bluuebunny/crossref_metadata_2025 huggingface dataset:
AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption
Authors: Whiting Jennifer L. , Ogier Leah , Forbush Katherine A. , Bucko Paula , Gopalan Janani , Seternes Ole-Morten , Langeberg Lorene K. , Scott John D.
Published: July 2016

Significance

Systemic control of water homeostasis is a vital physiological process. Vasopressin-regulated reabsorption of water through aquaporin-2 (AQP2) water pores in the kidney preserves fluid balance and results in more concentrated urine. We have discovered that the scaffolding protein A-Kinase Anchoring Protein 220 (AKAP220) controls vasopressin-independent aspects of AQP2 trafficking at apical membranes of cells of the kidney-collecting ducts. We postulate that this proceeds via a molecular mechanism that evokes RhoA-mediated modulation of “actin barrier” dynamics. Loss of AKAP220 leads to accumulation of AQP2 at the apical plasma membrane and reduces urine-diluting capacity during overhydration. This phenotype may be clinically relevant, as accumulation of AQP2 at the apical membrane is the desired therapeutic outcome when treating patients with certain renal disorders, including nephrogenic diabetes insipidus.
Testimonial injustice and prescriptive credibility deficits
Authors: Munroe Wade
Published: July 2016

In light of recent social psychological literature, I expand Miranda Fricker’s important notion of testimonial injustice. A fair portion of Fricker’s account rests on an older paradigm of stereotype and prejudice. Given recent empirical work, I argue for what I dub prescriptive credibility deficits in which a backlash effect leads to the assignment of a diminished level of credibility to persons who act in counter-stereotypic manners, thereby flouting prescriptive stereotypes. The notion of a prescriptive credibility deficit is not merely an interesting conceptual addendum that can be appended to Fricker’s theory without need for further emendation. I develop the wider implications of prescriptive credibility deficits and argue that they pose a challenge to Fricker’s conception of (1) the function of credibility assignments in conversational exchange and (2) how a virtuous listener should respond to the potential threat of a prejudicial stereotype affecting her credibility assignments.
Cortactin promotes exosome secretion by controlling branched actin dynamics
Authors: Sinha Seema , Hoshino Daisuke , Hong Nan Hyung , Kirkbride Kellye C. , Grega-Larson Nathan E. , Seiki Motoharu , Tyska Matthew J. , Weaver Alissa M.
Published: July 2016

Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs). Regulation of exosome secretion by cortactin requires binding to the branched actin nucleating Arp2/3 complex and to actin filaments. Furthermore, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin MVE docking sites and exosome secretion. Functionally, the addition of purified exosomes to cortactin-knockdown cells rescued defects of those cells in serum-independent growth and invasion. These data suggest a model in which cortactin promotes exosome secretion by stabilizing cortical actin-rich MVE docking sites.
Loss ofEzh2synergizes withJAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis
Authors: Shimizu Takafumi , Kubovcakova Lucia , Nienhold Ronny , Zmajkovic Jakub , Meyer Sara C. , Hao-Shen Hui , Geier Florian , Dirnhofer Stephan , Guglielmelli Paola , Vannucchi Alessandro M. , Feenstra Jelena D. Milosevic , Kralovics Robert , Orkin Stuart H. , Skoda Radek C.
Published: July 2016

Myeloproliferative neoplasm (MPN) patients frequently show co-occurrence of JAK2-V617F and mutations in epigenetic regulator genes, including EZH2. In this study, we show that JAK2-V617F and loss of Ezh2 in hematopoietic cells contribute synergistically to the development of MPN. The MPN phenotype induced by JAK2-V617F was accentuated in JAK2-V617F;Ezh2−/− mice, resulting in very high platelet and neutrophil counts, more advanced myelofibrosis, and reduced survival. These mice also displayed expansion of the stem cell and progenitor cell compartments and a shift of differentiation toward megakaryopoiesis at the expense of erythropoiesis. Single cell limiting dilution transplantation with bone marrow from JAK2-V617F;Ezh2+/− mice showed increased reconstitution and MPN disease initiation potential compared with JAK2-V617F alone. RNA sequencing in Ezh2-deficient hematopoietic stem cells (HSCs) and megakaryocytic erythroid progenitors identified highly up-regulated genes, including Lin28b and Hmga2, and chromatin immunoprecipitation (ChIP)–quantitative PCR (qPCR) analysis of their promoters revealed decreased H3K27me3 deposition. Forced expression of Hmga2 resulted in increased chimerism and platelet counts in recipients of retrovirally transduced HSCs. JAK2-V617F–expressing mice treated with an Ezh2 inhibitor showed higher platelet counts than vehicle controls. Our data support the proposed tumor suppressor function of EZH2 in patients with MPN and call for caution when considering using Ezh2 inhibitors in MPN.
Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator
Authors: Akiyama Nobuko , Takizawa Nobukazu , Miyauchi Maki , Yanai Hiromi , Tateishi Ryosuke , Shinzawa Miho , Yoshinaga Riko , Kurihara Masaaki , Demizu Yosuke , Yasuda Hisataka , Yagi Shintaro , Wu Guoying , Matsumoto Mitsuru , Sakamoto Reiko , Yoshida Nobuaki , Penninger Josef M. , Kobayashi Yasuhiro , Inoue Jun-ichiro , Akiyama Taishin
Published: July 2016

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire+ mTECs) is unclear. Here, we describe novel embryonic precursors of Aire+ mTECs. We found the candidate precursors of Aire+ mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire+ mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire+ mTECs and efficiently suppressed the onset of autoimmunity induced by Aire+ mTEC deficiency. Mechanistically, pMECs differentiated into Aire+ mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire+ mTECs.
Macrophage Migration Inhibitory Factor as a Novel Biomarker of Portopulmonary Hypertension
Authors: DuBrock Hilary M. , Rodriguez‐Lopez Josanna M. , LeVarge Barbara L. , Curry Michael P. , VanderLaan Paul A. , Zsengeller Zsuzsanna K. , Pernicone Elizabeth , Preston Ioana R. , Yu Paul B. , Nikolic Ivana , Xu Dihua , Thadhani Ravi I. , Channick Richard N. , Karumanchi S. Ananth
Published: July 2016

Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case‐control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary vascular resistance (PVR) >240 dynes·s·cm−5. Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme‐linked immunosorbent assay. Continuous variables were compared using a Mann‐Whitney U test and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls (median MIF level [interquartile range] in systemic circulation: 46.68 ng/mL [32.31–76.04] vs. 31.19 ng/mL [26.92–42.17], P = 0.009; in pulmonary circulation: 49.59 ng/mL [35.90–108.80] vs. 37.78 [21.78–45.53], P = 0.002). In patients with POPH, MIF levels were positively correlated with PVR (r = 0.58, P = 0.006) and inversely correlated with cardiac output (r = −0.57, P = 0.007). MIF >60 ng/mL or tricuspid regurgitation gradient >50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension.
Trade-off among different anti-herbivore defence strategies along an altitudinal gradient
Authors: Dostálek Tomáš , Rokaya Maan Bahadur , Maršík Petr , Rezek Jan , Skuhrovec Jiří , Pavela Roman , Münzbergová Zuzana
Published: July 2016

The type and intensity of plant–herbivore interactions are likely to be altered under climate change as a consequence of differential dispersal rates of plants and their herbivores. Here, we studied variation in herbivore damage on Salvia nubicola in the field and compared its growth and defence strategies against herbivores in controlled conditions using seeds from populations along a broad altitudinal gradient. Our work is one of the first studies to simultaneously measure complex intraspecific variation in plant growth, direct and indirect defences as well as plant tolerance (ability to regrow) as a consequence of herbivore attack simulated by clipping. In the field, we found that plants experienced higher herbivore pressure in lower altitudes. In the greenhouse, plants grown from seeds collected in lower-altitude populations grew better and produced a higher content of phenolic compounds (direct defence) and volatile organic compounds (indirect defence) in response to simulated herbivory. However, there were no differences in tolerance and effect of S. nubicola extracts on the model generalist herbivore Spodoptera littoralis (direct defence) along the altitudinal gradient. Although we found that S. nubicola developed a range of defence strategies, the strategies do not seem to be used simultaneously in all populations even though most of them are correlated with altitudinal gradient. Our finding is in agreement with the current knowledge that co-expression of multiple defences might be costly for a plant, since investment in defensive traits is assumed to reduce the resource availability for growth and reproduction. Our study thus shows the importance of simultaneous study of different defence strategies since understanding these trade-offs could be necessary for detecting the mechanisms by which plants are able to cope with future climate change.
A subpopulation model to analyze heterogeneous cell differentiation dynamics
Authors: Chan Yat Hin , Intosalmi Jukka , Rautio Sini , Lähdesmäki Harri
Published: July 2016

Motivation: Cell differentiation is steered by extracellular signals that activate a cell type specific transcriptional program. Molecular mechanisms that drive the differentiation can be analyzed by combining mathematical modeling with population average data. For standard mathematical models, the population average data is informative only if the measurements come from a homogeneous cell culture. In practice, however, the differentiation efficiencies are always imperfect. Consequently, cell cultures are inherently mixtures of several cell types, which have different molecular mechanisms and exhibit quantitatively different dynamics. There is an urgent need for data-driven mathematical modeling approaches that can detect possible heterogeneity and, further, recover the molecular mechanisms from heterogeneous data.

Results: We develop a novel method that models a heterogeneous population using homogeneous subpopulations that evolve in parallel. Different subpopulations can represent different cell types and each subpopulation can have cell type specific molecular mechanisms. We present statistical methodology that can be used to quantify the effect of heterogeneity and to infer the subpopulation specific molecular interactions. After a proof of principle study with simulated data, we apply our methodology to analyze the differentiation of human Th17 cells using time-course RNA sequencing data. We construct putative molecular networks driving the T cell activation and Th17 differentiation and allow the cell populations to be split into two subpopulations in the case of heterogeneous samples. Our analysis shows that the heterogeneity indeed has a statistically significant effect on observed dynamics and, furthermore, our statistical methodology can infer both the subpopulation specific molecular mechanisms and the effect of heterogeneity.

Availability and Implementation: An implementation of the method is available at http://research.ics.aalto.fi/csb/software/subpop/ .

Contact:  jukka.intosalmi@aalto.fi or harri.lahdesmaki@aalto.fi

Supplementary information:  Supplementary data are available at Bioinformatics online.
BioNetGen 2.2: advances in rule-based modeling
Authors: Harris Leonard A. , Hogg Justin S. , Tapia José-Juan , Sekar John A. P. , Gupta Sanjana , Korsunsky Ilya , Arora Arshi , Barua Dipak , Sheehan Robert P. , Faeder James R.
Published: July 2016

Summary : BioNetGen is an open-source software package for rule-based modeling of complex biochemical systems. Version 2.2 of the software introduces numerous new features for both model specification and simulation. Here, we report on these additions, discussing how they facilitate the construction, simulation and analysis of larger and more complex models than previously possible.

Availability and Implementation : Stable BioNetGen releases (Linux, Mac OS/X and Windows), with documentation, are available at http://bionetgen.org . Source code is available at http://github.com/RuleWorld/bionetgen .

Contact:  bionetgen.help@gmail.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
MIMEAnTo: profiling functional RNA in mutational interference mapping experiments
Authors: Smith Maureen R. , Smyth Redmond P. , Marquet Roland , von Kleist Max
Published: July 2016

Summary: The mutational interference mapping experiment (MIME) is a powerful method that, coupled to a bioinformatics analysis pipeline, allows the identification of domains and structures in RNA that are important for its function. In MIME, target RNAs are randomly mutated, selected by function, physically separated and sequenced using next-generation sequencing (NGS). Quantitative effects of each mutation at each position in the RNA can be recovered with statistical certainty using the herein developed user-friendly, cross-platform software MIMEAnTo ( MIME An alysis To ol).

Availability and implementation: MIMEAnTo is implemented in C ++ using the boost library as well as Qt for the graphical user interface and is distributed under GPL ( http://www.gnu.org/licences/gpl ). The libraries are statically linked in a stand alone executable and are not required on the system. The plots are generated with gnuplot. Gnuplot-iostream ( https://github.com/dstahlke/gnuplot-iostream ) serves as gnuplot interface. Standalone executables including examples and source code can be downloaded from https://github.com/maureensmith/MIMEAnTo .

Contacts:  msmith@zedat.fu-berlin.de or vkleist@zedat.fu-berlin.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
CO2 sensitivity experiments are not sufficient to show an effect of ocean acidification
Authors: McElhany Paul
Published: July 2016

The ocean acidification (OA) literature is replete with laboratory studies that report species sensitivity to seawater carbonate chemistry in experimental treatments as an “effect of OA”. I argue that this is unintentionally misleading, since these studies do not actually demonstrate an effect of OA but rather show sensitivity to CO2. Documenting an effect of OA involves showing a change in a species (e.g. population abundance or distribution) as a consequence of anthropogenic changes in marine carbonate chemistry. To date, there have been no unambiguous demonstrations of a population level effect of anthropogenic OA, as that term is defined by the IPCC.
Phenotype, proliferation and apoptosis of B lymphocytes in hemodialysis patients treated with recombinant human erythropoietin
Authors: Jasiulewicz Aleksandra , Lisowska Katarzyna A. , Dębska-Ślizień Alicja , Witkowski Jacek M.
Published: July 2016

One of the major causes of disorders of the immune response in patients undergoing hemodialysis (HD) is weaker activity of their helper T lymphocytes (T h cells), mainly reduced proliferative capacity associated with decreased expression of key surface antigens. Since cooperation between T h and B lymphocytes is essential for B cell function, changes in T h cell phenotype and ability to proliferate or produce cytokines could directly translate into an impaired humoral response. Therefore, we investigated the T cell-dependent activity of B cells in HD patients focusing mainly on their proliferative kinetics, susceptibility to apoptosis and the ability to produce antibodies. Since our previous studies have shown the beneficial effects of recombinant human erythropoietin (rhEPO) on T lymphocytes, we also investigated the in vivo and in vitro influence of rhEPO on B cells. Our results show that B lymphocytes of HD patients, especially of those who are not treated with rhEPO, have reduced proliferative capacity in vitro , reflected in low number of cell divisions, decreased percentage of proliferating cells and an increased susceptibility to apoptosis. They are also characterized by impaired ability to produce immunoglobulins. We have found no significant changes in the expression of key antigens of B lymphocytes with the exception of IL-10R. Furthermore, we demonstrated a time- and health status-dependent impact of rhEPO on patient’s B cells. Our results show possible mechanisms responsible for the deficiency of humoral responses in HD patients which, at least partially, can be modulated through the supplementation with rhEPO.
Online cancer communities as informatics intervention for social support: conceptualization, characterization, and impact
Authors: Zhang Shaodian , Bantum Erin O’Carroll , Owen Jason , Bakken Suzanne , Elhadad Noémie
Published: July 2016

Objectives: The Internet and social media are revolutionizing how social support is exchanged and perceived, making online health communities (OHCs) one of the most exciting research areas in health informatics. This paper aims to provide a framework for organizing research of OHCs and help identify questions to explore for future informatics research. Based on the framework, we conceptualize OHCs from a social support standpoint and identify variables of interest in characterizing community members. For the sake of this tutorial, we focus our review on online cancer communities.

Target audience: The primary target audience is informaticists interested in understanding ways to characterize OHCs, their members, and the impact of participation, and in creating tools to facilitate outcome research of OHCs. OHC designers and moderators are also among the target audience for this tutorial.

Scope: The tutorial provides an informatics point of view of online cancer communities, with social support as their leading element. We conceptualize OHCs according to 3 major variables: type of support, source of support, and setting in which the support is exchanged. We summarize current research and synthesize the findings for 2 primary research questions on online cancer communities: (1) the impact of using online social support on an individual's health, and (2) the characteristics of the community, its members, and their interactions. We discuss ways in which future research in informatics in social support and OHCs can ultimately benefit patients.
Online patient websites for electronic health record access among vulnerable populations: portals to nowhere?
Authors: Tieu Lina , Schillinger Dean , Sarkar Urmimala , Hoskote Mekhala , Hahn Kenneth J , Ratanawongsa Neda , Ralston James D , Lyles Courtney R
Published: July 2016

Objective: With the rapid rise in the adoption of patient portals, many patients are gaining access to their personal health information online for the first time. The objective of this study was to examine specific usability barriers to patient portal engagement among a diverse group of patients and caregivers.

Materials and Methods: We conducted interviews using performance testing and think-aloud methods with 23 patients and 2 caregivers as they first attempted to use features of a newly launched patient portal.

Results: In navigating the portal, participants experienced basic computer barriers (eg, difficulty using a mouse), routine computer barriers (eg, mistyping, navigation issues), reading/writing barriers, and medical content barriers. Compared to participants with adequate health literacy, participants with limited health literacy required 2 additional minutes to complete each task and were more likely to experience each type of navigational barrier. They also experienced more inaccuracies in interpreting a test result and finding a treatment plan within an after-visit summary.

Discussion: When using a patient portal for the first time, participants with limited health literacy completed fewer tasks unassisted, had a higher prevalence of encountering barriers, took longer to complete tasks, and had more problems accurately interpreting medical information.

Conclusion: Our findings suggest a strong need for tailored and accessible training and support to assist all vulnerable patients and/or caregivers with portal registration and use. Measuring the health literacy of a patient population might serve as a strong proxy for identifying patients who need the most support in using health technologies.
Feasibility of Posterior Cervical Foraminotomy in Cervical Foraminal Stenosis
Authors: Gu Bon Sub , Park Jin Hoon , Seong Han Yu , Jung Sang Ku , Roh Sung Woo
Published: July 2016

Study Design.

A retrospective cohort study.

Objective.

The aim of this study was to compare the feasibility of posterior cervical laminoforaminotomy (PCF) for V- or parallel-shaped foraminal stenosis (FS).

Summary of Background Data.

During PCF, the need for extensive facet resection would depend on the extent of any pathology. When resection is extensive, the possibilities of instability and incomplete decompression should be considered.

Methods.

From March 2004 to March 2015, we enrolled 36 patients following single-level PCF procedures for FS. We classified patients by foraminal shape on preoperative computed tomography (CT) scan into V-shaped and parallel-shaped groups. We then compared arm and neck pain using a numeric rating scale (NRS) and clinical outcomes using Odom criteria. Radiological evaluation included dynamic X-rays for instability and CT scans for facet resection.

Result.

We enrolled 16 and 20 patients in the V-shape and parallel-shape groups, respectively. By Odom criteria, no patient was graded fair or poor in the V group, but five patients were graded as fair and one patient as poor in the parallel group. Continued postoperative arm pain at 1 year, which was related to incomplete decompression, was significantly higher in parallel group. Only one patient complained of postoperative neck pain with an NRS >5, and another five patients sustained radiculopathy with an NRS >5. Among five patients who complained sustained radiculopathy, one patient required revision surgery for incomplete decompression. The amount of facet removal was not different significantly between groups, and no patient had postoperative instability.

Conclusion.

Although PCF seems to be a good surgical option for V-shaped FS, we experienced worse outcomes for patients with parallel-shaped FS. We recommend that ACDF or more aggressive posterior foraminotomy be performed with fusion when presented with parallel neuroforaminal compression.

Level of Evidence: 4
A universal metric for ferroic energy materials
Authors: Brück Ekkes , Yibole Hargen , Zhang Lian
Published: July 2016

After almost 20 years of intensive research on magnetocaloric effects near room temperature, magnetic refrigeration with first-order magnetocaloric materials has come close to real-life applications. Many materials have been discussed as potential candidates to be used in multicaloric devices. However, phase transitions in ferroic materials are often hysteretic and a metric is needed to estimate the detrimental effects of this hysteresis. We propose the coefficient of refrigerant performance, which compares the net work in a reversible cycle with the positive work on the refrigerant, as a universal metric for ferroic materials. Here, we concentrate on examples from magnetocaloric materials and only consider one barocaloric experiment. This is mainly due to lack of data on electrocaloric materials. It appears that adjusting the field-induced transitions and the hysteresis effects can minimize the losses in first-order materials.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Thermodynamics of multicaloric effects in multiferroic materials: application to metamagnetic shape-memory alloys and ferrotoroidics
Authors: Planes Antoni , Castán Teresa , Saxena Avadh
Published: July 2016

We develop a general thermodynamic framework to investigate multicaloric effects in multiferroic materials. This is applied to the study of both magnetostructural and magnetoelectric multiferroics. Landau models with appropriate interplay between the corresponding ferroic properties (order parameters) are proposed for metamagnetic shape-memory and ferrotoroidic materials, which, respectively, belong to the two classes of multiferroics. For each ferroic property, caloric effects are quantified by the isothermal entropy change induced by the application of the corresponding thermodynamically conjugated field. The multicaloric effect is obtained as a function of the two relevant applied fields in each class of multiferroics. It is further shown that multicaloric effects comprise the corresponding contributions from caloric effects associated with each ferroic property and the cross-contribution arising from the interplay between these ferroic properties.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
(Magneto)caloric refrigeration: is there light at the end of the tunnel?
Authors: Pecharsky Vitalij K. , Cui Jun , Johnson Duane D.
Published: July 2016

Caloric cooling and heat pumping rely on reversible thermal effects triggered in solids by magnetic, electric or stress fields. In the recent past, there have been several successful demonstrations of using first-order phase transition materials in laboratory cooling devices based on both the giant magnetocaloric and elastocaloric effects. All such materials exhibit non-equilibrium behaviours when driven through phase transformations by corresponding fields. Common wisdom is that non-equilibrium states should be avoided; yet, as we show using a model material exhibiting a giant magnetocaloric effect, non-equilibrium phase-separated states offer a unique opportunity to achieve uncommonly large caloric effects by very small perturbations of the driving field(s).

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Influence of the transition width on the magnetocaloric effect across the magnetostructural transition of Heusler alloys
Authors: Cugini F. , Porcari G. , Fabbrici S. , Albertini F. , Solzi M.
Published: July 2016

We report a complete structural and magneto-thermodynamic characterization of four samples of the Heusler alloy Ni-Co-Mn-Ga-In, characterized by similar compositions, critical temperatures and high inverse magnetocaloric effect across their metamagnetic transformation, but different transition widths. The object of this study is precisely the sharpness of the martensitic transformation, which plays a key role in the effective use of materials and which has its origin in both intrinsic and extrinsic effects. The influence of the transition width on the magnetocaloric properties has been evaluated by exploiting a phenomenological model of the transformation built through geometrical considerations on the entropy versus temperature curves. A clear result is that a large temperature span of the transformation is unfavourable to the magnetocaloric performance of a material, reducing both isothermal entropy change and adiabatic temperature change obtainable in a given magnetic field and increasing the value of the maximum field needed to fully induce the transformation. The model, which is based on standard magnetometric and conventional calorimetric measurements, turns out to be a convenient tool for the determination of the optimum values of transformation temperature span in a trade-off between sheer performance and amplitude of the operating range of a material.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Effect of crystallographic compatibility and grain size on the functional fatigue of sputtered TiNiCuCo thin films
Authors: Chluba C. , Ge W. , Dankwort T. , Bechtold C. , de Miranda R. Lima , Kienle L. , Wuttig M. , Quandt E.
Published: July 2016

The positive influence of crystallographic compatibility on the thermal transformation stability has been already investigated extensively in the literature. However, its influence on the stability of the shape memory effect or superelasticity used in actual applications is still unresolved. In this investigation sputtered films of a highly compatible TiNiCuCo composition with a transformation matrix middle eigenvalue of 1±0.01 are exposed to thermal as well as to superelastic cycling. In agreement with previous results the thermal transformation of this alloy is with a temperature shift of less than 0.1 K for 40 cycles very stable; on the other hand, superelastic degradation behaviour was found to depend strongly on heat treatment parameters. To reveal the transformation dissimilarities between the differently heat-treated samples, the microstructure has been analysed by transmission electron microscopy,
in situ
stress polarization microscopy and synchrotron analysis. It is found that good crystallographic stability is not a sufficient criterion to avoid defect generation which guarantees high superelastic stability. For the investigated alloy, a small grain size was identified as the determining factor which increases the yield strength of the composition and decreases the functional degradation during superelastic cycling.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Large electrocaloric effects in single-crystal ammonium sulfate
Authors: Crossley S. , Li W. , Moya X. , Mathur N. D.
Published: July 2016

Electrocaloric (EC) effects are typically studied near phase transitions in ceramic and polymer materials. Here, we investigate EC effects in an inorganic salt, namely ammonium sulfate (NH
4
)
2
SO
4
, with an order–disorder transition whose onset occurs at 223 K on cooling. For a single crystal thinned to 50 μm, we use a Maxwell relation to find a large isothermal entropy change of 30 J K
−1
 kg
−1
in response to a field change of 400 kV cm
−1
. The Clausius–Clapeyron equation implies a corresponding adiabatic temperature change of 4.5 K.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Electrocaloric response near room temperature in Zr- and Sn-doped BaTiO
3
systems
Authors: Hou Ying , Yang Lu , Qian Xiaoshi , Zhang Tian , Zhang Q. M.
Published: July 2016

The electrocaloric effect (ECE) in (1−
x
)BaZr
0.18
Ti
0.82
O
3
–(
x
)BaSn
0.11
Ti
0.89
O
3
(BZT18–BST11, 0.1≤
x
≤0.5) ceramics is investigated near room temperature using a calorimetry method. The ceramics exhibit relaxor-like ferroelectric characteristics and by merging phases, a large electrocaloric (EC) response is observed in the system. The largest entropy change is 4.8 Jkg
−1
K
−1
(along with a temperature change of 3.5 K), which is induced under an electric field of 10 MV m
−1
for the 0.8 BaZr
0.18
Ti
0.82
O
3
–0.2 BaSn
0.11
Ti
0.89
O
3
ceramics. This result reveals that the coexistence of multiple phases improves the ECE of the ceramics, which provides an effective route to achieve a large EC response using a small electric field.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Geo-climatic gradient shapes functional trait variations inSalix eriocephalaMichx
Authors: Shunmugam Arun S.K. , Soolanayakanahally Raju Y. , Guy Robert D.
Published: July 2016

Intraspecific variations in seasonal phenology and growth physiology reflect adaptation to local climate. To explore the patterns of local adaptation along latitudinal and longitudinal clines, we used thirty-four populations ofSalix eriocephalasourced from its natural ranges across Canada. The genotypes were examined for 6 phenology and 19 ecophysiology traits over two growing seasons under common garden condition. Photosynthetic assimilation rate (A) increased with increasein latitude when measured during free growth. In spite, the negative correlation between stomatal density and stomatal conductance (gs), higherAis facilitatedvialarger pore length among genotypes from short growing seasons. In addition, higherA, was positively associated with total leafnitrogen and leaf mass per unit area. No population level differences wereobserved for water use-efficiency (Δ13C), however nitrogen isotope discrimination (δ15N) displayed latitudinalclines. Growing season phenological traits considered in this study accounted highheritability (H2= 0.65-0.94).Melampsorarust infestation also displayed a strong latitudinal cline with high-latitude genotypes being more susceptible. Overall, the results support the hypothesis that functional trait variations are largely explained by climate of origin and facilitate selection of parents with superior adaptive traits in the Canadian willow improvement program forbioenergy and environmental applications.
Animals in the Zika virus life cycle: what to expect from megadiverse Latin American countries
Authors: Bueno Marina Galvão , Martinez Nádia , Abdala Lívia , dos Santos Claudia Nunes Duarte , Chame Marcia
Published: July 2016

Zika virus (ZIKV) was first isolated in 1947 in primates in Uganda, West Africa. The virus remained confined to the equatorial regions of Africa and Asia, cycling between infecting monkeys, arboreal mosquitoes, and occasional humans. The ZIKV Asiatic strain was probably introduced into Brazil in 2013. In the current critical human epidemic in the Americas, ZIKV is transmitted primarily byAedes aegyptimosquitoes, especially where the human population density is combined with poor sanitation. Presently, ZIKV is in contact with the rich biodiversity in all Brazilian biomes, bordering on other Latin American countries. Infections in Brazilian primates have been reported recently, but the overall impact of this virus on wildlife in the Americas is still unknown. The current epidemic in the Americas requires knowledge on the role of mammals, especially non-human primates, in ZIKV transmission to humans. The article discusses the available data on ZIKV in host animals, besides issues of biodiversity, rapid environmental change, and impact on human health in megadiverse Latin American countries. The authors reviewed scientific articles and recent news stories on ZIKV in animals, showing that 47 animal species from three orders (mammals, reptiles, and birds) have been investigated for the potential to establish a sylvatic cycle. The review aims to contribute to epidemiological studies and the knowledge on the natural history of ZIKV. The article concludes with questions that require urgent attention in epidemiological studies involving wildlife in order to understand their role as ZIKV hosts and to effectively control the epidemic.
Allelic spectrum of the RNA guided CRISPR/Cas9 DNA repair events at PAM associated trinucleotide repeat (NGG)n inCaenorhabditis elegans.
Authors: Kapulkin Wadim
Published: July 2016

This work describes the experience with implementation ofStreptococcus pyogenesCas9 nuclease, expressed inC. elegansgermline. The described work utilizes guide RNA-unc-22-1000 (GGAGAAGGAGGCGGTGCTGG) designed to target the polyglycine encoding stretch within theunc-22gene embedding the impure trinucleotide (NGG)n PAM repeat region. We describe the allelic spectrum of mutational events identified at position specified by gRNA-unc-22-1000. Of above experiments we conclude: i. the trinucleotide (NGG)n PAM repeat is a receptive target for the CRISPR/Cas9 experiments inC. elegansii. we conclude the allelic spectrum indicates the gRNA-unc-22-1000 induces fairly frequent NHEJ joining events involving deletions and indels but also, a phenotypically distinct class of small in-frame deletions indicative for microhomology-mediated end-joining (MMEJ) as a result ofS. pyogenesCas9 activity at the trinucleotide (NGG)n PAM repeat region. We demonstrate guide RNA-unc-22-1000 could be used to modify complex transgenicC. elegansline expressing human beta-amyloid protein. We provide the evidence for bi-allelic transaction resulting from Cas9 action recovered in experiment in CB1138him-6background. We contrast the expected performance of gRNA-unc-22-1000 with guide targeting another type ofC. elegansrepeat embeddingS. pyogenesPAM, the telomeric repeat (TTAGGC)n. We propose that preferential frame restoring MMEJ repair of the Cas9 cut at the 'modules' encoding for poly-glycine in +2(NGG)n position could be useful mode of genome engineering at the naturally occurring (NGG)n PAM embedding repeats dispersed across animal genomes.
A DNA-based T cell receptor reveals a role for receptor clustering in ligand discrimination
Authors: Taylor Marcus J. , Husain Kabir , Gartner Zev J. , Mayor Satyajit , Vale Ronald D.
Published: July 2016

T cells mount an immune response by measuring the binding strength of its T cell receptor (TCR) for peptide-loaded MHCs (pMHC) on an antigen-presenting cell. How T cells convert the lifetime of the extracellular TCR-pMHC interaction into an intracellular signal remains unknown. Here, we developed a synthetic signaling system in which the extracellular domains of the TCR and pMHC were replaced with short hybridizing strands of DNA. Remarkably, T cells can discriminate between DNA ligands differing by a single base pair. Single molecule imaging reveals that signaling is initiated when single ligand-bound receptors are converted into clusters, a time-dependent process requiring ligands with longer bound times. A computation model reveals that receptor clustering serves a kinetic proofreading function, enabling ligands with longer bound times to have disproportionally greater signaling outputs. These results suggest that spatial reorganization of receptors plays an important role in ligand discrimination in T cell signaling.
Schizophrenia hiPSC neurons display expression changes that are enriched for disease risk variants and a blunted activity-dependent response
Authors: Roussos Panos , Guennewig Boris , Kaczorowski Dominik C. , Barry Guy , Brennand Kristen J.
Published: July 2016

IMPORTANCE

Schizophrenia (SCZ) is a common illness with complex genetic architecture where both common genetic variation and rare mutations have been implicated. SCZ candidate genes participate in common molecular pathways that are regulated by activity-dependent changes in neurons, including the signaling network that modulates synaptic strength and the network of genes that are targets of fragile X mental retardation protein. One important next step is to further our understanding on the role of activity-dependent changes of genes expression in the etiopathogenesis of SCZ.

OBJECTIVE

To examine whether neuronal activity-dependent changes of gene expression is dysregulated in SCZ.

DESIGN, SETTING, AND PARTICIPANTS

Neurons differentiated from human induced pluripotent stem cells (hiPSCs) derived from 4 cases with SCZ and 4 unaffected controls were depolarized using potassium chloride. RNA was extracted followed by genome-wide profiling of the transcriptome.

MAIN OUTCOMES AND MEASURES

We performed differential expression analysis and gene co-expression analysis to identify activity-dependent or disease-specific changes of the transcriptome. Further, we used gene set analyses to identify co-expressed modules that are enriched for SCZ risk genes.

RESULTS

We identified 1,669 genes that are significantly different in SCZ-associated vs. control hiPSC-derived neurons and 1,199 genes that are altered in these cells in response to depolarization. We show that the effect of activity-dependent changes of gene expression in SCZ-associated neurons is attenuated compared to controls. Furthermore, these differentially expressed genes are co-expressed in modules that are highly enriched for genes affected by genetic risk variants in SCZ and other neurodevelopmental disorders.

CONCLUSIONS AND RELEVANCE

Our results show that SCZ candidate genes converge to gene networks that are associated with a blunted effect of activity-dependent changes of gene expression in SCZ-associated neurons. Overall, these findings show that hiPSC neurons demonstrate activity-dependent transcriptional changes that can be utilized to examine underlying mechanisms and therapeutic interventions related to SCZ.
Quantum Transition in Zinc Atoms of Flavavirus Polymerase Triggers the Conformation of the Polymerase Motif F
Authors: Potapova Uliana , Feranchuk Sergey , Belikov Sergei
Published: July 2016

Flavavirus RdRp contains two zinc atoms located in two specific zinc binding sites in the protein. Molecular dynamics experiments with flavavirus RdRp suggest that the conformation of the conservative motif F in the polymerase is highly sensitive to the bond lengths between the zinc atoms and their four coordinating atoms. In the experimental structures of flavavirus RdRp, motif F is presented in two different conformations. The polymerase acts as a catalyst only in one of the motif F conformations. We hypothesize that the second conformation is required for the formation of the viral replicative complex and that it is the quantum transition in the zinc atoms which slightly changes the bond lengths; thus assisting the switch between the two motif F conformations.
Prober: A general toolkit for analyzing sequencing-based ‘toeprinting’ assays
Authors: Li Bo , Tambe Akshay , Aviran Sharon , Pachter Lior
Published: July 2016

A number of high-throughput transcriptase drop-off assays have recently been developed to probe post-transcriptional dynamics of RNA-protein interaction, RNA structure, and post-transcriptional modifications. Although these assays survey a diverse set of ‘epitranscriptomic’ marks, they share methodological similarities and as such their interpretation is predicated on addressing similar computational challenges. Among these, a key question is how to learn isoform-specific chemical modification profiles in the face of complex read multi-mapping. In this paper, we propose PROBer, the first rigorous statistical model to handle these challenges for a general set of sequencing-based ‘toeprinting’ assays.
Origins of pandemicVibrio choleraefrom environmental gene pools
Authors: Shapiro B. Jesse , Levade Inès , Kovacikova Gabriela , Taylor Ronald K. , Almagro-Moreno Salvador
Published: July 2016

Some microbes can transition from an environmental lifestyle to a pathogenic one1–3. This ecological switch typically occurs through the acquisition of horizontally acquired virulence genes4,5. However, the genomic features that must be present in a population prior to the acquisition of virulence genes and emergence of pathogenic clones remain unknown. We hypothesized that virulence adaptive polymorphisms (VAPs) circulate in environmental populations and are required for this transition. We developed a comparative genomic framework for identifying VAPs, usingVibrio choleraeas a model. We then characterized several environmental VAP alleles to show that, while some of them reduced the ability of clinical strains to colonize a mammalian host, other alleles conferred efficient host colonization. These results show that VAPs are present in environmental bacterial populations prior to the emergence of virulent clones. We propose a scenario in which VAPs circulate in the environment, they become selected and enriched under certain ecologicalconditions, and finally a genomic background containing several VAPs acquires virulence factors that allows for its emergence as a pathogenic clone.
Boosting alignment accuracy through adaptive local realignment
Authors: DeBlasio Dan , Kececioglu John
Published: July 2016

Motivation

While mutation rates can vary across the residues of a protein, when computing alignments of protein sequences the same setting of values for substitution score and gap penalty parameters is typically used across their entire length. We provide for the first time a new method calledadaptive local realignmentthat automatically uses diverse parameter settings in different regions of the input sequences when computing multiple sequence alignments. This allows parameter settings to adapt to more closely match the local mutation rate across a protein.

Method

Our method builds on our prior work on global alignmentparameter advisingwith theFacetalignment accuracy estimator. Given a computed alignment, in each region that has low estimated accuracy, a collection of candidate realignments is generated using a precomputed set of alternate parameter settings. If one of these alternate realignments has higher estimated accuracy than the original subalignment, the region is replaced with the new realignment, and the concatenation of these realigned regions forms the final alignment that is output.

Results

Adaptive local realignment significantly improves the quality of alignments over using the single best default parameter setting. In particular, this new method oflocal advising, when combined with prior methods forglobal advising, boosts alignment accuracy by as much as 26% over the best default setting on hard-to-align benchmarks (and by 6.4% over using global advising alone).

Availability

A new version of theOpalmultiple sequence aligner that incorporates adaptive local realignment using Facet for parameter advising, is available free for non-commercial use athttp://facet.cs.arizona.edu.

Contact

deblasio@cs.arizona.edu