2. Restoring endothelial PtdIns(4,5)P2 homeostasis may be the cornerstone to treat these patients.
An Algorithmic Barrier to Neural Circuit Understanding
Authors: Ramaswamy Venkatakrishnan
Published: May 2019

Neuroscience is witnessing extraordinary progress in experimental techniques, especially at the neural circuit level. These advances are largely aimed at enabling us to understand how neural circuit computations mechanisticallycausebehavior. Here, using techniques from Theoretical Computer Science, we examine how many experiments are needed to obtain such an empirical understanding. It is proved, mathematically, that establishing the most extensive notions of understandingneedexponentially-many experiments in the number of neurons, in general, unless a widely-posited hypothesis about computation is false. Worse still, the feasible experimental regime is one where the number of experiments scales sub-linearly in the number of neurons, suggesting a fundamental impediment to such an understanding. Determining which notions of understanding are algorithmically tractable, thus, becomes an important new endeavor in Neuroscience.
Graphene-enabled, spatially controlled electroporation of adherent cells for live-cell super-resolution microscopy
Authors: Moon Seonah , Li Wan , Xu Ke
Published: May 2019

The incorporation of exogenous molecules into live cells is essential for both biological research and therapeutic applications. In particular, for the emerging field of super-resolution microscopy of live mammalian cells, reliable fluorescent labeling of intracellular targets remains a challenge. Here, utilizing the unique mechanical, electrical, and optical properties of graphene, a single layer of bonded carbon atoms, we report a facile approach that enables both high-throughput delivery of fluorescent probes into adherent live cells andin situsuper-resolution microscopy on the same device. ∼90% delivery efficiencies are achieved for free dyes and dye-tagged affinity probes, short peptides, and whole antibodies, thus enabling high-quality super-resolution microscopy. Moreover, we demonstrate excellent spatiotemporal controls, which, in combination with the ready patternablity of graphene, allow for the spatially selective delivery of two different probes for cells at different locations on the same substrate. We thus open up a new pathway to the microscopic manipulation and visualization of live cells.
Evolution of vascular plants through redeployment of ancient developmental regulators
Authors: van ’t Wout Hofland Nicole , Lu Kuan-Ju , Mor Eliana , Mutte Sumanth , Abrahams Paul , Kato Hirotaka , Vandepoele Klaas , Weijers Dolf , De Rybel Bert
Published: May 2019

Vascular plants provide most of the biomass, food and feed on earth; yet the molecular innovations that led to the evolution of their conductive tissues are unknown. Here, we reveal the evolutionary trajectory for the heterodimeric TMO5/LHW transcription factor complex, which is rate-limiting for vascular cell proliferation in Arabidopsis thaliana. Both regulators have origins predating vascular tissue emergence, and even terrestrialization. We further show that TMO5 evolved its modern function, including dimerization with LHW, at the origin of land plants. A second innovation in LHW, coinciding with vascular plant emergence, conditioned obligate heterodimerization and generated the critical function in vascular development. In summary, our results suggest that division potential of vascular cells may have been a major driver in the evolution of vascular plants.
Epigenetic loss of heterozygosity of Apc and an inflammation-associated mutational signature detected in Lrig1+/--driven murine colonic adenomas
Authors: Preston Jessica
Published: May 2019

Murine colonic adenomas induced by the loss of a single copy of the tumor suppressor gene Apc in Lrig1+/- expressing progenitor cells grow rapidly, with high penetrance and tumor multiplicity. This study investigates the prevalence of intertumoral genetic heterogeneity and phenotypic variation across tumors, and attempts to identify the genomic cause of the unusual phenotype. Adult Lrig1-CreERT2/+; Apc-flox/+ mice were intraperitoneal injected with 2mg tamoxifen for 3 consecutive days which induced highly penetrant, dysplastic adenomas in the distal colon ∼100 days later. Whole tumors (n=14) from 8 mice were excised and tumor exome DNA and mRNA were sequenced. Somatic mutations present in the tumor exome DNA were compared with adjacent normal colon (n=9 tumors from 3 mice). Putative somatic mutations were called after stringent filtering using SeuratSomatic, a Genome Analysis Toolkit software module. RNA-Seq was performed on tumor mRNA (n=5 tumors from 5 mice) compared to wildtype colon (n=3). Differential gene expression was profiled using the R package DESeq2. Copy number variations and splicing defects were assessed using custom tracks on the UCSC genome browser.

Adenomas resulting from the loss of Apc in Lrig1+/-- expressing colonic progenitor cells are genetically heterogeneous and hypermutated, containing ∼25-30 high-quality somatic mutations per megabase. A loss of heterozygosity of Apc was not observed in the tumor genomes, however evidence of an epigenetic loss of heterozygosity was readily apparent in the tumor transcriptome. The tumors display a strong bias toward G: C > A: T point mutations, which are a signature of guanine adducts, associated with tobacco tar and H. pylori infections. Putative tumor-driving mutations were detected and thousands of differentially expressed genes were identified including several UDP glucuronosyltransferases. Abnormal splicing patterns characterized by a loss of intron retention were detected in several RNA-binding genes throughout the tumor transcriptome. The widespread defects in gene expression, genomic stability, and splicing patterns implies that an early epigenetic loss of Apc in Lrig1+/--expressing progenitor cells causes a rapid formation of guanine adducts and a corresponding accumulation of mutation C>A point mutations. This study demonstrates that randomly-appearing oncogenic mutations can become fixed into a latent genomic reservoir prior to advanced disease.
Systematic exploration of protein conformational space using a Distance Geometry approach
Authors: Malliavin Thérèse E. , Mucherino Antonio , Lavor Carlile , Liberti Leo
Published: May 2019

The optimisation approaches classically used during the determination of protein structure encounter various diffculties, specially when the size of the conformational space is large. Indeed, in such case, algorithmic convergence criteria are more difficult to set up. Moreover, the size of the search space makes it difficult to achieve a complete exploration. The interval Branch-and-Prune (iBP) approach, based on the reformulating of the Distance Geometry Problem (DGP) provides a theoretical frame for the generation of protein conformations, by systematically sampling the conformational space. When an appropriate subset of inter-atomic distances is known exactly, this worst-case exponential-time algorithm is provably complete and fixed-parameter tractable. These guarantees, however, immediately disappear as distance measurement errors are introduced. Here we propose an improvement of this approach: the threading-augmented interval Branch-and-Prune (TAiBP), where the combinatorial explosion of the original iBP approach arising from its exponential complexity is alleviated by partitioning the input instances into consecutive peptide fragments and by using Self-Organizing Maps (SOMs) to obtain clusters of similar solutions. A validation of the TAiBP approach is presented here on a set of proteins of various sizes and structures. The calculation inputs are: a uniform covalent geometry extracted from force field covalent terms, the backbone dihedral angles with error intervals, and a few long-range distances. For most of the proteins smaller than 50 residues and interval widths of 20°, the TAiBP approach yielded solutions with RMSD values smaller than 3 Å with respect to the initial protein conformation. The efficiency of TAiBP approach for proteins larger than 50 residues will require the use of non-uniform covalent geometry, and may have benefits from the recent development of residue-specific force-fields.
Unfolded protein-independent IRE1 activation contributes to multifaceted developmental processes in Arabidopsis
Authors: Mishiba Kei-ichiro , Iwata Yuji , Mochizuki Tomofumi , Matsumura Atsushi , Nishioka Nanami , Hirata Rikako , Koizumi Nozomu
Published: May 2019

As an initial step for the unfolded protein response (UPR) pathway, the luminal domain of inositol requiring enzyme 1 (IRE1) senses unfolded proteins in the endoplasmic reticulum (ER). Recent findings in yeast and metazoans suggest alternative IRE1 activation without the sensor domain, although its mechanism and physiological significance remain to be elucidated. In Arabidopsis, the IRE1A and IRE1B double mutant (ire1a/b) is unable to activate cytoplasmic splicing of bZIP60 mRNA and regulated IRE1-dependent decay (RIDD) under ER stress, while the mutant does not exhibit severe developmental defects and is fertile under non-stress conditions. In this study, we focused on a third Arabidopsis IRE1 gene, designated as IRE1C, whose product lacks a sensor domain. We found that even though ire1c and ire1a/c mutants did not exhibit defective bZIP60 splicing and RIDD under ER stress, the ire1a/b/c triple mutant is lethal. Heterozygous IRE1C (ire1c/+) mutation in the ire1a/b mutants resulted in growth defects and reduction of the number of pollen grains. Genetic analysis revealed that IRE1C is required for male gametophyte development in the ire1a/b mutant background. Expression of a mutant form of IRE1B that lacks the luminal sensor domain (ΔLD) in the ire1a/b mutant did not complement defects in ER stress-dependent bZIP60 splicing and RIDD. Nevertheless, expression of ΔLD complemented a developmental defect in the male gametophyte in ire1a/b/c haplotype. In vivo, the ΔLD protein was activated by glycerol treatment that increases the composition of saturated lipid and was able to activate RIDD but not bZIP60 splicing. Phenotypes of IRE1B mutants lacking the sensor domain produced by CRISPR/Cas9-mediated gene editing in the ire1a/c mutant background were essentially same as those of ΔLD-expressing ire1a/b mutant. These observations suggest that IRE1 contributes to plant development, especially male gametogenesis, using an alternative activation mechanism that bypasses the unfolded protein-sensing luminal domain.
Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs
Authors: Miles Jennifer A. , Hobor Fruzsina , Taylor James , Tiede Christian , Rowell Philip R. , Trinh Chi H. , Jackson Brian , Nadat Fatima , Kyle Hannah F. , Wicky Basile I. M. , Clarke Jane , Tomlinson Darren C. , Wilson Andrew J. , Edwards Thomas A.
Published: May 2019

The BCL-2 family is a challenging set of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are desirable as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL, BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective and potent recognition of their target BCL-2 protein. For anti-apoptotic targets, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug bound like conformation. These results indicate Affimers can be used as alternative templates to inspire design of selective BCL-2 family modulators, and provide proof-of-concept for the elaboration of selective non-antibody binding reagents for use in cell-biology applications.
Accelerating Sequence Alignment to Graphs
Authors: Jain Chirag , Dilthey Alexander , Misra Sanchit , Zhang Haowen , Aluru Srinivas
Published: May 2019

Aligning DNA sequences to an annotated reference is a key step for genotyping in biology. Recent scientific studies have demonstrated improved inference by aligning reads to a variation graph, i.e., a reference sequence augmented with known genetic variations. Given a variation graph in the form of a directed acyclic string graph, the sequence to graph alignment problem seeks to find the best matching path in the graph for an input query sequence. Solving this problem exactly using a sequential dynamic programming algorithm takes quadratic time in terms of the graph size and query length, making it difficult to scale to high throughput DNA sequencing data. In this work, we propose the first parallel algorithm for computing sequence to graph alignments that leverages multiple cores and single-instruction multiple-data (SIMD) operations. We take advantage of the available inter-task parallelism, and provide a novel blocked approach to compute the score matrix while ensuring high memory locality. Using a 48-core Intel Xeon Skylake processor, the proposed algorithm achieves peak performance of 317 billion cell updates per second (GCUPS), and demonstrates near linear weak and strong scaling on up to 48 cores. It delivers significant performance gains compared to existing algorithms, and results in run-time reduction from multiple days to three hours for the problem of optimally aligning high coverage long (PacBio/ONT) or short (Illumina) DNA reads to an MHC human variation graph containing 10 million vertices.

Availability

The implementation of our algorithm is available at https://github.com/ParBLiSS/PaSGAL. Data sets used for evaluation are accessible using https://alurulab.cc.gatech.edu/PaSGAL.
Pathogen susceptibility and fitness costs explain variation in immune priming across natural populations of flour beetles
Authors: Khan Imroze , Prakash Arun , Agashe Deepa
Published: May 2019

In many insects, individuals primed with low doses of pathogens early in life have higher survival after exposure to the same pathogen later in life. Yet, our understanding of the evolutionary and ecological history of priming of immune response in natural insect populations is limited. Previous work demonstrated population‐, sex‐ and stage‐specific variation in the survival benefit of priming response in flour beetles (Tribolium castaneum) infected with their natural pathogen Bacillus thuringiensis. However, the evolutionary forces responsible for this natural variation remained unclear.

In the present work, we tested whether the strength of the priming response (measured as the survival benefit after priming and subsequent infection, relative to unprimed controls) was associated with multiple fitness parameters and immune components across 10 flour beetle populations collected from different locations in India.

Our results suggest two major selective pressures that may explain the observed inter‐population variation in priming: (a) Basal pathogen susceptibility – populations that were more susceptible to infection produced a stronger priming response, and (b) Short‐term early reproductive success – populations where primed females produced more offspring early in life (measured over 2 days) had lower survival benefit (measured over 120 days), suggesting a potential trade‐off between early reproduction and priming response. However, the negative association between survival and reproduction is limited to priming and infection in adults, but not in larvae. While other components of beetle fitness (starvation resistance and larval development) and immune function (haemolymph antibacterial activity and antimicrobial quinone secretion) also varied widely across populations, none of them was correlated with the variation in priming responses across populations.

Our work is the first systematic empirical demonstration of multiple selective pressures that may govern the evolution of immune priming in the wild. We hope that this motivates further experiments to establish the role of pathogen‐imposed selection and fitness costs in the evolution of priming in natural insect populations.
Grape Peel Extract and Resveratrol Inhibit Wrinkle Formation in Mice Model Through Activation of Nrf2/HO‐1 Signaling Pathway
Authors: Kim Jungeun , Oh Jisun , Averilla Janice N. , Kim Hyo Jung , Kim Jae‐Sik , Kim Jong‐Sang
Published: May 2019

Considering the anti‐photoaging effect of antioxidant compounds, we investigated the protective capacity of grape peel extract (GPE) and resveratrol on ultraviolet (UV)‐induced skin wrinkle formation. Total phenolic, total anthocyanin, and total flavonoid content in GPE prepared from peel of Campbell Early variety were 23.96 ± 0.09, 3.27 ± 0.40, and 1.24 ± 0.09 mg/g dry weight, respectively. Additionally, trans‐resveratrol and piceid content of the resulting GPE were 117.14 ± 19.97 and 85.23 ± 8.89 µg/g dry weight, respectively. Oral administration of either 2 g GPE or 2 mg resveratrol per kg body weight in mice attenuated UVB‐induced epidermal thickening (the thickness was reduced by about 63% and 55% with GPE and resveratrol consumption prior to exposure to UVB, respectively, compared to only UVB‐treated condition) and had marginally protective effect on wrinkle formation of skin exposed to UVB. As introduction of either GPE or resveratrol induced Nrf2‐dependent antioxidant enzymes including heme oxygenase‐1 (HO‐1) in liver and skin as well as inhibited metalloproteinases, it is highly probable that the extract or resveratrol mitigated UVB‐induced photoaging through activation of Nrf2/HO‐1 signaling pathway.

Practical Application

This study proved that resveratrol and the extract of grape peel, a common by‐product of grape juice processing, provide effective protection from UV‐induced skin wrinkle formation. Therefore, grape peel extract, which contains an appreciable amount of bioactive compound resveratrol, can be utilized as functional food ingredient for the manufacture of inner beauty products.
“Gracias por escucharnos”: Listening and Learning from Latinx Immigrant Parents Through Video‐Cued Ethnography
Authors: Colegrove Kiyomi Sánchez-Suzuki
Published: May 2019

This article highlights the voices and expertise of Latinx immigrant parents when describing their and their children's experiences with schools in Texas and California. The video‐cued ethnography method allowed participants to engage in dialogue among themselves across space and time as well as explore issues regarding their voice and power. By creating dialogic spaces and listening to Latinx immigrant parents, stakeholders can better understand and address the needs of Latinx communities.
Life cycle models of women's body mass index and probability of being obese: Evidence from panel data
Authors: Huang Ying , Huffman Wallace E.
Published: May 2019

The objective of this paper is to develop a multiperiod, finite‐life, life cycle models of household decisions on food, leisure, and health (body mass index [BMI] or being obese) and to estimate econometric versions of these models treating SNAP (Supplemental Nutrition Assistance Program) participation as endogenous. A key insight from the economic models is that households allocate their wealth over the multiperiod life cycle to equalize the marginal utility of wealth in each period. The observations for this study are a balanced panel of over 1,600 women from the National Longitudinal Survey of Youth, 1979 Cohort (NLSY79). We focus on the 20‐year period starting in 1986, when SNAP data first became available. Women of all ages are included in the study because at the beginning of adulthood women cannot accurately predict over their life cycle labor and marriage market and health shocks that can thrust them into an economic position where they would qualify for SNAP. New findings include that a woman's household SNAP participation with or without updating for last periods health status and higher local dairy product prices reduce significantly her BMI and probability of being obese.
Involvement of STAT3 in the synergistic induction of 11β‐HSD1 by SAA1 and cortisol in human amnion fibroblasts
Authors: Lu Yi , Zhou Qiong , Lu Jiang‐Wen , Wang Wang‐Sheng , Sun Kang
Published: May 2019

Problem

Cortisol, which is regenerated from biologically inactive cortisone by 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) in human fetal membranes, may play an important role in human parturition. Recently, we have demonstrated that human fetal membranes are capable of de novo synthesis of serum amyloid A1 (SAA1), an acute‐phase protein of inflammation, and SAA1 may be engaged in multiple actions associated with human parturition. It remains to be determined whether SAA1 can interact with cortisol in the regulation of 11β‐HSD1 in the fetal membranes.

Method of Study

In the current study, we examined the regulation of 11β‐HSD1 expression by SAA1, and the interaction between SAA1 and cortisol in the regulation of 11β‐HSD1 expression in primary human amnion fibroblasts and amnion tissue.

Results

Either SAA1 or cortisol induced 11β‐HSD1 expression in a concentration‐dependent manner. Combination of SAA1 and cortisol synergistically enhanced 11β‐HSD1 expression. Mechanism studies revealed that SAA1 and cortisol induced the phosphorylation of the transcription factor STAT3 in a sequential order with the induction by SAA1 preceding the induction by cortisol. Furthermore, the induction of 11β‐HSD1 expression by either SAA1 or cortisol or combination of SAA1 and cortisol was blocked by STAT3 inhibition with its antagonist S3I‐201 or siRNA‐mediated knockdown.

Conclusion

This study has demonstrated that SAA1 and cortisol can reinforce each other in the induction of 11β‐HSD1 expression through sequential phosphorylation of STAT3. The synergistic enhancement of 11β‐HSD1 expression by SAA1 and cortisol may lead to excessive cortisol accumulation in the fetal membranes at parturition.
Early childhood infections and the use of antibiotics and antipyretic‐analgesics in Finland, Estonia and Russian Karelia
Authors: Mustonen Neea , Siljander Heli , Peet Aleksandr , Tillmann Vallo , Härkönen Taina , Ilonen Jorma , Hyöty Heikki , Knip Mikael ,   the DIABIMMUNE Study Group
Published: May 2019

Aim

Infections in early childhood are common reasons to seek medical attention. This study compares the prevalence of infections, and the use of antibiotics and antipyretic–analgesics, in children from Finland, Estonia and Russian Karelia.

Methods

Children with a genetically increased risk for type 1 diabetes (N = 797) were observed from birth up to 3 years of age. Illnesses and medications were reported by parents continuously. All reported infections, antibiotics and antipyretic–analgesics were compared between Finland and Estonia, and to a lesser extent with Russian Karelia, due to poor study compliance.

Results

Compared with Estonians, Finns reported more infections during the first and second years of life. During the follow‐up, Finnish children had 10 infections while Estonians only had 8 (p < 0.001). Finns also used more antibiotics and antipyretic–analgesics in each year during the follow‐up. Russian Karelians reported the lowest frequency of infections and the most infrequent use of antibiotics and antipyretic–analgesics in the first two years of life.

Conclusion

Infections and the use of antibiotics and antipyretic–analgesics in early childhood were most frequent in Finland, where socio‐economic conditions are the most developed and microbial encounters are sparse. This may reflect on the hygiene hypothesis, a less effective immune system that allows normally harmless microbes to attack and cause clinical infections.
Political geography and language: A reappraisal for a diverse discipline
Authors: Medby Ingrid A.
Published: May 2019

After decades of going beyond the linguistic and textual concerns of early critical geopolitical scholarship, literatures in political geography are today offering rich engagements with the affective, material, embodied, and technological world. However, this paper argues that despite pressures to continually break new intellectual ground, political geography needs not and should not move wholly past concerns with language and language use. Instead, there is at present a need to reassess the value of language as both analytical topic and academic practice; not as alternative, but additive to new insights and conversations. The paper sketches how attention to language has been foregrounded and backgrounded in political geographical endeavours, using the examples of “new Cold War” claims and cybersecurity to show what some consider dichotomous approaches may be brought into conversation. A new research agenda is broadly outlined in order to diversify the discipline. This call for engagement with the linguistic extends not just to the empirical and methodological, but also the academically political: in efforts to diversify the academy, language is a key topic to be grappled with. In reconsidering academic practices, the argument thus extends to writing, publishing, and research writ large: through language and language use, political geography too may be re‐articulated.
Pharmacology and function of the orphan GPR139 G protein‐coupled receptor
Authors: Vedel Line , Nøhr Anne Cathrine , Gloriam David E. , Bräuner‐Osborne Hans
Published: May 2019

G protein‐coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory. GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α‐helices spanning the cell membrane, and forming the majority of the known ortho‐ or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently marketed drugs. GPCRs activate one or more of the four G protein families (Gq/11, Gi/o, Gs and G12/13) and/or ß‐arrestin. About a third of the non‐olfactory GPCRs are referred to as orphan receptors which means that their endogenous agonist(s) have not yet been found or firmly established. In this MiniReview, we focus on the orphan GPR139 receptor, for which the aromatic amino acids L‐Trp and L‐Phe as well as ACTH/α‐MSH‐related peptides have been proposed as endogenous agonists. GPR139 has been reported to activate several G protein pathways of which Gq/11 is the primary one. The receptor shows the highest expression in the striatum, thalamus, hypothalamus, pituitary and habenula of the human, rat and mouse CNS. We review the surrogate agonists and antagonists that have been published as well as the agonist pharmacophore and binding site. Finally, the putative physiological functions and therapeutic potential are outlined.
Utilizing a PLASMIC score‐based approach in the management of suspected immune thrombotic thrombocytopenic purpura: a cost minimization analysis within the Harvard TMA Research Collaborative
Authors: Upadhyay Vivek A. , Geisler Benjamin P. , Sun Lova , Uhl Lynne , Kaufman Richard M. , Stowell Christopher , Makar Robert S. , Bendapudi Pavan K.
Published: May 2019

The PLASMIC score is a recently described clinical scoring algorithm that rapidly assesses the probability of severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency among patients presenting with microangiopathic haemolytic anaemia. Using a large multi‐institutional cohort, we explored whether an approach utilizing the PLASMIC score to risk‐stratify patients with suspected immune thrombotic thrombocytopenic purpura (iTTP) could lead to significant cost savings. Our consortium consists of institutions with an unrestricted approach to ADAMTS13 testing (Group A) and those that require pre‐approval by the transfusion medicine service (Group B). Institutions in Group A tested more patients than those in Group B (P < 0·001) but did not identify more cases of iTTP (P = 0·29) or have lower iTTP‐related mortality (P = 0·84). Decision tree cost analysis showed that applying a PLASMIC score‐based strategy to screen patients for ADAMTS13 testing in Group A would have reduced costs by approximately 27% over the 12‐year period of our study compared to the current approach. Savings were primarily driven by a reduction in unnecessary therapeutic plasma exchanges, but lower utilization of ADAMTS13 testing and subspecialty consultations also contributed. Our data indicate that using the PLASMIC score to guide ADAMTS13 testing and the management of patients with suspected iTTP could be associated with significant cost savings.
Development and content validation of the Urethroplasty Training and Assessment Tool (UTAT) for dorsal onlay buccal mucosa graft urethroplasty
Authors: Jasionowska Sara , Shabbir Majed , Brunckhorst Oliver , Khan Muhammad Shamim , Manzoor Hussain , Dasgupta Prokar , Anderson Paul , Barbagli Guido , Ahmed Kamran
Published: May 2019

Objectives

To develop and validate the Urethroplasty Training and Assessment Tool (UTAT) using Healthcare Failure Mode and Effect Analysis (HFMEA) for training and assessment of urology trainees learning this urethral reconstruction technique, as urethroplasty is the ‘gold standard’ treatment for long and recurrent urethral strictures and with a variety of techniques and a lack of standardised reconstructive curricula, there is a need for procedure‐specific training tools to improve surgeon training and patient safety.

Materials and Methods

This international observational study was performed over an 11‐month period. The HFMEA was used to identify and evaluate hazardous stages of urethroplasty to develop the UTAT. Hazard scores were calculated for the included steps of urethroplasty. Content validation was performed by 12 expert surgeons and multidisciplinary teams from international tertiary centres.

Results

The HFMEA process resulted in an internationally validated UTAT. Hazard scores ≥4 and single point weaknesses were included to implement actions and outcome measures. Content validation was achieved by circulating the process map, hazard analysis table, and developed tools. Changes were implemented based on the feedback received from expert surgeons. The content validated dorsal onlay buccal mucosa graft bulbar UTAT contained five phases, 10 processes and 23 sub‐processes.

Conclusions

The modular UTAT offers a comprehensive validated training tool developed via a detailed HFMEA protocol. This may be utilised to standardise the training and assessment of urology trainees.
Systemic risk contagion in FX market: A frequency connectedness and network analysis
Authors: Polat Onur
Published: May 2019

In this study, we analyse systemic risk contagion between a set of most actively traded currencies (EURO, JPY, GBP, AUD, CAD and CHF) by application of VAR based frequency connectedness proposed by Baruník and Křehlík. By using this novel approach, we gauge foreign exchange (FX) market connectedness in 200‐day frequency band using spectral representation of variance decompositions of VAR and identify directional spillovers between the most actively traded foreign exchange rates. Dynamics of the overall spillover index reveals that the index capture well‐known financial stress incidents properly. Finally, network topology of directional spillovers between currency pairs is provided for visulalization interconnectedness between them.