bluuebunny/crossref_metadata_2025 huggingface dataset:
Different cAMP sources are critically involved in G protein–coupled receptor CRHR1 signaling
Authors: Inda Carolina , dos Santos Claro Paula A. , Bonfiglio Juan J. , Senin Sergio A. , Maccarrone Giuseppina , Turck Christoph W. , Silberstein Susana
Published: July 2016

Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein–dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP.
Spatial resolution of cAMP signaling by soluble adenylyl cyclase
Authors: Caldieri Giusi , Sigismund Sara
Published: July 2016

G protein–coupled receptor signaling starts at the plasma membrane and continues at endosomal stations. In this issue, Inda et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201512075) show that different forms of adenylyl cyclase are activated at the plasma membrane versus endosomes, providing a rationale for the spatial encoding of cAMP signaling.
Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets
Authors: Ma Cindy S. , Wong Natalie , Rao Geetha , Nguyen Akira , Avery Danielle T. , Payne Kathryn , Torpy James , O’Young Patrick , Deenick Elissa , Bustamante Jacinta , Puel Anne , Okada Satoshi , Kobayashi Masao , Martinez-Barricarte Ruben , Elliott Michael , Sebnem Kilic Sara , El Baghdadi Jamila , Minegishi Yoshiyuki , Bousfiha Aziz , Robertson Nic , Hambleton Sophie , Arkwright Peter D. , French Martyn , Blincoe Annaliesse K. , Hsu Peter , Campbell Dianne E. , Stormon Michael O. , Wong Melanie , Adelstein Stephen , Fulcher David A. , Cook Matthew C. , Stepensky Polina , Boztug Kaan , Beier Rita , Ikincioğullari Aydan , Ziegler John B. , Gray Paul , Picard Capucine , Boisson-Dupuis Stéphanie , Phan Tri Giang , Grimbacher Bodo , Warnatz Klaus , Holland Steven M. , Uzel Gulbu , Casanova Jean-Laurent , Tangye Stuart G.
Published: July 2016

Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation.
Developmental regulation of myeloerythroid progenitor function by the Lin28b–let-7–Hmga2 axis
Authors: Rowe R. Grant , Wang Leo D. , Coma Silvia , Han Areum , Mathieu Ronald , Pearson Daniel S. , Ross Samantha , Sousa Patricia , Nguyen Phi T. , Rodriguez Antony , Wagers Amy J. , Daley George Q.
Published: July 2016

For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development.
Participation in Rural Land Rental Markets in Sub‐Saharan Africa: Who Benefits and by How Much? Evidence from Malawi and Zambia
Authors: Chamberlin Jordan , Ricker‐Gilbert Jacob
Published: July 2016

We use nationally representative household‐level panel survey data in two neighboring countries in Southern Africa—Zambia and Malawi—to characterize the current status of rural land rental market participation by smallholder farmers, and their subsequent welfare impacts. Rural rental market participation is much higher in densely‐populated Malawi than in lower‐density Zambia, reflecting the role of land scarcity in driving rental market development. Consistent with previous literature, we find evidence that rental markets contribute to efficiency gains within the smallholder sector by facilitating the transfer of land from less‐able to more‐able producers, on average, in both countries. Furthermore, we find that rental markets serve to re‐allocate land from relatively land‐rich to land‐poor households. We examine the impacts of participation on a number of welfare outcomes and find evidence for generally positive returns to renting in land in both countries, on average. However, our analysis also indicates that the returns to renting in land vary strongly with scale of production: tenants who produce more have larger returns to renting in, and many of the smaller producers who rent in do so at an economic loss. The impacts of renting out (i.e., participating in markets as landlords) are decidedly more mixed, with overall negative returns to landlords in Malawi and negligible returns to landlords in Zambia. The findings in this article highlight the need for researchers and policymakers in sub‐Saharan Africa to stay attuned to how land rental market participation and its impacts evolve in the near future.
Psychosocial Correlates of Nocturnal Blood Pressure Dipping in African Americans: The Jackson Heart Study
Authors: Spruill Tanya M. , Shallcross Amanda J. , Ogedegbe Gbenga , Chaplin William F. , Butler Mark , Palfrey Amy , Shimbo Daichi , Muntner Paul , Sims Mario , Sarpong Daniel F. , Agyemang Charles , Ravenell Joseph
Published: July 2016

BACKGROUND

African Americans exhibit a lower degree of nocturnal blood pressure (BP) dipping compared with Whites, but the reasons for reduced BP dipping in this group are not fully understood. The aim of this study was to identify psychosocial factors associated with BP dipping in a population-based cohort of African Americans.

METHODS

This cross-sectional study included 668 Jackson Heart Study (JHS) participants with valid 24-hour ambulatory BP data and complete data on psychosocial factors of interest including stress, negative emotions, and psychosocial resources (e.g., perceived support). The association of each psychosocial factor with BP dipping percentage and nondipping status (defined as <10% BP dipping) was assessed using linear and Poisson regression models, respectively, with progressive adjustment for demographic, socioeconomic, biomedical, and behavioral factors.

RESULTS

The prevalence of nondipping was 64%. Higher depressive symptoms, higher hostility, and lower perceived social support were associated with a lower BP dipping percentage in unadjusted models and after adjustment for age, sex, body mass index, and mean 24-hour systolic BP ( P < 0.05). Only perceived support was associated with BP dipping percentage in fully adjusted models. Also, after full multivariable adjustment, the prevalence ratio for nondipping BP associated with 1 SD (7.1 unit) increase in perceived support was 0.93 (95% CI: 0.88–0.99). No other psychosocial factors were associated with nondipping status.

CONCLUSIONS

Lower perceived support was associated with reduced BP dipping in this study. The role of social support as a potentially modifiable determinant of nocturnal BP dipping warrants further investigation.
Aldosterone Antagonists or Renin-Guided Therapy for Treatment-Resistant
Hypertension: A Comparative Effectiveness Pilot Study in Primary Care
Authors: Egan Brent M. , Laken Marilyn A. , Sutherland Susan E. , Qanungo Suparna , Fleming Douglas O. , Cook Anne G. , Hester William H. , Jones Kelly W. , Jebaily Gerard C. , Valainis Gregory T. , Way Charles F. , Wright Mary Beth , Davis Robert A.
Published: July 2016

BACKGROUND

Uncontrolled treatment-resistant hypertension (TRH), i.e., blood pressure (BP, mm Hg) ≥140/≥90mm Hg in and out of office on ≥3 different BP medications at optimal doses, is common and has a poor prognosis. Aldosterone antagonist (AA) and renin-guided therapy (RGT) are effective strategies for improving BP control in TRH but have not been compared.

METHODS

A comparative effectiveness TRH pilot study of AA vs. RGT was conducted in 4 primary care clinics with 2 each randomized to AA or RGT. The primary outcome was change in clinic BP defined by means of 5 automated office BP values. Eighty-nine patients with apparent TRH were screened and 44 met criteria for true TRH.

RESULTS

Baseline characteristics of 20 patients in the AA (70% Black, 45% female, mean age: 57.4 years) and 24 patients in RGT (79% Black, 50% female, 57.8 years) arms were similar with baseline BP 162±5/90±3 vs. 153±3/84±3, respectively, P = 0.11/0.20. BP declined to 144±5/86±4 in AA vs. 132±4/75±3 in RGT, P = 0.07/0.01; BP was controlled to JNC7 (Seventh Joint National Committee Report) goal in 25% vs. 62.5%, respectively, P < 0.01. Although BP changes from baseline, the primary outcome, were not different (−17.6±5.1/−4.0±3.0 AA vs. −20.4±3.8/−9.7±2.0 RGT, P = 0.65/0.10.), more BP medications were added with AA than RGT (+0.9±0.1 vs. +0.4±0.1 per patient, P < 0.01).

CONCLUSIONS

In this TRH pilot study, AA and RGT lowered BP similarly, although fewer additional medications were required with RGT. A larger comparative effectiveness study could establish the utility of these treatment strategies for lowering BP of uncontrolled TRH patients in primary care.
samExploreR: exploring reproducibility and robustness of RNA-seq results based on SAM files
Authors: Stupnikov Alexey , Tripathi Shailesh , de Matos Simoes Ricardo , McArt Darragh , Salto-Tellez Manuel , Glazko Galina , Dehmer Matthias , Emmert-Streib Frank
Published: July 2016

Motivation: Data from RNA-seq experiments provide us with many new possibilities to gain insights into biological and disease mechanisms of cellular functioning. However, the reproducibility and robustness of RNA-seq data analysis results is often unclear. This is in part attributed to the two counter acting goals of (i) a cost efficient and (ii) an optimal experimental design leading to a compromise, e.g. in the sequencing depth of experiments.

Results: We introduce an R package called samExploreR that allows the subsampling (m out of n bootstraping) of short-reads based on SAM files facilitating the investigation of sequencing depth related questions for the experimental design. Overall, this provides a systematic way for exploring the reproducibility and robustness of general RNA-seq studies. We exemplify the usage of samExploreR by studying the influence of the sequencing depth and the annotation on the identification of differentially expressed genes.

Availability and Implementation: samExploreR is available as an R package from Bioconductor.

Contact:  v@bio-complexity.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
New quality measure for SNP array based CNV detection
Authors: Macé A. , Tuke M.A. , Beckmann J.S. , Lin L. , Jacquemont S. , Weedon M.N. , Reymond A. , Kutalik Z.
Published: July 2016

Motivation: Only a few large systematic studies have evaluated the impact of copy number variants (CNVs) on common diseases. Several million individuals have been genotyped on single nucleotide variation arrays, which could be used for genome-wide CNVs association studies. However, CNV calls remain prone to false positives and only empirical filtering strategies exist in the literature. To overcome this issue, we defined a new quality score (QS) estimating the probability of a CNV called by PennCNV to be confirmed by other software.

Results: Out-of-sample comparison showed that the correlation between the consensus CNV status and the QS is twice as high as it is for any previously proposed CNV filters. ROC curves displayed an AUC higher than 0.8 and simulations showed an increase up to 20% in statistical power when using QS in comparison to other filtering strategies. Superior performance was confirmed also for alternative consensus CNV definition and through improving known CNV-trait associations.

Availability and Implementation:  http://goo.gl/T6yuFM

Contact:  zoltan.kutalik@unil.ch or aurelien@mace@unil.ch

Supplementary information:  Supplementary data are available at Bioinformatics online.
The
Affaire des placards
, Polemical Humour, and The Sardonic Laugh
Authors: Hayes Bruce
Published: July 2016

Working with Erasmus’s exploration of the sardonic laugh, this article begins with the placard of the notorious Affaire des placards of 17–18 October 1534. The aim is to uncover uses of polemical humour in pamphlets produced during the early years of religious conflict in France. Starting with Antoine Marcourt, the likely author of the placard, the article investigates Marcourt’s first known satirical pamphlet, the
Livre des marchans
. This is followed by a study of Jérome Hangest’s response to the affaire. Hangest was not only the person designated by the Sorbonne to produce a response to the placards, but also one of the first Catholics to attempt to counteract the effects of Protestant propaganda in France. Finally, this article examines Marcourt’s enigmatic co-religionist, Marie Dentière, whose work also contains illuminating examples of the sardonic laugh. In all of this, the goal is to uncover connections between humour and violence, as well as growing suspicions about the uses and dangers of laughter. As new, more vicious forms of satire are developed, suspicions about these also intensify, and, in an increasingly polarized society, there is little room left for laughter other than the sardonic laugh.
Impact of computerized provider order entry (CPOE) on length of stay and mortality
Authors: Lyons Ann M , Sward Katherine A , Deshmukh Vikrant G , Pett Marjorie A , Donaldson Gary W , Turnbull Jim
Published: July 2016

Objective: To examine changes in patient outcome variables, length of stay (LOS), and mortality after implementation of computerized provider order entry (CPOE).

Materials and Methods: A 5-year retrospective pre-post study evaluated 66 186 patients and 104 153 admissions (49 683 pre-CPOE, 54 470 post-CPOE) at an academic medical center. Generalized linear mixed statistical tests controlled for 17 potential confounders with 2 models per outcome.

Results: After controlling for covariates, CPOE remained a significant statistical predictor of decreased LOS and mortality. LOS decreased by 0.90 days, P < .0001. Mortality decrease varied by model: 1 death per 1000 admissions (pre = 0.006, post = 0.0005, P < .001) or 3 deaths (pre = 0.008, post = 0.005, P < .01). Mortality and LOS decreased in medical and surgical units but increased in intensive care units.

Discussion: This study examined CPOE at multiple levels. Given the inability to randomize CPOE assignment, these results may only be applicable to the local setting. Temporal trends found in this study suggest that hospital-wide implementations may have impacted nursing staff and new residents. Differences in the results were noted at the patient care unit and room levels. These differences may partly explain the mixed results from previous studies.

Conclusion: Controlling for confounders, CPOE implementation remained a statistically significant predictor of LOS and mortality at this site. Mortality appears to be a sensitive outcome indicator with regard to hospital-wide implementations and should be further studied.
Tyrosine receptor kinase B is a drug target in astrocytomas
Authors: Ni Jing , Xie Shaozhen , Ramkissoon Shakti H. , Luu Victor , Sun Yu , Bandopadhayay Pratiti , Beroukhim Rameen , Roberts Thomas M. , Stiles Charles D. , Segal Rosalind A. , Ligon Keith L. , Hahn William C. , Zhao Jean J.
Published: July 2016

Background.

Astrocytomas are the most common primary human brain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and low-grade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type.

Methods.

To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a−/−/Arf−/− astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas.

Results.

Activated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with human astrocytoma transformed Ink4a−/−/Arf−/− astrocytes, and this process was also mediated via STAT3 signaling.

Conclusions.

Our findings provide evidence that constitutively activated NTRK2 alleles, notably the human tumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytoma patients defined by QKI-NTRK2 fusion.
Measuring Economic Policy Uncertainty*
Authors: Baker Scott R. , Bloom Nicholas , Davis Steven J.
Published: July 2016

We develop a new index of economic policy uncertainty (EPU) based on newspaper coverage frequency. Several types of evidence—including human readings of 12,000 newspaper articles—indicate that our index proxies for movements in policy-related economic uncertainty. Our U.S. index spikes near tight presidential elections, Gulf Wars I and II, the 9/11 attacks, the failure of Lehman Brothers, the 2011 debt ceiling dispute, and other major battles over fiscal policy. Using firm-level data, we find that policy uncertainty is associated with greater stock price volatility and reduced investment and employment in policy-sensitive sectors like defense, health care, finance, and infrastructure construction. At the macro level, innovations in policy uncertainty foreshadow declines in investment, output, and employment in the United States and, in a panel vector autoregressive setting, for 12 major economies. Extending our U.S. index back to 1900, EPU rose dramatically in the 1930s (from late 1931) and has drifted upward since the 1960s.
Evaluating Public Programs with Close Substitutes: The Case of Head
Start*
Authors: Kline Patrick , Walters Christopher R.
Published: July 2016

We use data from the Head Start Impact Study (HSIS) to evaluate the cost-effectiveness of Head Start, the largest early childhood education program in the United States. Head Start draws roughly a third of its participants from competing preschool programs, many of which receive public funds. We show that accounting for the fiscal impacts of such program substitution pushes estimates of Head Start’s benefit-cost ratio well above one under a wide range of assumptions on the structure of the market for preschool services and the dollar value of test score gains. To parse the program’s test score impacts relative to home care and competing preschools, we selection-correct test scores in each care environment using excluded interactions between experimental assignments and household characteristics. We find that Head Start generates larger test score gains for children who would not otherwise attend preschool and for children who are less likely to participate in the program.
Electrocaloric and elastocaloric effects in soft materials
Authors: Trček Maja , Lavrič Marta , Cordoyiannis George , Zalar Boštjan , Rožič Brigita , Kralj Samo , Tzitzios Vassilios , Nounesis George , Kutnjak Zdravko
Published: July 2016

Materials with large caloric effect have the promise of realizing solid-state refrigeration which has potential to be more efficient and environmentally friendly compared with current cooling technologies. Recently, the focus of caloric effects investigations has shifted towards soft materials. An overview of recent direct measurements of the large electrocaloric effect (ECE) in a composite mixture of a liquid crystal and nanoparticles (NPs) and large elastocaloric (eC) effect in main-chain liquid crystal elastomers is given. In mixtures of 12CB liquid crystal with functionalized CdSSe NPs, an ECE exceeding 5 K was found in the vicinity of the isotropic to smectic A phase transition. It is shown that the NPs smear the isotropic to smectic coexistence range in which a large ECE is observed due to latent heat enhancement. NPs acting as traps for ions reduce the moving-ion density and consequently the Joule heating. Direct eC measurements indicate that the significant eC response can be found in main-chain liquid crystalline elastomers, but at a fraction of the stress field in contrast to other eC materials. Both soft materials could play a significant role as active cooling elements or parts of thermal diodes in development of new cooling devices.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Magnetic relaxation dynamics driven by the first-order character of magnetocaloric La(Fe,Mn,Si)
13
Authors: Lovell Edmund , Bratko Milan , Caplin A. David , Barcza Alexander , Katter Matthias , Ghivelder Luis , Cohen Lesley F.
Published: July 2016

Here, we study the temporal evolution of the magnetic field-driven paramagnetic to ferromagnetic transition in the La(Fe,Mn,Si)
13
material family. Three compositions are chosen that show varying strengths of the first-order character of the transition, as determined by the relative magnitude of their magnetic hysteresis and temperature separation between the zero-field transition temperature
T
c
and the temperature
T
crit
, where the transition becomes continuous. Systematic variations in the fixed field, isothermal rate of relaxation are observed as a function of temperature and as a function of the degree of first-order character. The relaxation rate is reduced in more weakly first-order compositions and is also reduced as the temperature is increased towards
T
crit
. At temperatures above
T
crit
, the metastability of the transition vanishes along with its associated temporal dynamics.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Mastering hysteresis in magnetocaloric materials
Authors: Gutfleisch O. , Gottschall T. , Fries M. , Benke D. , Radulov I. , Skokov K. P. , Wende H. , Gruner M. , Acet M. , Entel P. , Farle M.
Published: July 2016

Hysteresis is more than just an interesting oddity that occurs in materials with a first-order transition. It is a real obstacle on the path from existing laboratory-scale prototypes of magnetic refrigerators towards commercialization of this potentially disruptive cooling technology. Indeed, the reversibility of the magnetocaloric effect, being essential for magnetic heat pumps, strongly depends on the width of the thermal hysteresis and, therefore, it is necessary to understand the mechanisms causing hysteresis and to find solutions to minimize losses associated with thermal hysteresis in order to maximize the efficiency of magnetic cooling devices. In this work, we discuss the fundamental aspects that can contribute to thermal hysteresis and the strategies that we are developing to at least partially overcome the hysteresis problem in some selected classes of magnetocaloric materials with large application potential. In doing so, we refer to the most relevant classes of magnetic refrigerants La–Fe–Si-, Heusler- and Fe
2
P-type compounds.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Elastocaloric effect in CuAlZn and CuAlMn shape memory alloys under compression
Authors: Qian Suxin , Geng Yunlong , Wang Yi , Pillsbury Thomas E. , Hada Yoshiharu , Yamaguchi Yuki , Fujimoto Kenjiro , Hwang Yunho , Radermacher Reinhard , Cui Jun , Yuki Yoji , Toyotake Koutaro , Takeuchi Ichiro
Published: July 2016

This paper reports the elastocaloric effect of two Cu-based shape memory alloys: Cu68Al16Zn16(CuAlZn) and Cu73Al15Mn12(CuAlMn), under compression at ambient temperature. The compression tests were conducted at two different rates to approach isothermal and adiabatic conditions. Upon unloading at a strain rate of 0.1 s−1(adiabatic condition) from 4% strain, the highest adiabatic temperature changes (ΔTad) of 4.0 K for CuAlZn and 3.9 K for CuAlMn were obtained. The maximum stress and hysteresis at each strain were compared. The stress at the maximum recoverable strain of 4.0% for CuAlMn was 120 MPa, which is 70% smaller than that of CuAlZn. A smaller hysteresis for the CuAlMn alloy was also obtained, about 70% less compared with the CuAlZn alloy. The latent heat, determined by differential scanning calorimetry, was 4.3 J g−1for the CuAlZn alloy and 5.0 J g−1for the CuAlMn alloy. Potential coefficients of performance (COPmat) for these two alloys were calculated based on their physical properties of measured latent heat and hysteresis, and a COPmatof approximately 13.3 for CuAlMn was obtained.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Large elastic strain and elastocaloric effect caused by lattice softening in an iron-palladium alloy
Authors: Kakeshita Tomoyuki , Xiao Fei , Fukuda Takashi
Published: July 2016

A Fe-31.2Pd (at.%) alloy exhibits a weak first-order martensitic transformation from a cubic structure to a tetragonal structure near 230 K. This transformation is associated with significant softening of elastic constant
C
′. Because of the softening, the alloy shows a large elastic strain of more than 6% in the [001] direction. In addition, the alloy has a critical point and shows a high elastocaloric effect in a wide temperature range for both the parent and the martensite phases.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Thickness-dependent electrocaloric effect in mixed-phase Pb
0.87
Ba
0.1
La
0.02
(Zr
0.6
Sn
0.33
Ti
0.07
)O
3
thin films
Authors: Correia T. M. , Zhang Q.
Published: July 2016

Full-perovskite Pb
0.87
Ba
0.1
La
0.02
(Zr
0.6
Sn
0.33
Ti
0.07
)O
3
(PBLZST) thin films were fabricated by a sol–gel method. These revealed both rhombohedral and tetragonal phases, as opposed to the full-tetragonal phase previously reported in ceramics. The fractions of tetragonal and rhombohedral phases are found to be strongly dependent on film thickness. The fraction of tetragonal grains increases with increasing film thickness, as the substrate constraint throughout the film decreases with film thickness. The maximum of the dielectric constant (
ε
m
) and the corresponding temperature (
T
m
) are thickness-dependent and dictated by the fraction of rhombohedral and tetragonal phase, with
ε
m
reaching a minimum at 400 nm and
T
m
shifting to higher temperature with increasing thickness. With the thickness increase, the breakdown field decreases, but field-induced antiferroelectric–ferroelectric (
E
AFE−FE
) and ferroelectric–antiferroelectric (
E
FE−AFE
) switch fields increase. The electrocaloric effect increases with increasing film thickness.

This article is part of the themed issue ‘Taking the temperature of phase transitions in cool materials’.
Estimates of local biodiversity change over time stand up to scrutiny
Authors: Vellend Mark , Dornelas Maria , Baeten Lander , Beauséjour Robin , Brown Carissa D. , De Frenne Pieter , Elmendorf Sarah C. , Gotelli Nicholas J. , Moyes Faye , Myers-Smith Isla H. , Magurran Anne E. , McGill Brian J. , Shimadzu Hideyasu , Sievers Caya
Published: July 2016

Two recent meta-analyses of local-scale biodiversity change over time, by the authors of the present paper, have been subject to a harsh critique. Here we use new data and analyses to respond to the main points of this critique. First, a central argument of the critique was that short-term time series lead to biased estimates of long-term biodiversity change. However, we show here that this conclusion was based entirely on two fundamental mistakes in the simulations used to support it. Second, we show that the critic's conclusion that there are negative relationships between temporal biodiversity change and study duration is entirely dependent on: (i) the unrealistic assumption that biodiversity change can be positive when study duration = 0; (ii) the use of only a subset of the available data; (iii) inclusion of a single outlier data point in a single study (out of 100 in this case); and/or (iv) a choice to use log ratios rather than slopes (when available) as the metric of temporal biodiversity change. In short, the evidence does not support the conclusion that studies of longer duration tend to find local diversity decline. Finally, the critique highlighted the obviously true fact that studies in the ecological literature represent a geographically biased sample of locations on Earth; this issue was noted in both original papers, and is relevant for all ecological data syntheses. This fact was used by the critics to cast doubt on our conclusion that, outside of areas converted to croplands or asphalt, the distribution of temporal biodiversity trends is centered on zero. As a scientific rule, future studies based on more or different data may cause us to modify our conclusion, but at present, alternative conclusions based on the geographic-bias argument rely entirely on speculation. In sum, the critique raises points of uncertainty typical of all ecological studies, but it falls far short of providing an evidence-based alternative interpretation for our results, which are now supported by syntheses of hundreds of individual data sets of temporal biodiversity change.
Rare copy number variants inNRXN1andCNTN6increase risk for Tourette syndrome
Authors: Huang Alden Y. , Yu Dongmei , Davis Lea K. , Sul Jae-Hoon , Tsetsos Fotis , Ramensky Vasily , Zelaya Ivette , Ramos Eliana Marisa , Osiecki Lisa , Chen Jason A. , McGrath Lauren M. , Illmann Cornelia , Sandor Paul , Barr Cathy L. , Grados Marco , Singer Harvey S. , Noethen Markus M. , Hebebrand Johannes , King Robert A. , Dion Yves , Rouleau Guy , Budman Cathy L. , Depienne Christel , Worbe Yulia , Hartmann Andreas , Muller-Vahl Kirsten R. , Stuhrmann Manfred , Aschauer Harald , Stamenkovic Mara , Schloegelhofer Monika , Konstantinidis Anastasios , Lyon Gholson J. , McMahon William M. , Barta Csaba , Tarnok Zsanett , Nagy Peter , Batterson James R. , Rizzo Renata , Cath Danielle C. , Wolanczyk Tomasz , Berlin Cheston , Malaty Irene A. , Okun Michael S. , Woods Douglas W. , Rees Elliott , Pato Carlos N. , Pato Michele T. , Knowles James A , Posthuma Danielle , Pauls David L. , Cox Nancy J. , Neale Benjamin M. , Freimer Nelson B. , Paschou Peristera , Mathews Carol A. , Scharf Jeremiah M. , Coppola Giovanni
Published: July 2016

Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cause(s) has remained elusive. We examined a European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants (CNVs) using SNP microarrays and identified two genome-wide significant loci that confer a substantial increase in risk for TS (NRXN1, OR=20.3, 95%CI [2.6-156.2], p=6.0 × 10−6;CNTN6, OR=10.1, 95% CI [2.3-45.4], p=3.7 × 10−5). Approximately 1% of TS cases carried one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.
Whole genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver
Authors: Li Xin , Liu Yun , Salz Tal , Hansen Kasper D. , Feinberg Andrew
Published: July 2016

DNA methylation at the 5-postion of cytosine (5mC) is a well-established epigenetic modification which regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family is able to oxidize 5mC to 5-hydroxymethyl-cytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer. We found that 5hmC is significantly enriched in CpG island (CGI) shores while depleted in CGIs themselves, in particular at active genes, resulting in a 5hmC but not 5mC bimodal distribution around CGI corresponding to H3K4me1 marks. Hydroxymethylation on promoters, gene bodies, and transcription termination regions showed strong positive correlation with gene expression within and across tissues, suggesting that 5hmC is a mark of active genes and could play a role gene expression mediated by DNA demethylation. Comparative analysis of methylomes and hydroxymethylomes revealed that 5hmC is significantly enriched in both tissue specific DMRs (t-DMRs) and cancer specific DMRs (c-DMRs), and 5hmC is negatively correlated with methylation changes, particularly in non-CGI associated DMRs. Together these findings indicate that changes in 5mC as well as in 5hmC and coupled to H3K4me1 correspond to differential gene expression in tissues and matching tumors, revealing an intricate gene expression regulation through interplay of methylome, hydroxyl-methylome, and histone modifications.
Climate change vulnerability for species – assessing the assessments
Authors: Wheatley Christopher J. , Beale Colin M. , Bradbury Richard B. , Pearce-Higgins James W. , Critchlow Rob , Thomas Chris D.
Published: July 2016

Climate change vulnerability assessments are commonly used to identify species at risk from global climate change, but the wide range of methodologies available makes it difficult for end users, such as conservation practitioners or policy makers, to decide which method to use as a basis for decision-making. Here, we compare the outputs of 12 such climate change vulnerability assessment methodologies, using both real and simulated species, and we test the methods using historic data for British birds and butterflies (i.e., using historical data to assign risks, and more recent data for validation). Our results highlight considerable inconsistencies in species risk assignment across all the approaches considered and suggest the majority of the frameworks are poor predictors of risk under climate change – two methods performed worse than random. Methods that incorporated historic trend data were the only ones to have any validity at predicting distributional trends in subsequent time periods.
An RNA editing/binding-independent gene regulatory mechanism of ADARs and its clinical implication in cancer
Authors: Qi Lihua , Song Yangyang , Chan Tim Hon Man , Yang Henry , Lin Chi Ho , Tay Daryl Jin Tai , Hong HuiQi , Lin Jaymie Siqi , Ng Vanessa Hui En , Maury Julien Jean Pierre , Tenen Daniel G. , Chen Leilei
Published: July 2016

Adenosine-to-inosine (A-to-I) editing, catalysed by Adenosine DeAminases acting on double-stranded RNA (dsRNA) (ADAR), occurs predominantly in the 3’ untranslated regions (3’UTRs). Here we uncover an unanticipated link between ADARs (ADAR1 and ADAR2) and the expression of target genes undergoing extensive 3’UTR editing. UsingMETTL7A(Methyltransferase Like 7A), a novel tumor suppressor as an exemplary target gene, we demonstrate that its expression could be repressed by ADARs beyond their RNA editing and dsRNA binding functions. ADARs interact with Dicer to augment the processing of pre-miR-27a to mature miR-27a. Consequently, mature miR-27a targets theMETTL7A3’UTR to repress its expression level. In sum, our study unveils that the extensive 3’UTR editing is merely a footprint of ADAR binding, and is dispensable for the regulation of at least a subset of target genes. Instead, ADARs contribute to cancer progression by regulating cancer-related gene expression through their non-canonical functions independent of RNA editing and dsRNA binding. The functional significance of ADARs is much more diverse than previously appreciated and this gene regulatory function of ADARs is most likely to be of higher importance than the best-studied editing function. This novel non-editing side of ADARs opens another door to target cancer. This study is timely and represents a major break-through in the field of ADAR gene regulation and cancer biology.
Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes
Authors: Ehrhart Friederike , Coort Susan L.M. , Cirillo Elisa , Smeets Eric , Evelo Chris T. , Curfs Leopold M.
Published: July 2016

Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6-18 after normal pre-and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized. It is discussed how they are leading to some characteristic RTT phenotypes and identifies the gaps of knowledge, namely which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways. As a result of this review the visualization of the biologic pathways showing MECP2 up-and downstream regulation was developed and published onWikiPathways.
Inbreeding parents should invest more resources in fewer offspring
Authors: Duthie A. Bradley , Lee Aline M. , Reid Jane M.
Published: July 2016

Inbreeding increases parent-offspring relatedness and commonly reduces offspring viability, shaping selection on reproductive interactions involving relatives and associated parental investment (PI). Nevertheless, theories predicting selection for inbreeding versus inbreeding avoidance and selection for optimal PI have only been considered separately, precluding prediction of optimal PI and associated reproductive strategy given inbreeding. We unify inbreeding and PI theory, demonstrating that optimal PI increases when a female's inbreeding decreases the viability of her offspring. Inbreeding females should therefore produce fewer offspring due to the fundamental trade-off between offspring number and PI. Accordingly, selection for inbreeding versus inbreeding avoidance changes when females can adjust PI with the degree that they inbreed. In contrast, optimal PI does not depend on whether a focal female is herself inbred. However, inbreeding causes optimal PI to increase given strict monogamy and associated biparental investment compared to female-only investment. Our model implies that understanding evolutionary dynamics of inbreeding strategy, inbreeding depression, and PI requires joint consideration of the expression of each in relation to the other. Overall, we demonstrate that existing PI and inbreeding theories represent special cases of a more general theory, implying that intrinsic links between inbreeding and PI affect evolution of behaviour and intra-familial conflict.
Foxc1controls cell fate decisions during transforming growth factor β induced epithelial to mesenchymal transition through the regulation of fibroblast growth factor receptor 1 expression
Authors: Hopkins Alex , Coatham Mackenzie L. , Berry Fred B.
Published: July 2016

Epithelial to mesenchymal transition (EMT) is an important physiological process that drives tissue formation during development but also contributes to disease pathogenesis including fibrosis and cancer metastasis. The forkhead box transcription factor gene FOXC1 is an important developmental regulator in the generation of mesenchymal cells necessary in the formation of the anterior segment of the eye, the craniofacial skeleton and the meninges. Recently elevated expression ofFOXC1has been detected in several metastatic cancers that have undergone EMT events. We sought to determine the role of FOXC1 in the initiation of EMT events using NMuMG cells treated with TFGβ1. We found that although Foxc1 expression was increased following TFGβ1 induced EMT, Foxc1 was not required for this induction. Instead we propose that Foxc1 is required for the specification of the mesenchyme cell type, promoting an activated fibroblast phenotype over a myofibroblast phenotype following the initiation of EMT. This cells type specification was achieved through the regulation of Fibroblast growth factor (Fgfr) 1 expression. Using an RNA sequencing approach, we determined that levels of Fgfr1 normally activated upon TFGβ1 treatment were reduced in Foxc1-knockdown cells. Through chromatin immunoprecipitation experiments we determined that FOXC1 could bind to an Fgfr1 upstream regulatory region. Furthermore, expression of the myofibroblast marker α-smooth muscle actin (αSMA) was elevated in Foxc1 knockdown cells. Finally we determined that FGF2 mediated three dimensional migratory ability was greatly impaired in Foxc1-knockdown cells. Together these results define a role for Foxc1 in specifying a mesenchymal cell type following TFGβ1 mediated EMT events.
Do Dams Also Stop Frogs? Assessing Population Connectivity of Coastal Tailed Frogs (Ascaphus truei) in the North Cascades National Park Service Complex
Authors: Grummer Jared A. , Leaché Adam D.
Published: July 2016

We investigated the effects of three hydroelectric dams and their associated lakes on the population structure and connectivity of the coastal tailed frog, Ascaphus truei, in the North Cascades National Park Service Complex. Three dams were erected on the Skagit River in northern-central Washington state between 1924 and 1953 and subsequently changed the natural shape and movement of the Skagit River and its tributaries. We collected 183 individuals from 13 tributaries and generated a dataset of >2,500 loci (unlinked SNPs) using double digestion restriction site-associated DNA sequencing (ddRADseq). An analysis of molecular variance (AMOVA) identified ~99% of the genetic variation within groups, and the remaining variation among groups separated by dams, or the Skagit River. All populations exhibited low FSTvalues with a maximum of 0.03474. A ‘de novo’ discriminant analysis of principal components revealed two populations with no geographic cohesiveness. However, testing groups that were partitioneda prioriby the dams revealed distinctiveness of populations down-river of the lowest dam. Coalescent-based analyses of recent migration suggest that up to 17.3% of each population is composed of migrants from other populations, and an estimation of effective migration rates revealed high levels of migration heterogeneity and population connectivity in this area. Our results suggest that although the populations down-river from the lowest dam are distinguishable, a high level ofA.trueipopulation connectivity exists throughout the North Cascades National Park Service Complex.
Coral life history differences determine the refugium potential of a remote Caribbean reef
Authors: Davies Sarah W. , Strader Marie E. , Kool Johnathan T. , Kenkel Carly D. , Matz Mikhail V.
Published: July 2016

Remote populations can influence connectivity and may serve as refugia from climate change. Here, we investigated two reef-building corals (Pseudodiploria strigosaandOrbicella franksi) from the Flower Garden Banks (FGB) – the most isolated, high-latitude Caribbean reef system that retains high coral cover. We characterized coral size frequency distributions, quantified larval mortality rates and onset of competence, estimated larval production, and created detailed biophysical models incorporating these parameters to evaluate source-sink dynamics from 2009 to 2012. Mortality rates were similar across species but competency differed dramatically:P. strigosawas capable of metamorphosis within 2.5 days post fertilization (dpf), whileO. franksiwere not competent until >20dpf and remained competent up to 120dpf Despite these differences, models demonstrated that larvae of both types were similarly successful in reseeding the FGB. Nevertheless, corals with shorter pelagic larval durations (PLD), such asP. strigosa, were highly isolated from the rest of the Caribbean, while long PLD corals, such asO. franksi, could export larvae to distant northern Caribbean reefs. These results suggest that FGB coral populations are self-sustaining and highlight the potential of long PLD corals, such as endangeredOrbicella, to act as larval sources for other degraded Caribbean reefs.