bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexually transmitted infection testing practices among ‘money boys’ and general men who have sex with men in Shanghai, China: objective versus self-reported status
Authors: Lin Lavinia , Nehl Eric J. , Tran Alvin , He Na , Zheng Tony , Wong Frank Y.
Published: March 2014

Little is known about sexually transmitted infection (STI) testing among Chinese men who have sex with men (MSM). This study describes the prevalence of STI testing, associated factors and the validity of STI self-reporting among Chinese MSM. Findings indicated a high prevalence of STIs and low testing rates among MSM in Shanghai. Monthly income was significantly associated with STI testing (odds ratio: 0.37, 95% confidence interval (CI): 0.18 to 0.76). Depression was significantly associated with STI testing for general MSM (odds ratio: 1.09, 95% CI: 1.01 to 1.17). Syphilis self-reported status had the highest validity (k = 0.33, χ2 = 3.76, 95% CI: –0.003 to 0.65). Efforts are needed to ensure that STI testing services are accessible to MSM in China. Future HIV and STI interventions should be tailored to the needs of different subsets of MSM.
Extinct New Zealand megafauna were not in decline before human colonization
Authors: Allentoft Morten Erik , Heller Rasmus , Oskam Charlotte L. , Lorenzen Eline D. , Hale Marie L. , Gilbert M. Thomas P. , Jacomb Christopher , Holdaway Richard N. , Bunce Michael
Published: March 2014

Significance

In New Zealand, nine species of moa (large, wingless ratite birds) went extinct shortly after Polynesian settlement. In this study, we characterize the gene pools of four moa species during the final 4,000 y of their existence and gain new insights into moa biology and their population sizes. Our analyses show that moa populations were large and viable prior to human arrival in New Zealand, and their demise therefore represents a striking example of human overexploitation of megafauna.
High carbon dioxide uptake by subtropical forest ecosystems in the East Asian monsoon region
Authors: Yu Guirui , Chen Zhi , Piao Shilong , Peng Changhui , Ciais Philippe , Wang Qiufeng , Li Xuanran , Zhu Xianjin
Published: March 2014

Significance

Understanding the location of carbon sources and sinks is essential for accurately predicting future changes in atmospheric carbon dioxide and climate. Mid- to high-latitude terrestrial ecosystems are well known to be the principal carbon sink regions, yet less attention has been paid to the mid- to low-latitude ecosystems. In this study, long-term eddy covariance observations demonstrate that there is a high carbon dioxide uptake (net ecosystem productivity) by the mid- to low-latitude East Asian monsoon subtropical forests that were shaped by the uplift of the Tibetan Plateau. Increasing nitrogen deposition, a young forest age structure, and sufficient water and heat availability combined to contribute to this large carbon dioxide uptake.
Soil biodiversity and soil community composition determine ecosystem multifunctionality
Authors: Wagg Cameron , Bender S. Franz , Widmer Franco , van der Heijden Marcel G. A.
Published: March 2014

Significance

Biological diversity is the foundation for the maintenance of ecosystems. Consequently it is thought that anthropogenic activities that reduce the diversity in ecosystems threaten ecosystem performance. A large proportion of the biodiversity within terrestrial ecosystems is hidden below ground in soils, and the impact of altering its diversity and composition on the performance of ecosystems is still poorly understood. Using a novel experimental system to alter levels of soil biodiversity and community composition, we found that reductions in the abundance and presence of soil organisms results in the decline of multiple ecosystem functions, including plant diversity and nutrient cycling and retention. This suggests that below-ground biodiversity is a key resource for maintaining the functioning of ecosystems.
M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7
Authors: Xiao Xiangwei , Gaffar Iljana , Guo Ping , Wiersch John , Fischbach Shane , Peirish Lauren , Song Zewen , El-Gohary Yousef , Prasadan Krishna , Shiota Chiyo , Gittes George K.
Published: March 2014

Significance

Here, we show how, mechanistically, inflammation-recruited macrophages may stimulate beta-cell proliferation in the pancreas, and specifically identify that TGFβ1 and EGF, which are secreted by M2 macrophages, induce SMAD7 expression in beta cells. SMAD7 not only activates cell cycle activators but also induces the nuclear exclusion of cell cycle inhibitors to promote beta-cell replication. Our study thus reveals a molecular pathway to induce beta-cell proliferation through enhanced SMAD7 activity specifically in beta cells.
Single-molecule spectroscopy reveals polymer effects of disordered proteins in crowded environments
Authors: Soranno Andrea , Koenig Iwo , Borgia Madeleine B. , Hofmann Hagen , Zosel Franziska , Nettels Daniel , Schuler Benjamin
Published: March 2014

Significance

In the interior of a cell, the volume accessible to each protein molecule is restricted by the presence of the large number of other macromolecules. Such a crowded environment is known to affect the stability and folding rates of proteins. In the case of intrinsically disordered proteins (IDPs), however, a class of proteins that lack stable structure, much less is known about the role of crowding effects. We have quantified the conformational changes occurring in IDPs in the presence of high concentrations of different polymers that act as crowding agents. Using single-molecule spectroscopy, we have identified effects that are typical of polymer solutions and have direct implications for the behavior of IDPs within the cell.
Selective attention in the honeybee optic lobes precedes behavioral choices
Authors: Paulk Angelique C. , Stacey Jacqueline A. , Pearson Thomas W. J. , Taylor Gavin J. , Moore Richard J. D. , Srinivasan Mandyam V. , van Swinderen Bruno
Published: March 2014

Significance

Attention, observed in a wide variety of animals from insects to humans, involves selectively attending to behaviorally relevant stimuli while filtering out other stimuli. We designed a paradigm that allowed us to record brain activity in tethered, walking bees selecting virtual visual objects. We found that stimulus-specific brain activity increased when the bees controlled the position of the visual objects, and that activity decreased when bees were not in control. When bees were presented with competing objects, brain activity in the optic lobes preceded behavioral choices; this suggests that in animals with tiny brains, such as bees, attention-like processes are pushed far out into the sensory periphery. This trait is likely important for efficiently navigating complex visual environments.
Decoupling catalytic activity from biological function of the ATPase that powers lipopolysaccharide transport
Authors: Sherman David J. , Lazarus Michael B. , Murphy Lea , Liu Charles , Walker Suzanne , Ruiz Natividad , Kahne Daniel
Published: March 2014

Significance

Gram-negative bacteria contain an unusual outer membrane that prevents the entry of most currently available antibiotics. This membrane contains a complex glycolipid, LPS, on the exterior. It is not understood how such a large molecule, which can contain hundreds of sugars and six fatty acyl chains, is transported across the cell envelope from its site of synthesis in the cytoplasmic membrane to the cell surface. Using a combination of genetics, biochemistry, and structural biology, we characterized residues in the protein that powers LPS transport to gain mechanistic insight into how ATP hydrolysis is coupled to the biological function of the transporter. These tools help us understand how to design antibiotics targeting this essential pathway.
Flying
Drosophila
stabilize their vision-based velocity controller by sensing wind with their antennae
Authors: Fuller Sawyer Buckminster , Straw Andrew D. , Peek Martin Y. , Murray Richard M. , Dickinson Michael H.
Published: March 2014

Significance

Insects are widely appreciated for their aerial agility, but the organization of their control system is not well understood. In particular, it is not known how they rapidly integrate information from different sensory systems—such as their eyes and antennae—to regulate flight speed. Although vision may provide an estimate of the true groundspeed in the presence of wind, delays inherent in visual processing compromise the performance of the flight speed regulator and make the animal unstable. Mechanoreceptors on the antennae of flies cannot measure groundspeed directly, but can detect changes in airspeed more quickly. By integrating information from both senses, flies achieve stable regulation of flight speed that is robust to perturbations such as gusts of wind.
Representations of space, time, and number in neonates
Authors: de Hevia Maria Dolores , Izard Véronique , Coubart Aurélie , Spelke Elizabeth S. , Streri Arlette
Published: March 2014

Significance

Space, time, and number are connected in the world and in the human mind. How do these connections arise? Do we learn to link larger numbers and durations to longer spatial extents because they are correlated in the world, or is the human mind built to capture these relations? We showed that neonates relate both number and duration to spatial length when these dimensions vary in the same direction (number or duration increases as length increases), but not in opposite directions (number or duration increases and length decreases). After being familiarized to a pairing between two magnitudes, newborns expect these dimensions to change in the same direction. At birth, humans are sensitive to the common structure of these fundamental magnitudes.
High-resolution antibody dynamics of vaccine-induced immune responses
Authors: Laserson Uri , Vigneault Francois , Gadala-Maria Daniel , Yaari Gur , Uduman Mohamed , Vander Heiden Jason A. , Kelton William , Taek Jung Sang , Liu Yi , Laserson Jonathan , Chari Raj , Lee Je-Hyuk , Bachelet Ido , Hickey Brendan , Lieberman-Aiden Erez , Hanczaruk Bozena , Simen Birgitte B. , Egholm Michael , Koller Daphne , Georgiou George , Kleinstein Steven H. , Church George M.
Published: March 2014

Significance

The immune system must constantly adapt to combat infections and other challenges. This is accomplished by continuously evolving the antibody repertoire, and by maintaining memory of prior challenges. By using next-generation DNA sequencing technology, we have examined the shear amount of antibody made by individuals during a flu vaccination trial. We demonstrate one of the first characterizations of the fast antibody dynamics through time in multiple individuals responding to an immune challenge.
Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease
Authors: Mistry Pramod K. , Liu Jun , Sun Li , Chuang Wei-Lien , Yuen Tony , Yang Ruhua , Lu Ping , Zhang Kate , Li Jianhua , Keutzer Joan , Stachnik Agnes , Mennone Albert , Boyer James L. , Jain Dhanpat , Brady Roscoe O. , New Maria I. , Zaidi Mone
Published: March 2014

Significance

Type 1 Gaucher disease (GD1) is a rare autosomal recessive disorder caused by inherited mutations in the glucocerebrosidase (
GBA1
) gene. This disease results in a marked accumulation of glycosphingolipid substrates, causing visceromegaly, cytopenia, and osteopenia. Here, we have rescued this clinical phenotype in GD1 mice by genetically deleting
Gba2
, a gene encoding a downstream extralysosomal enzyme, GBA2. We also report that sphingosine production in GD1 patients may contribute to the low-turnover bone loss. Our data suggest that GBA2 and sphingosine are potential targets for pharmacological intervention in GD1 patients.
Periodic root branching in
Arabidopsis
requires synthesis of an uncharacterized carotenoid derivative
Authors: Van Norman Jaimie M. , Zhang Jingyuan , Cazzonelli Christopher I. , Pogson Barry J. , Harrison Peter J. , Bugg Timothy D. H. , Chan Kai Xun , Thompson Andrew J. , Benfey Philip N.
Published: March 2014

Significance

A fundamental question in developmental biology is how patterns are established in space and time. In plants, key differences in root system architecture are attributed to the spatial distribution pattern of lateral roots (LRs), yet how the pattern of LRs is established is only beginning to be understood. We demonstrate that the establishment of sites competent to form LRs roots requires carotenoid biosynthesis. Furthermore, our results implicate an uncharacterized carotenoid-derived molecule that functions non–cell-autonomously, specifically in LR formation. The results of this study reveal novel aspects of carotenoid biology and expand the roles of carotenoid-derived molecules into root developmental patterning.
Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides
Authors: Bansal-Mutalik Ritu , Nikaido Hiroshi
Published: March 2014

Significance

Mycobacteria include human pathogens that still kill millions annually. They are naturally resistant to commonly used antibiotics, presumably because the cell interior is well protected by the presence of the lipid-rich cell wall, which is thought to exist as a membrane, or the outer membrane. However, it was not known whether a sufficient number of lipid molecules existed to form a bilayer within the cell wall. We used a unique method that extracts only cell-wall lipids and showed that there are indeed enough lipids to cover the cell surface entirely as a bilayer. The analysis of inner, cell-membrane lipids also gave an unexpected insight, suggesting that the nature of the inner membrane might also contribute to generalized drug resistance.
Contextualized violence: politics and terror in Dagestan
Authors: Ibragimov Magomed-Rasul , Matsuzato Kimitaka
Published: March 2014

Despite the escalating terrorist actions, there is no polarized constellation in the Islamic politics of Dagestan. Russia's Federal Security Service (FSB) officers regard the corrupt Dagestan authorities to be significantly responsible for the massive conversion of youths to terrorism, and began to contact with moderate Salafis to isolate the “forest brothers” (armed Salafis) in 2010. Exploiting the FSB's soft strategy, secular intellectuals requested to reform the Muslim Spiritual Board of Dagestan by electing a legitimate mufti. Having seen the incompetence of intra-Sufi opposition (non-Avar sheikhs) in the War on Terror, the Spiritual Board jumped on the bandwagon of dialog strategy in 2012. The secular authorities of Dagestan, indifferent to intra-Muslim politics, limit their activities to the call for dialog between the secular authorities and the forest brothers. In this way, political actors hijack the master narrative of the “War on Terror” and these narratives are imported to local politics.
Introduction: Border communities: microstudies on everyday life, politics and memory in European Societies from 1945 to the present
Authors: Oates-Indruchová Libora , Blaive Muriel
Published: March 2014

The 1989/1991 demise of European communist regimes created a powerful impulse for the investigation of memory cultures at Cold War borders and, subsequently, for reflections on the creation of new European border regimes. The four studies included in this special section investigate these two processes on a micro level of their dynamics in new and old borderlands from the perspectives of history, anthropology and political science. At the same time, they explore the relations between the everyday life experience of borderland communities and larger historical and political processes, sometimes going back to the re-drawing of European borders in the aftermath of the First World War.

It is the hybrid nature of borders as at the same time separating and connecting (Anzaldúa 1987; Gupta and Fergusson 1997), as the place where “a transition between two worlds is most pronounced” (Van Gennep 1960 paraphrased in Berdahl 1999, 12) that makes them such an attractive and interdisciplinary site of research. It is of interest to geographers, historians, anthropologists, sociologists and other social scientists (e.g. Donnan and Wilson 1994; Anderson 1997; Ganster et al. 1997; Breysach, Paszek, and Tölle 2003; Wastl-Walter 2010). Daphne Berdahl sees boundaries as “symbols through which states, nations, and localities define themselves. They define at once territorial limits and sociocultural space” (Berdahl 1999, 3). Border research distinguishes between “border,” “bordering,” and “borderland” or “frontier” (the term first defined by Turner 1921). While borders connote a dividing line, borderlands connote an area, and bordering refers to the process of border- and borderland-creation. Borders are established through a three-stage process of allocation, delimitation and demarcation: a territory is first placed (allocated) under the jurisdiction of a government, then an imaginary line is drawn (delimited) on a map, and finally the boundary is marked with physical markers (demarcated) in the terrain (Sahlins 1989, 2). Borderlands or frontier zones are “privileged sites for the articulation of national distinctions” (Sahlins 1989, 271), and as such are places where difference is produced and institutionalized through territorial sovereignty, but also constantly renegotiated by multiple actors.
BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups
Authors: Berres Marie-Luise , Lim Karen Phaik Har , Peters Tricia , Price Jeremy , Takizawa Hitoshi , Salmon Hélène , Idoyaga Juliana , Ruzo Albert , Lupo Philip J. , Hicks M. John , Shih Albert , Simko Stephen J. , Abhyankar Harshal , Chakraborty Rikhia , Leboeuf Marylene , Beltrão Monique , Lira Sérgio A. , Heym Kenneth M. , Clausen Björn E. , Bigley Venetia , Collin Matthew , Manz Markus G. , McClain Kenneth , Merad Miriam , Allen Carl E.
Published: March 2014

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207+ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207+ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c+ and CD14+ fractions and in bone marrow (BM) CD34+ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207+ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
Structural diversity of ABC transporters
Authors: ter Beek Josy , Guskov Albert , Slotboom Dirk Jan
Published: March 2014

ATP-binding cassette (ABC) transporters form a large superfamily of ATP-dependent protein complexes that mediate transport of a vast array of substrates across membranes. The 14 currently available structures of ABC transporters have greatly advanced insight into the transport mechanism and revealed a tremendous structural diversity. Whereas the domains that hydrolyze ATP are structurally related in all ABC transporters, the membrane-embedded domains, where the substrates are translocated, adopt four different unrelated folds. Here, we review the structural characteristics of ABC transporters and discuss the implications of this structural diversity for mechanistic diversity.
First Successful Lung Transplantation for Sickle Cell Disease with Severe Pulmonary Arterial Hypertension and Pulmonary Veno‐Occlusive Disease
Authors: George M. Patricia , Novelli Enrico M. , Shigemura Norihisa , Simon Marc A. , Feingold Brian , Krishnamurti Lakshmanan , Morrell Matthew R. , Gries Cynthia G. , Haider Syed , Johnson Bruce A. , Crespo Maria M. , Bhama Jay K. , Bermudez Christian , Yousem Samuel A. , Toyoda Yoshiya , Champion Hunter C. , Pilewski Joseph M. , Gladwin Mark T.
Published: March 2014

Little is known about the use of lung transplantation in the management of sickle cell disease– associated pulmonary arterial hypertension (SCD‐PAH). We present clinical and pathological data and report the first successful outcome of bilateral lung transplantation in a patient with severe SCD‐PAH and pulmonary veno‐occlusive disease (PVOD). We discuss the complexities of multidisciplinary planning and management of lung transplantation in patients with SCD‐associated pulmonary vascular complications. This case reports the first documented successful lung transplant and first case of PVOD in a patient with SCD‐PAH.
Oxidative‐Stress Biomarkers in Patients with Pulmonary Hypertension
Authors: Reis Graziela S. , Augusto Viviane S. , Silveira Ana Paula C. , Jordão Alceu A. , Baddini‐Martinez José , Neto Omero Poli , Rodrigues Alfredo José , Evora Paulo Roberto B.
Published: March 2014

This controlled, prospective, nonrandomized clinical investigation has as its chief strength the fact that it was done in humans with active disease and apparently on fairly modest therapeutic regimens. The aim was to present the results of oxidative‐stress biomarkers in humans suffering from pulmonary artery hypertension (PAH). Inflammation and oxidative stress are essential in PAH with increased lipid peroxidation and reduced antioxidant defenses. Twenty‐four adult patients of both sexes, with a mean age of 21 years, were subdivided into 2 groups: a control group of 12 healthy, nonsmoking volunteers and a PAH group (PAHG) of 12 volunteers with PAH receiving outpatient treatment. Oxidative stress was evaluated by plasma activity of reduced glutathione (GSH); lipid peroxidation was expressed by malondialdehyde (MDA) and lipid hydroperoxide (ferrous oxidation of xylenol orange [FOX] assay); vitamin E was measured by high‐performance liquid chromatography and tumor necrosis factor‐α (TNF‐α) by enzyme‐linked immunosorbent assay. Statistical analyses showed significant differences for (1) the TNF‐α measure, with highest values in PAHG patients; (2) the plasma GSH, with lowest values in PAHG patients; (3) vitamin E, with the lowest concentrations in PAHG patients; (4) MDA measure, with highest values in PAHG patients; and (5) the lipid hydroperoxide FOX measure, with highest values in PAHG patients. In conclusion, inflammation and oxidative stress are present in patients with PAH, as confirmed by increased lipid peroxidation, reduced GSH, and low concentrations of vitamin E.
Transient Receptor Potential Channels and Regulation of Lung Endothelial Permeability
Authors: Villalta Patricia C. , Townsley Mary I.
Published: March 2014

This review highlights our current knowledge regarding expression of transient receptor potential (TRP) cation channels in lung endothelium and evidence for their involvement in regulation of lung endothelial permeability. Six mammalian TRP families have been identified and organized on the basis of sequence homology: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin). To date, only TRPC1/4, TRPC6, TRPV4, and TRPM2 have been extensively studied in lung endothelium. Calcium influx through each of these channels has been documented to increase lung endothelial permeability, although their channel‐gating mechanisms, downstream signaling mechanisms, and impact on endothelial structure and barrier integrity differ. While other members of the TRPC, TRPV, and TRPM families may be expressed in lung endothelium, we have little or no evidence linking these to regulation of lung endothelial permeability. Further, neither the expression nor functional role(s) of any TRPML, TRPP, and TRPA family members has been studied in lung endothelium. In addition to this assessment organized by TRP channel family, we also discuss TRP channels and lung endothelial permeability from the perspective of lung endothelial heterogeneity, using outcomes of studies focused on TRPC1/4 and TRPV4 channels. The diversity within the TRP channel family and the relative paucity of information regarding roles of a number of these channels in lung endothelium make this field ripe for continued investigation.
Interdisciplinary Networks for the Treatment of Childhood Pulmonary Vascular Disease: What Pulmonary Hypertension Doctors Can Learn from Pediatric Oncologists
Authors: Hansmann Georg
Published: March 2014

The pathobiology of pulmonary arterial hypertension (PAH) is complex and multifactorial. None of the current therapies has been shown to be universally effective or able to reverse advanced pulmonary vascular disease, characterized by plexiform vascular lesions, or to prevent right ventricular failure in advanced PAH. It is thus unlikely that only one factor, pathway, or gene mutation will explain all forms and cases. Pediatric oncologists recognized a need for intensified, collaborative research within their field more than 40 years ago and implemented major clinical and translational networks worldwide to achieve evidence‐based “tailored therapies.” The similarities in the pathobiology (e.g., increased proliferation and resistance to apoptosis in vascular cells and perivascular inflammation) and the uncertainties in the proper treatment of both cancer and pulmonary hypertension (PH) have led to the idea of building interdisciplinary networks among PH centers to achieve rapid translation of basic research findings, optimal diagnostic algorithms, and significant, sustained treatment results. Such networks leading to patient registries, clinical trials, drug development, and innovative, effective therapies are urgently needed for the care of children with PH. This article reviews the current status, limitations, and recent developments in the field of pediatric PH. It is suggested that the oncologists' exemplary networks, concepts, and results in the treatment of acute lymphoblastic leukemia are applicable to future networks and innovative therapies for pediatric pulmonary hypertensive vascular disease and right ventricular dysfunction.
Coagulation and the Vessel Wall in Pulmonary Embolism
Authors: Alias Sherin , Lang Irene M.
Published: March 2014

Venous thromboembolism comprises deep‐vein thrombosis, thrombus in transit, acute pulmonary embolism, and chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary thromboemboli commonly resolve, with restoration of normal pulmonary hemodynamics. When they fail to resorb, permanent occlusion of the deep veins and/or CTEPH are the consequences. Apart from endogenous fibrinolysis, venous thrombi resolve by a process of mechanical fragmentation, through organization of the thromboembolus by invasion of endothelial cells, leukocytes, and fibroblasts leading to recanalization. Recent data utilizing various models have contributed to a better understanding of venous thrombosis and the resolution process that is directed at maintaining vascular patency. This review summarizes the plasmatic and cellular components of venous thrombus formation and resolution.
A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?
Authors: Maarman Gerald , Lecour Sandrine , Butrous Ghazwan , Thienemann Friedrich , Sliwa Karen
Published: March 2014

Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.
Pass‐Through and Consumer Search: An Empirical Analysis
Authors: Richards Timothy J. , Gómez Miguel I. , Lee Jun
Published: March 2014

Retail‐price pass‐through is one of the most important issues facing manufacturers of consumer packaged goods. Although retailers tend to pass higher wholesale prices through to consumers quickly and completely, they often do not pass on trade promotions. Currently, asymmetric pass‐through is commonly thought to result from retailers' exercise of market power. Alternatively, it may be because of consumer search behavior and retailers' competitive response. We test this theory using a panel threshold asymmetric error‐correction model applied to wholesale and retail scanner data for ready‐to‐eat cereal for a number of retailers in the Los Angeles metropolitan market. We find that consumer search behavior contributes significantly to imperfect pass‐through. By allowing pass‐through to depend on market power and consumer search costs, we find results that are contrary to the conventional wisdom. Namely, market power causes retail prices to fall quickly and rise slowly, whereas consumer search behavior causes retail prices to rise quickly and fall slowly—precisely the “rockets and feathers” phenomenon.
Stock identification of Atlantic cod (Gadus morhua) in US waters: an interdisciplinary approach
Authors: Zemeckis Douglas R. , Martins David , Kerr Lisa A. , Cadrin Steven X.
Published: March 2014

Mismatches between biological population structure and management unit boundaries often violate the unit-stock assumption, which can reduce the accuracy and relevance of stock assessment results and lead to ineffective fishery management. Since 1972, Atlantic cod (Gadus morhua) have been managed in US waters as two units: the Gulf of Maine and the Georges Bank stocks, both of which have experienced recent difficulties in rebuilding. An interdisciplinary review of available biological information was conducted to investigate cod population structure in US waters and to evaluate the biological appropriateness of the current two-stock model. Our review demonstrates that spawning components in the Great South Channel, Nantucket Shoals, southern New England, and Middle Atlantic are more connected with spawning components in the Gulf of Maine than on eastern Georges Bank, with which they are currently managed. Therefore, a modification of current stock boundaries is recommended to provide a more accurate representation of biological population structure. Proposed alternatives divide inshore and offshore spawning components into separate management units, thereby separating the current Georges Bank stock longitudinally. Continued research, including stock composition analysis, is required to evaluate uncertainties, delineate biological stocks, and develop sustainable management practices that account for intrastock diversity (e.g. winter and spring-spawning components that overlap spatially).
A model of subjective report and objective discrimination as categorical decisions in a vast representational space
Authors: King J-R. , Dehaene S.
Published: March 2014

Subliminal perception studies have shown that one can objectively discriminate a stimulus without subjectively perceiving it. We show how a minimalist framework based on Signal Detection Theory and Bayesian inference can account for this dissociation, by describing subjective and objective tasks with similar decision-theoretic mechanisms. Each of these tasks relies on distinct response classes, and therefore distinct priors and decision boundaries. As a result, they may reach different conclusions. By formalizing, within the same framework, forced-choice discrimination responses, subjective visibility reports and confidence ratings, we show that this decision model suffices to account for several classical characteristics of conscious and unconscious perception. Furthermore, the model provides a set of original predictions on the nonlinear profiles of discrimination performance obtained at various levels of visibility. We successfully test one such prediction in a novel experiment: when varying continuously the degree of perceptual ambiguity between two visual symbols presented at perceptual threshold, identification performance varies quasi-linearly when the stimulus is unseen and in an ‘all-or-none’ manner when it is seen. The present model highlights how conscious and non-conscious decisions may correspond to distinct categorizations of the same stimulus encoded by a high-dimensional neuronal population vector.
Blinded by the load: attention, awareness and the role of perceptual load
Authors: Lavie Nilli , Beck Diane M. , Konstantinou Nikos
Published: March 2014

What is the relationship between attention and conscious awareness? Awareness sometimes appears to be restricted to the contents of focused attention, yet at other times irrelevant distractors will dominate awareness. This contradictory relationship has also been reflected in an abundance of discrepant research findings leading to an enduring controversy in cognitive psychology. Lavie's load theory of attention suggests that the puzzle can be solved by considering the role of perceptual load. Although distractors will intrude upon awareness in conditions of low load, awareness will be restricted to the content of focused attention when the attended information involves high perceptual load. Here, we review recent evidence for this proposal with an emphasis on the various subjective blindness phenomena, and their neural correlates, induced by conditions of high perceptual load. We also present novel findings that clarify the role of attention in the response to stimulus contrast. Overall, this article demonstrates a critical role for perceptual load across the spectrum of perceptual processes leading to awareness, from the very early sensory responses related to contrast detection to explicit recognition of semantic content.
Can binocular rivalry reveal neural correlates of consciousness?
Authors: Blake Randolph , Brascamp Jan , Heeger David J.
Published: March 2014

This essay critically examines the extent to which binocular rivalry can provide important clues about the neural correlates of conscious visual perception. Our ideas are presented within the framework of four questions about the use of rivalry for this purpose: (i) what constitutes an adequate comparison condition for gauging rivalry's impact on awareness, (ii) how can one distinguish abolished awareness from inattention, (iii) when one obtains unequivocal evidence for a causal link between a fluctuating measure of neural activity and fluctuating perceptual states during rivalry, will it generalize to other stimulus conditions and perceptual phenomena and (iv) does such evidence necessarily indicate that this neural activity constitutes a neural correlate of consciousness? While arriving at sceptical answers to these four questions, the essay nonetheless offers some ideas about how a more nuanced utilization of binocular rivalry may still provide fundamental insights about neural dynamics, and glimpses of at least some of the ingredients comprising neural correlates of consciousness, including those involved in perceptual decision-making.
Rhizobium flavum sp. nov., a triazophos-degrading bacterium isolated from soil under the long-term application of triazophos
Authors: Gu Tao , Sun Li Na , Zhang Jun , Sui Xin Hua , Li Shun Peng
Published: March 2014

A Gram-stain-negative, non-motile, pale yellow, rod-shaped bacterial strain, YW14T, was isolated from soil and its taxonomic position was investigated by a polyphasic study. Strain YW14Tdid not form nodules on three different legumes, and thenodDandnifHgenes were not detected by PCR. Strain YW14Tcontained Q-10 as the predominant ubiquinone. The major cellular fatty acid was C18 : 1ω7c. Phylogenetic analyses based on 16S rRNA gene sequences and seven housekeeping gene sequences (recA, atpD,glnII, gyrB, rpoB, dnaKandthrC) showed that strain YW14Tbelonged to the genusRhizobium. Strain YW14Tshowed 16S rRNA gene sequence similarity of 93.4–97.3 % to the type strains of recognized species of the genusRhizobium. DNA–DNA relatedness between strain YW14Tand the type strains ofRhizobium sullaeIS123TandRhizobium yanglingenseCCBAU 71623Twas 19.6–25.7 %, indicating that strain YW14Twas distinct from them genetically. Strain YW14Tcould also be differentiated from these phylogenetically related species of the genusRhizobiumby various phenotypic properties. On the basis of phenotypic properties, phylogenetic distinctiveness and genetic data, strain YW14Tis considered to represent a novel species of the genusRhizobium, for which the nameRhizobiumflavumsp. nov. is proposed. The type strain is YW14T( = KACC 17222T = CCTCC AB2013042T).
Rapidly characterizing the fast dynamics of RNA genetic circuitry with cell-free transcription-translation (TX-TL) systems
Authors: Takahashi Melissa K , Chappell James , Hayes Clarmyra A , Sun Zachary Z , Singhal Vipul , Spring Kevin J , Al-Khabouri Shaima , Fall Christopher P , Noireaux Vincent , Murray Richard M , Lucks Julius B
Published: March 2014

RNA regulators are emerging as powerful tools to engineer synthetic genetic networks or rewire existing ones. A potential strength of RNA networks is that they may be able to propagate signals on timescales that are set by the fast degradation rates of RNAs. However, a current bottleneck to verifying this potential is the slow design-build-test cycle of evaluating these networks in vivo. Here we adapt anEscherichia coli-based cell- free transcription-translation (TX-TL) system for rapidly prototyping RNA networks. We used this system to measure the response time of an RNA transcription cascade to be approximately five minutes per step of the cascade. We also show that this response time can be adjusted with temperature and regulator threshold response tuning. Finally we use TX-TL to prototype a new RNA network, an RNA single input module, and show that this network temporally stages the expression of two genesin vivo. Now published as: ACS Synthetic Biology doi:10.1021/sb400206c
The yeast and human FACT chromatin-reorganizing complexes solve R-loop-mediated transcription–replication conflicts
Authors: Herrera-Moyano Emilia , Mergui Xénia , García-Rubio María L. , Barroso Sonia , Aguilera Andrés
Published: March 2014

FACT (facilitates chromatin transcription) is a chromatin-reorganizing complex that swaps nucleosomes around the RNA polymerase during transcription elongation and has a role in replication that is not fully understood yet. Here we show that recombination factors are required for the survival of yeast FACT mutants, consistent with an accumulation of DNA breaks that we detected by Rad52 foci and transcription-dependent hyperrecombination. Breaks also accumulate in FACT-depleted human cells, as shown by γH2AX foci and single-cell electrophoresis. Furthermore, FACT-deficient yeast and human cells show replication impairment, which in yeast we demonstrate by ChIP–chip (chromatin immunoprecipitation [ChIP] coupled with microarray analysis) of Rrm3 to occur genome-wide but preferentially at highly transcribed regions. Strikingly, in yeast FACT mutants, high levels of Rad52 foci are suppressed by RNH1 overexpression; R loops accumulate at high levels, and replication becomes normal when global RNA synthesis is inhibited in FACT-depleted human cells. The results demonstrate a key function of FACT in the resolution of R-loop-mediated transcription–replication conflicts, likely associated with a specific chromatin organization.
Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis
Authors: Wu Tongde , Zhao Fei , Gao Beixue , Tan Can , Yagishita Naoko , Nakajima Toshihiro , Wong Pak K. , Chapman Eli , Fang Deyu , Zhang Donna D.
Published: March 2014

Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1–Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Down-regulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1–Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.
Structure and possible mechanism of the CcbJ methyltransferase fromStreptomyces caelestis
Authors: Bauer Jacob , Ondrovičová Gabriela , Najmanová Lucie , Pevala Vladimír , Kameník Zdeněk , Koštan Július , Janata Jiří , Kutejová Eva
Published: March 2014

TheS-adenosyl-L-methionine (SAM)-dependent methyltransferase CcbJ fromStreptomyces caelestiscatalyzes one of the final steps in the biosynthesis of the antibiotic celesticetin, methylation of the N atom of its proline moiety, which greatly enhances the activity of the antibiotic. Since several celesticetin variants exist, this enzyme may be able to act on a variety of substrates. The structures of CcbJ determined by MAD phasing at 3.0 Å resolution, its native form at 2.7 Å resolution and its complex withS-adenosyl-L-homocysteine (SAH) at 2.9 Å resolution are reported here. Based on these structures, three point mutants, Y9F, Y17F and F117G, were prepared in order to study its behaviour as well as docking simulations of both CcbJ–SAM–substrate and CcbJ–SAH–product complexes. The structures show that CcbJ is a class I SAM-dependent methyltransferase with a wide active site, thereby suggesting that it may accommodate a number of different substrates. The mutation results show that the Y9F and F117G mutants are almost non-functional, while the Y17F mutant has almost half of the wild-type activity. In combination with the docking studies, these results suggest that Tyr9 and Phe117 are likely to help to position the substrate for the methyl-transfer reaction and that Tyr9 may also facilitate the reaction by removing an H+ion. Tyr17, on the other hand, seems to operate by helping to stabilize the SAM cofactor.
The crystal structure of wild-type human brain neuroglobin reveals flexibility of the disulfide bond that regulates oxygen affinity
Authors: Guimarães Beatriz G. , Hamdane Djemel , Lechauve Christophe , Marden Michael C. , Golinelli-Pimpaneau Béatrice
Published: March 2014

Neuroglobin plays an important function in the supply of oxygen in nervous tissues. In human neuroglobin, a cysteine at position 46 in the loop connecting the C and D helices of the globin fold is presumed to form an intramolecular disulfide bond with Cys55. Rupture of this disulfide bridge stabilizes bi-histidyl haem hexacoordination, causing an overall decrease in the affinity for oxygen. Here, the first X-ray structure of wild-type human neuroglobin is reported at 1.74 Å resolution. This structure provides a direct observation of two distinct conformations of the CD region containing the intramolecular disulfide link and highlights internal cavities that could be involved in ligand migration and/or are necessary to enable the conformational transition between the low and high oxygen-affinity states following S—S bond formation.
Partial rotational lattice order–disorder in stefin B crystals
Authors: Renko Miha , Taler-Verčič Ajda , Mihelič Marko , Žerovnik Eva , Turk Dušan
Published: March 2014

At present, the determination of crystal structures from data that have been acquired from twinned crystals is routine; however, with the increasing number of crystal structures additional crystal lattice disorders are being discovered. Here, a previously undescribed partial rotational order–disorder that has been observed in crystals of stefin B is described. The diffraction images revealed normal diffraction patterns that result from a regular crystal lattice. The data could be processed in space groupsI4 andI422, yet one crystal exhibited a notable rejection rate in the higher symmetry space group. An explanation for this behaviour was found once the crystal structures had been solved and refined and the electron-density maps had been inspected. The lattice of stefin B crystals is composed of five tetramer layers: four well ordered layers which are followed by an additional layer of alternatively placed tetramers. The presence of alternative positions was revealed by the inspection of electron-density score maps. The well ordered layers correspond to the crystal symmetry of space groupI422. In addition, the positions of the molecules in the additional layer are related by twofold rotational axes which correspond to space groupI422; however, these molecules lie on the twofold axis and can only be related in a statistical manner. When the occupancies of alternate positions and overlapping are equal, the crystal lattice indeed fulfills the criteria of space groupI422; when these occupancies are not equal, the lattice only fulfills the criteria of space groupI4.
Structural basis for the selective nuclear import of the C2H2 zinc-finger protein Snail by importin β
Authors: Choi Saehae , Yamashita Eiki , Yasuhara Noriko , Song Jinsue , Son Se-Young , Won Young Han , Hong Hye Rim , Shin Yoon Sik , Sekimoto Toshihiro , Park Il Yeong , Yoneda Yoshihiro , Lee Soo Jae
Published: March 2014

Snail contributes to the epithelial–mesenchymal transition by suppressing E-cadherin in transcription processes. The Snail C2H2-type zinc-finger (ZF) domain functions both as a nuclear localization signal which binds to importin β directly and as a DNA-binding domain. Here, a 2.5 Å resolution structure of four ZF domains of Snail1 complexed with importin β is presented. The X-ray structure reveals that the four ZFs of Snail1 are required for tight binding to importin β in the nuclear import of Snail1. The shape of the ZFs in the X-ray structure is reminiscent of a round snail, where ZF1 represents the head, ZF2–ZF4 the shell, showing a novel interaction mode, and the five C-terminal residues the tail. Although there are many kinds of C2H2-type ZFs which have the same fold as Snail, nuclear import by direct recognition of importin β is observed in a limited number of C2H2-type ZF proteins such as Snail, Wt1, KLF1 and KLF8, which have the common feature of terminating in ZF domains with a short tail of amino acids.