bluuebunny/crossref_metadata_2025 huggingface dataset:
Large scale chromosome folding is stable against local changes in chromatin structure
Authors: Florescu Ana-Maria , Therizols Pierre , Rosa Angelo
Published: May 2016

Characterizing the link between small-scale chromatin structure and large-scale chromosome folding during interphase is a prerequisite for understanding transcription. Yet, this link remains poorly investigated. Here, we introduce a simple biophysical model where interphase chromosomes are described in terms of the folding of chromatin sequences composed of alternating blocks of fibers with different thicknesses and flexibilities, and we use it to study the influence of sequence disorder on chromosome behaviors in space and time. By employing extensive computer simulations,we thus demonstrate that chromosomes undergo noticeable conformational changes only on length-scales smaller than 105basepairs and time-scales shorter than a few seconds, and we suggest there might exist effective upper bounds to the detection of chromosome reorganization in eukaryotes. We prove the relevance of our framework by modeling recent experimental FISH data on murine chromosomes.

Author Summary

A key determining factor in many important cellular processes as DNA transcription, for instance, the specific composition of the chromatin fiber sequence has a major influence on chromosome folding during interphase. Yet, how this is achieved in detail remains largely elusive. In this work, we explore this link by means of a novel quantitative computational polymer model for interphase chromosomes where the associated chromatin filaments are composed of mixtures of fibers with heterogeneous physical properties. Our work suggests a scenario where chromosomes undergo only limited reorganization, namely on length-scales below 105basepairs and time-scales shorter than a few seconds. Our conclusions are supported by recent FISH data on murine chromosomes.
Motivational state, reward value, and Pavlovian cues differentially affect skilled forelimb grasping in rats
Authors: Mosberger Alice C. , de Clauser Larissa , Kasper Hansjörg , Schwab Martin E.
Published: May 2016

Motor skills represent high-precision movements performed at optimal speed and accuracy. Such motor skills are learned with practice over time. Besides practice, effects of motivation have also been shown to influence speed and accuracy of movements, suggesting that fast movements are performed to maximize gained reward over time as noted in previous studies. In rodents, skilled motor performance has been successfully modeled with the skilled grasping task, in which animals use their forepaw to grasp for sugar pellet rewards through a narrow window. Using sugar pellets, the skilled grasping task is inherently tied to motivation processes. In the present study, we performed three experiments modulating animals’ motivation during skilled grasping by changing the motivational state, presenting different reward value ratios, and displaying Pavlovian stimuli. We found in all three studies that motivation affected the speed of skilled grasping movements, with the strongest effects seen due to motivational state and reward value. Furthermore, accuracy of the movement, measured in success rate, showed a strong dependence on motivational state as well. Pavlovian cues had only minor effects on skilled grasping, but results indicate an inverse Pavlovian-instrumental transfer effect on movement speed. These findings have broad implications considering the increasing use of skilled grasping in studies of motor system structure, function, and recovery after injuries.
The calmodulin-binding transcription activator CAMTA1 is required for long-term memory formation in mice
Authors: Bas-Orth Carlos , Tan Yan-Wei , Oliveira Ana M.M. , Bengtson C. Peter , Bading Hilmar
Published: May 2016

The formation of long-term memory requires signaling from the synapse to the nucleus to mediate neuronal activity-dependent gene transcription. Synapse-to-nucleus communication is initiated by influx of calcium ions through synaptic NMDA receptors and/or L-type voltage-gated calcium channels and involves the activation of transcription factors by calcium/calmodulin signaling in the nucleus. Recent studies have drawn attention to a new family of transcriptional regulators, the so-called calmodulin-binding transcription activator (CAMTA) proteins. CAMTAs are expressed at particularly high levels in the mouse and human brain, and we reasoned that, as calmodulin-binding transcription factors, CAMTAs may regulate the formation of long-term memory by coupling synaptic activity and calcium/calmodulin signaling to memory-related transcriptional responses. This hypothesis is supported by genetic studies that reported a correlation between Camta gene polymorphisms or mutations and cognitive capability in humans. Here, we show that acute knockdown of CAMTA1, but not CAMTA2, in the hippocampus of adult mice results in impaired performance in two memory tests, contextual fear conditioning and object–place recognition test. Short-term memory and neuronal morphology were not affected by CAMTA knockdown. Gene expression profiling in the hippocampus of control and CAMTA knockdown mice revealed a number of putative CAMTA1 target genes related to synaptic transmission and neuronal excitability. Patch clamp recordings in organotypic hippocampal slice cultures provided further evidence for CAMTA1-dependent changes in electrophysiological properties. In summary, our study provides experimental evidence that confirms previous human genetic studies and establishes CAMTA1 as a regulator of long-term memory formation.
Vascular Cell Induction Culture System Using Arabidopsis Leaves (VISUAL) Reveals the Sequential Differentiation of Sieve Element-Like Cells
Authors: Kondo Yuki , Nurani Alif Meem , Saito Chieko , Ichihashi Yasunori , Saito Masato , Yamazaki Kyoko , Mitsuda Nobutaka , Ohme-Takagi Masaru , Fukuda Hiroo
Published: May 2016

Cell differentiation is a complex process involving multiple steps, from initial cell fate specification to final differentiation. Procambial/cambial cells, which act as vascular stem cells, differentiate into both xylem and phloem cells during vascular development. Recent studies have identified regulatory cascades for xylem differentiation. However, the molecular mechanism underlying phloem differentiation is largely unexplored due to technical challenges. Here, we established an ectopic induction system for phloem differentiation named Vascular Cell Induction Culture System Using Arabidopsis Leaves (VISUAL). Our results verified similarities between VISUAL-induced Arabidopsis thaliana phloem cells and in vivo sieve elements. We performed network analysis using transcriptome data with VISUAL to dissect the processes underlying phloem differentiation, eventually identifying a factor involved in the regulation of the master transcription factor gene APL. Thus, our culture system opens up new avenues not only for genetic studies of phloem differentiation, but also for future investigations of multidirectional differentiation from vascular stem cells.
Examining the effects of doing business on Iran and MENA countries’ economic growth
Authors: Mehrabani Fatemeh , Basirat Mehdi , Abdollahi Fereshte
Published: May 2016

Purpose

The purposes of this paper are: reviewing economic growth in Iran, investigating and comparing Iran doing business (DB) with those of Middle East and North Africa (MENA) countries and evaluating the relation between DB and economic growth for a selected sample during 2006-2012.

Design/methodology/approach

The paper uses the panel data model and takes a comparative approach.

Findings

The main findings of our investigation are: first, economic growth in Iran has decreased in recent years due the lack of proper business environment. Second, studying Iran DB indicators and comparing them with those of the MENA countries show that they are low and Iran’s ranking is undesirable. Third, the results show a robust support for the claim that the improvement in DB indicators will lead to an increase in economic growth.

Researchlimitations/implications

MENA countries’ experience shows that they are promoting their economic growth by improving their business environment, so the key element for increasing Iran’ economic growth is by improving the business environment.

Originality/value

This study contributes to the literature in at least two aspects. First is the comparative analysis of Iran’s DB with MENA countries, and second is considering the effect of DB on Iran’s and selected countries’ economic growth.
Does a retailer’s charisma matter? A study of frontline employee perceptions of charisma in the retail setting
Authors: Lindblom Arto , Kajalo Sami , Mitronen Lasse
Published: May 2016

Purpose

In today’s retail environment, retailers’ leadership skills can make the difference between the success and failure of their retail stores. Despite the acknowledgment that retailers’ leadership skills and behaviour are important, treatment of the topic within the retail marketing and management literatures is still very limited. Against this backdrop, this paper aims to focus on the relationship between the retailers’ charismatic leadership and frontline employee outcomes.

Design/methodology/approach

For the purpose of this study, the authors develop hypotheses about the influence of the retailers’ charismatic leadership on frontline employee job satisfaction, self-efficacy, organizational identification and turnover intentions. Using structural equation modelling, hypotheses are tested using a sample of 208 frontline employees from the Finnish retail industry.

Findings

As a first main contribution, the findings of this study indicate that charismatic leadership has a very strong positive impact on job satisfaction. As a second contribution, this study shows that there is strong positive link between charismatic leadership and the self-efficacy of frontline employees. As a third contribution, this study indicates that charismatic leadership is positively related to organizational identification. And finally, this study indicates that charismatic leadership has a very strong negative impact on employee turnover intentions.

Originality/value

This study contributes to retail management and services marketing literature by broadening the current understanding of the leadership behaviour of retailers and its effectiveness and demonstrating how frontline employees respond to charismatic leadership in the retail setting.
Foregrounding Justice in Nuclear Disarmament: A Practitioner Commentary
Authors: Acheson Ray
Published: May 2016

Injustice and inequity are fundamental to the possession of nuclear weapons. But these concepts have not been at the forefront of mainstream discourse surrounding these weapons, which has instead focused on concepts of ‘deterrence’, ‘strategic stability’, and ‘national security’. The Humanitarian Initiative (see the introductory essay in this Special Section for background) recaptures ground in terms of how nuclear weapons are discussed and perceived internationally. The reemergence of a focus on the physical effects of a nuclear weapon detonation has initiated a process of stigmatising these weapons. But this changing discourse, in order to effectively lead to the elimination of nuclear weapons, also requires the recognition that nuclear weapons represent an elite threat of terror and perpetuate inequity between countries, with broader implications for humanity. Arguments about injustice help unmask additional aspects of the unacceptability of nuclear weapons. Within this broader critique, gender analysis is crucial, helping to illuminate and challenge structures of power that sustain nuclear weapons. This is not a theoretical exercise. It has practical implications for pursuing the prohibition and elimination of nuclear weapons. A gender perspective challenges governments and people to act on moral, ethical, humanitarian, legal, political, and economic grounds without waiting for those benefiting from the status quo.
Systematic review with meta‐analysis: the effect of tobacco smoking on the natural history of ulcerative colitis
Authors: To N. , Ford A. C. , Gracie D. J.
Published: May 2016

Background

Tobacco smoking is associated with a reduced risk of developing ulcerative colitis (UC). A high proportion of UC patients perceive a benefit in disease outcomes secondary to smoking. However, the effects of smoking on the natural history of UC are uncertain.

Aim

To conduct a systematic review and meta‐analysis of the effects of tobacco smoking on the natural history of UC.

Methods

A search of MEDLINE, EMBASE and EMBASE classic was carried out (up to December 2015) to identify observational studies reporting data on smoking and rates of colectomy, flare of disease activity, proximal disease extension, and development of pouchitis following panproctocolectomy and ileal pouch‐anal anastomosis in patients with UC. Dichotomous data were pooled to obtain odds ratios (ORs), with 95% confidence intervals (CIs).

Results

The search identified 16 eligible studies: five (2615 patients) studying colectomy; four (620 patients) reporting on flare of disease activity; four (687 patients) examining proximal disease extension and three (355 patients) assessing development of pouchitis. Compared with nonsmokers, the odds of colectomy (OR = 0.89; 95% CI 0.62–1.26), flare of disease activity (OR = 1.26; 95% CI 0.65–2.44), proximal extension of disease (OR = 0.57; 95% CI 0.20–1.66) or the development of pouchitis (OR = 0.57; 95% CI 0.21–1.53) were not significantly lower in smokers.

Conclusions

Smoking may not improve the natural history of ulcerative colitis. Given the health benefits of smoking cessation and the lack of clear benefit in ulcerative colitis, smoking cessation advice should be incorporated into guidance on the management of ulcerative colitis.
New variant of acute promyelocytic leukemia with IRF2BP2–RARA fusion
Authors: Shimomura Yoshimitsu , Mitsui Hideki , Yamashita Yukiko , Kamae Tsuyoshi , Kanai Akinori , Matsui Hirotaka , Ishibashi Tomohiko , Tanimura Akira , Shibayama Hirohiko , Oritani Kenji , Kuyama Jun , Kanakura Yuzuru
Published: May 2016

We present an acute promyelocytic leukemia (APL) patient with two subtypes of IRF2BP2–RARA, in which the IRF2BP2 gene showed completely new breakpoints. Bone marrow examination revealed morphologic features indicative of APL. However, promyelocytic leukemia–RARA fusion was not detected. A paired‐end mRNA sequencing followed by RT‐PCR and direct sequencing revealed two types of fusion transcripts between exon 1B of IRF2BP2 and exon 3 of RARA. The patient received all‐trans retinoic acid and conventional chemotherapy, but showed resistance. This is the second report of IRF2BP2 involvement in APL, and we describe various breakpoints for the IRF2BP2–RARA fusion gene.
When dermoscopy is supported by Tzanck smear
Authors: Piccolo V. , Russo T. , Mascolo M. , Longo C. , Alfano R. , Ruocco E. , Argenziano G.
Published: May 2016

By employing cytology together with dermoscopy, the clinically similar lesions of molluscum contagiosum and basal cell carcinoma could be distinguished.
Cell surface glycans in the human stratum corneum: distribution and depth‐related changes
Authors: Abdayem Rawad , Formanek Florian , Minondo Anne Marie , Potter Anne , Haftek Marek
Published: May 2016

During the formation of the stratum corneum (SC) barrier, the extracellular spaces of viable epidermis, rich in glycans, are filled with a highly organized lipid matrix and the plasma membranes of keratinocytes are replaced by cornified lipid envelopes. These structures comprise cross‐linked proteins, including transmembrane glycoproteins and proteoglycans, covalently bound to a monolayer of cell surface ceramides. Little is known about the presence and distribution of glycans on the SC corneocytes despite their possible involvement in SC hydration, cohesion and desquamation. In this work, we visualized ultrastructurally and quantified the distribution of glycans on the surface of native and delipidated corneocytes. The cells were harvested at different depths of the SC, allowing us to define the relationship between the distribution of various glycans, proteoglycans and glycoproteins, and other changes occurring in SC. At the cell periphery, we found a correlation between the depth‐related alterations of corneodesmosome glycoproteins and α‐d‐mannosyl and N‐acetyl‐d‐glucosamine‐labelling patterns. Elimination of the terminal sugars, α‐linked fucose and α‐(2,3) linked sialic acid, was less abrupt, but also the initial extent of their peripheral distribution was overall lower than that of concanavalin A and wheat germ agglutinin lectin‐detected glycans. Diffuse labelling of heparan sulphate glycosaminoglycans disappeared completely from the outermost corneocytes, whereas that of several simple carbohydrates could be detected at all SC levels. Our results suggest that specific glycan distribution may participate in the progressive changes of SC, as it evolves from the SC compactum to the SC disjunctum, towards desquamation.
Empirical Zoning Distributions for Small Area Data
Authors: Burden Sandy , Steel David
Published: May 2016

It is well established that using data summaries for a set of geographic areas or zones to estimate the parameters of a statistical model, commonly called ecological inference, frequently leads to the modifiable area unit problem (MAUP). In this article, the zoning effect of the MAUP is investigated for a range of scales. A zoning distribution is defined, and then used to characterize the zoning effect for parameter estimates from ecological analyses. Zone‐independent parameter estimates are obtained using the mean of the zoning distribution, and assessed using the variance of the zoning distribution. Zoning distributions are illustrated for parameter estimates from two ecological regression models at multiple scales using Australian National Health Survey data. For both a continuous response variable and a binary response variable, the empirical zoning distributions are unimodal, relatively symmetrical with appreciable variation, even when based on a large number of zones. The “ecological mean,” or expected value of the empirical zoning distribution at each scale, displays systematic variation with scale and the zoning distribution variance also depends on scale. The results demonstrate that the zoning effect should not be ignored, and the sensitivity of ecological analysis results to the analysis zones should be assessed.
Feeding behavior in freshwater bryozoans: function, form, and flow
Authors: Tamberg Yuta , Shunatova Natalia
Published: May 2016

Bryozoans are impressively active suspension feeders, with diverse feeding behaviors. These have been studied extensively in marine bryozoans, but less so in their freshwater counterparts. Here we identified 16 distinct behaviors in three phylactolaemate species and classified them into behaviors involving separate tentacles, groups of tentacles, lophophore arms, the introvert, or multiple zooids. We examined (1) the repertoire of behaviors in each species, and each behavior's (2) absolute frequency, (3) relative frequency and (4) duration in each of the three species, at two flow velocities (0 and 0.2 cm s−1). Nine feeding behaviors were shared by all three species, but the occurrence of other behaviors in a given species was limited by its morphology. Behaviors involved in particle capture were the most frequent, and were often faster than the reactions involved in particle rejection. By contrast, the absolute frequency of behaviors varied widely among species without clear associations with species form, or function of the behavior. Flow velocity had only minor effects on the feeding behaviors exhibited by a species, or their frequencies or durations. Our results show that phylactolaemates have the same key feeding behaviors of the individual polypides (especially involving separate tentacles) as previously described in gymnolaemate and stenolaemate bryozoans, although their behaviors tend to be carried out more slowly than those of stenolaemates or gymnolaemates. Feeding behaviors involving multiple zooids were nearly absent in the studied phylactolaemates, but are common in gymnolaemates. Freshwater bryozoans appear to be intermediate between stenolaemate and gymnolaemate bryozoans in terms of richness of the repertoire of feeding behaviors.
Can Robert Adams Survive Moral Twin Earth?
Authors: Taylor Luke
Published: May 2016

Richard Boyd and Robert Adams have both developed semantic accounts of moral terms based on Hilary Putnam's causal regulation theory for natural kind terms, according to which the terms in question refer to the properties which predominantly causally regulated the terms. However, Terence Horgan and Mark Timmons have mounted an objection to Boyd's semantics—their Moral Twin Earth argument. If this argument is successful against Boyd then it might be thought that it should also be successful against Adams, given the similarity between their semantic accounts. I will argue in this essay that Adams's semantics is sufficiently different from Boyd's to enable him to survive Moral Twin Earth, but that he is vulnerable to a modified version of Moral Twin Earth that I describe.
Law, Ethics, and the Needs of History: Mendelssohn, Krochmal, and Moral Philosophy
Authors: Sacks Elias
Published: May 2016

Although the role of ethics in modern Jewish thought has been widely explored, major works by foundational philosophers remain largely absent from such discussions. This essay contributes to the recovery of these voices, focusing on the Hebrew writings of Moses Mendelssohn (1729–1786) and Nachman Krochmal (1785–1840). I argue that these texts reveal the existence of a shared ethical project animating these founding philosophical voices of Jewish modernity, and that reconstructing their claims contributes to broader conversations about the relationship between ethics and law. Mendelssohn and Krochmal present Jewish law as addressing needs emerging from the history of moral philosophy—from the modern histories of Platonic and Aristotelian ethics. Moreover, my reading highlights these thinkers’ ongoing relevance, suggesting that their work illuminates the role of law in ethical cultivation.
Sebacinales – one thousand and one interactions with land plants
Authors: Weiß Michael , Waller Frank , Zuccaro Alga , Selosse Marc‐André
Published: May 2016

Root endophytism and mycorrhizal associations are complex derived traits in fungi that shape plant physiology. Sebacinales (Agaricomycetes, Basidiomycota) display highly diverse interactions with plants. Although early‐diverging Sebacinales lineages are root endophytes and/or have saprotrophic abilities, several more derived clades harbour obligate biotrophs forming mycorrhizal associations. Sebacinales thus display transitions from saprotrophy to endophytism and to mycorrhizal nutrition within one fungal order. This review discusses the genomic traits possibly associated with these transitions. We also show how molecular ecology revealed the hyperdiversity of Sebacinales and their evolutionary diversification into two sister families: Sebacinaceae encompasses mainly ectomycorrhizal and early‐diverging saprotrophic species; the second family includes endophytes and lineages that repeatedly evolved ericoid, orchid and ectomycorrhizal abilities. We propose the name Serendipitaceae for this family and, within it, we transfer to the genus Serendipita the endophytic cultivable species Piriformospora indica and P. williamsii. Such cultivable Serendipitaceae species provide excellent models for root endophytism, especially because of available genomes, genetic tractability, and broad host plant range including important crop plants and the model plant Arabidopsis thaliana. We review insights gained with endophytic Serendipitaceae species into the molecular mechanisms of endophytism and of beneficial effects on host plants, including enhanced resistance to abiotic and pathogen stress.

Contents

Summary
20

I.
Introduction
21

II.
Phylogeny and systematics of Sebacinales
21

III.
Ecology and diversity of Sebacinales interactions with plants
23

IV.
Endophytism in Serendipitaceae: changing phenotype of the host plants
29

V.
Endophytism in Serendipitaceae: a fungal adaptation to biotrophy
33

VI.
Conclusion and future directions
35

Acknowledgements
36

Author contributions
36

References
36
Immunoglobulin M for Acute Infection: True or False?
Authors: Landry Marie Louise
Published: May 2016

Immunoglobulin M (IgM) tests have clear clinical utility but also suffer disproportionately from false-positive results, which in turn can lead to misdiagnoses, inappropriate therapy, and premature closure of a diagnostic workup. Despite numerous reports in the literature, many clinicians and laboratorians remain unaware of this issue. In this brief review, a series of virology case examples is presented. However, a false-positive IgM can occur with any pathogen. Thus, when an accurate diagnosis is essential for therapy, prognosis, infection control, or public health, when the patient is sick enough to be hospitalized, or when the clinical or epidemiologic findings do not fit, IgM detection should not be accepted as a stand-alone test. Rather, whenever possible, the diagnosis should be confirmed by other means, including testing of serial samples and the application of additional test methods.
A New Genomics-Driven Taxonomy of Bacteria and Archaea: Are We There Yet?
Authors: Garrity George M.
Published: May 2016

Taxonomy is often criticized for being too conservative and too slow and having limited relevance because it has not taken into consideration the latest methods and findings. Yet the cumulative work product of its practitioners underpins contemporary microbiology and serves as a principal means of shaping and referencing knowledge. Using methods drawn from the field of exploratory data analysis, this minireview examines the current state of the field as it transitions from a taxonomy based on 16S rRNA gene sequences to one based on whole-genome sequences and tests the validity of some commonly held beliefs.
Multicenter Evaluation of Meridian Bioscience HSV 1&2 Molecular Assay for Detection of Herpes Simplex Virus 1 and 2 from Clinical Cutaneous and Mucocutaneous Specimens
Authors: Faron Matthew L. , Ledeboer Nathan A. , Patel Anami , Beqa Safedin H. , Yen-Lieberman Belinda , Kohn Debra , Leber Amy L. , Mayne Donna , Northern William I. , Buchan Blake W.
Published: May 2016

Herpes simplex virus (HSV) causes acute and relapsing symptoms characterized by ulcerative lesions. Laboratory diagnosis of HSV in cutaneous or mucocutaneous lesions has historically been performed with the use of viral cell culture systems; however, these tests are laborious and suffer decreased sensitivity for advanced-stage lesions. The recent availability of FDA-cleared moderately complex assays has resulted in the increased use of molecular diagnostics for the routine detection of HSV in superficial swab specimens. We performed a clinical evaluation of the recently FDA-cleared
illumi
gene HSV 1&2 loop-mediated isothermal amplification (LAMP) assay (Meridian Bioscience, Cincinnati OH) for the detection and differentiation of HSV-1 and HSV-2 in cutaneous and mucocutaneous swab specimens. A total of 1,153 clinical swab specimens were collected and tested at 7 different clinical centers. Each specimen was tested for the presence of HSV-1 and HSV-2 using the
illumi
gene assay, and results were compared to those of the enzyme-linked virus-inducible system (ELVIS) as the reference method. Overall, the
illumi
gene assay demonstrated a sensitivity and specificity of 94.8% and 95.5%, respectively, for the detection of HSV-1. Detection of HSV-2 was similar, with a sensitivity of 98.9% and a specificity of 95.5%. Discrepant analysis was performed using an alternative molecular test (AmpliVue HSV1+2 assay; Quidel Molecular, San Diego, CA) on 91/99 specimens that were recorded as false positive (FP) or false negative (FN) compared to the reference method. In total, 57/78 (73%) FP and 9/13 (69%) FN
illumi
gene results were supported by the AmpliVue result. The
illumi
gene HSV 1&2 assay demonstrated high sensitivity and specificity to detect and differentiate HSV in clinical specimens and identified 57 additional specimens that were positive for HSV compared to culture. The use of LAMP eliminates the need for the cycling of temperatures and provides results in less than 60 min, with approximately 2 min of hands-on time per specimen.
Treponema pallidum Strain Types and Association with Macrolide Resistance in Sydney, Australia: New TP0548 Gene Types Identified
Authors: Read Phillip , Tagg Kaitlin A. , Jeoffreys Neisha , Guy Rebecca J. , Gilbert Gwendolyn L. , Donovan Basil
Published: May 2016

Strain typing of
Treponema pallidum
, using the three-target enhanced classification scheme, was performed with 191 samples obtained between 2004 and 2011 in Sydney, Australia. The most common strain type was 14d/g (92/191 samples [48%]). Two new TP0548 gene types were detected (m and n). Strain type was associated with macrolide resistance and possible acquisition outside Australia.
CD8
+
T Cell Breadth and
Ex Vivo
Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles
Authors: Koofhethile Catherine K. , Ndhlovu Zaza M. , Thobakgale-Tshabalala Christina , Prado Julia G. , Ismail Nasreen , Mncube Zenele , Mkhize Lungile , van der Stok Mary , Yende Nonhlanhla , Walker Bruce D. , Goulder Philip J. R. , Ndung'u Thumbi
Published: May 2016

The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (
P
= 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8
+
T cell responses against Gag and enhanced ability of CD8
+
T cells to suppress viral replication
ex vivo
. In some cases, loss of virological control was associated with reduction in the total breadth of CD8
+
T cell responses in the absence of differences in HIV-1-specific CD8
+
T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8
+
T cell responses characterized by reduced ability to suppress viral replication
ex vivo
. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8
+
T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8
+
T cell-independent mechanisms.

IMPORTANCE
Host mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8
+
T cells that targeted the Gag protein, and CD8
+
T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8
+
T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine.
A Novel Open and Infectious Form of Echovirus 1
Authors: Myllynen Mira , Kazmertsuk Artur , Marjomäki Varpu
Published: May 2016

One of the hallmarks of enterovirus genome delivery is the formation of an uncoating intermediate particle. Based on previous studies of mostly heated picornavirus particles, intermediate particles were shown to have externalized the innermost capsid protein (VP4) and exposed the N terminus of VP1 and to have reduced infectivity. Here, in addition to the native and intact particle type, we have identified another type of infectious echovirus 1 (E1) particle population during infection. Our results show that E1 is slightly altered during entry, which leads to the broadening of the major virion peak in the sucrose gradient. In contrast, CsCl gradient separation revealed that in addition to the light intact and empty particles, a dense particle peak appeared during infection in cells. When the broad peak from the sucrose gradient was subjected to a CsCl gradient, it revealed light and dense particles, further suggesting that the shoulder represents the dense particle. The dense particle was permeable to SYBR green II, it still contained most of its VP4, and it was able to bind to its receptor α
2
β
1
integrin and showed high infectivity. A thermal assay further showed that the α
2
β
1
integrin binding domain (I-domain) stabilized the virus particle. Finally, heating E1 particles to superphysiological temperatures produced more fragile particles with aberrant ultrastructural appearances, suggesting that they are distinct from the dense E1 particles. These results describe a more open and highly infectious E1 particle that is naturally produced during infection and may represent a novel form of an uncoating intermediate.

IMPORTANCE
In this paper, we have characterized a possible uncoating intermediate particle of E1 that is produced in cells during infection. Before releasing their genome into the host cytosol, enteroviruses go through structural changes in their capsid, forming an uncoating intermediate particle. It was shown previously that structural changes can be induced by receptor interactions and, in addition, by heating the native virion to superphysiological temperatures. Here, we demonstrate that an altered, still infectious E1 particle is found during infection. This particle has a more open structure, and it cannot be formed by heating. It still contains the VP4 protein and is able to bind to its receptor and cause infection. Moreover, we show that in contrast to some other enteroviruses, the receptor-virion interaction has a stabilizing effect on E1. This paper highlights the differences between enterovirus species and further increases our understanding of various uncoating forms of enteroviruses.
Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP
Authors: Rouleau Cecile , Pores Fernando Arun T. , Hwang Justin H. , Faure Nathalie , Jiang Tao , White Elizabeth A. , Roberts Thomas M. , Schaffhausen Brian S.
Published: May 2016

Murine polyomavirus has repeatedly provided insights into tumorigenesis, revealing key control mechanisms such as tyrosine phosphorylation and phosphoinositide 3-kinase (PI3K) signaling. We recently demonstrated that polyomavirus small T antigen (ST) binds YAP, a major effector of Hippo signaling, to regulate differentiation. Here we characterize YAP as a target of middle T antigen (MT) important for transformation. Through a surface including residues R103 and D182, wild-type MT binds to the YAP WW domains. Mutation of either R103 or D182 of MT abrogates YAP binding without affecting binding to other signaling molecules or the strength of PI3K or Ras signaling. Either genetic abrogation of YAP binding to MT or silencing of YAP via short hairpin RNA (shRNA) reduced MT transformation, suggesting that YAP makes a positive contribution to the transformed phenotype. MT targets YAP both by activating signaling pathways that affect it and by binding to it. MT signaling, whether from wild-type MT or the YAP-binding MT mutant, promoted YAP phosphorylation at S127 and S381/397 (YAP2/YAP1). Consistent with the known functions of these phosphorylated serines, MT signaling leads to the loss of YAP from the nucleus and degradation. Binding of YAP to MT brings it together with protein phosphatase 2A (PP2A), leading to the dephosphorylation of YAP in the MT complex. It also leads to the enrichment of YAP in membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that may depart from YAP's canonical oncogenic transcriptional activation functions.

IMPORTANCE
The highly conserved Hippo/YAP pathway is important for tissue development and homeostasis. Increasingly, changes in this pathway are being associated with cancer. Middle T antigen (MT) is the primary polyomavirus oncogene responsible for tumor formation. In this study, we show that MT signaling promotes YAP phosphorylation, loss from the nucleus, and increased turnover. Notably, MT genetics demonstrate that YAP binding to MT is important for transformation. Because MT also binds PP2A, YAP bound to MT is dephosphorylated, stabilized, and localized to membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that depart from YAP's canonical oncogenic transcriptional activation functions.
Dynein Regulators Are Important for Ecotropic Murine Leukemia Virus Infection
Authors: Valle-Tenney Roger , Opazo Tatiana , Cancino Jorge , Goff Stephen P. , Arriagada Gloria
Published: May 2016

During the early steps of infection, retroviruses must direct the movement of the viral genome into the nucleus to complete their replication cycle. This process is mediated by cellular proteins that interact first with the reverse transcription complex and later with the preintegration complex (PIC), allowing it to reach and enter the nucleus. For simple retroviruses, such as murine leukemia virus (MLV), the identities of the cellular proteins involved in trafficking of the PIC in infection are unknown. To identify cellular proteins that interact with the MLV PIC, we developed a replication-competent MLV in which the integrase protein was tagged with a FLAG epitope. Using a combination of immunoprecipitation and mass spectrometry, we established that the microtubule motor dynein regulator DCTN2/p50/dynamitin interacts with the MLV preintegration complex early in infection, suggesting a direct interaction between the incoming viral particles and the dynein complex regulators. Further experiments showed that RNA interference (RNAi)-mediated silencing of either DCTN2/p50/dynamitin or another dynein regulator, NudEL, profoundly reduced the efficiency of infection by ecotropic, but not amphotropic, MLV reporters. We propose that the cytoplasmic dynein regulators are a critical component of the host machinery needed for infection by the retroviruses entering the cell via the ecotropic envelope pathway.

IMPORTANCE
Retroviruses must access the chromatin of host cells to integrate the viral DNA, but before this crucial event, they must reach the nucleus. The movement through the cytoplasm—a crowded environment where diffusion is slow—is thought to utilize retrograde transport along the microtubule network by the dynein complex. Different viruses use different components of this multisubunit complex. We found that the preintegration complex of murine leukemia virus (MLV) interacts with the dynein complex and that regulators of this complex are essential for infection. Our study provides the first insight into the requirements for retrograde transport of the MLV preintegration complex.
Resistance training reduces systolic blood pressure in metabolic syndrome: a systematic review and meta-analysis of randomised controlled trials
Authors: Lemes Ítalo Ribeiro , Ferreira Paulo Henrique , Linares Stephanie Nogueira , Machado Aryane Flauzino , Pastre Carlos Marcelo , Netto Jayme
Published: May 2016

Aim

To evaluate the effects of resistance training on metabolic syndrome risk factors through comparison with a control group.

Design

Meta-analysis comparing resistance training interventions with control groups. Two independent reviewers selected the studies and assessed their quality and data. The pooled mean differences between resistance training and the control group were calculated using a fixed-effects model.

Data sources

The MEDLINE, PEDro, EMBASE, SPORTDiscus and The Cochrane Library databases were searched from their earliest records to 10 January 2015.

Eligibility criteria for selecting studies

Randomised controlled trials that compared the effect of resistance training on metabolic syndrome risk factors with a control group were included. All types of resistance training, irrespective of intensity, frequency or duration, were eligible.

Results

Only systolic blood pressure was significantly reduced, by 4.08 mm Hg (95% CI 1.33 to 6.82; p<0.01), following resistance training. The pooled effect showed a reduction of 0.04 mmol/L (95% CI −0.12, 0.21; p>0.05) for fasting plasma glucose, 0.00 (95% CI −0.05, 0.04; p>0.05) for high-density lipoprotein (HDL) cholesterol, 0.03 (95% CI −0.14, 0.20; p>0.05) for triglycerides, 1.39 mm Hg (95% CI −0.19, 2.98; p=0.08) for diastolic blood pressure and 1.09 cm (95% CI −0.12, 2.30; p=0.08) for waist circumference. Inconsistency (I2) for all meta-analysis was 0%.

Conclusions

Resistance training may help reduce systolic blood pressure levels, stroke mortality and mortality from heart disease in people with metabolic syndrome.

Trial registration number

CRD42015016538.
Overnutrition, Ectopic Lipid and the Metabolic Syndrome
Authors: Grundy Scott M
Published: May 2016

The metabolic syndrome is a constellation of metabolic risk factors including atherogenic dyslipidemia (elevated serum triglycerides, reduced high-density lipoprotein (HDL) cholesterol), elevated blood pressure, dysglycemia (insulin resistance and elevated serum glucose), a pro-inflammatory state, and a prothrombotic state. Most persons with metabolic syndrome are obese, and usually have abdominal obesity. Generally, obesity is a reflection of overnutrition. A current view is that when adipose tissue fails to store all excess nutrients as triglyceride, lipid begins to accumulate in various tissues (eg, muscle, liver, pancreas, and heart). This accumulation is called ectopic lipid. Various mechanisms have been proposed whereby ectopic lipid is detrimental in different tissues; these derangements induce metabolic risk factors. The foundation of the metabolic syndrome thus appears to be overnutrition, that is, more nutrient intake than can be safely disposed by lipid oxidation. Excess dietary carbohydrate also induces ectopic lipid. Of interest, less than half of obese individuals develop metabolic syndrome. Through various mechanisms they adapt to overnutrition so as to minimize lipid overload in tissues, and consequently, prevent the syndrome.
Cosmic parity violation due to a flavor-space locked gauge field
Authors: Caldwell Robert
Published: May 2016

A flavor-space locked gauge field is shown to behave like a birefringent medium, imparting a preferred left- or right-circular polarization onto gravitational waves. In a cosmological scenario, such a gauge field can cause a primordial spectrum of gravitational waves to develop a net handedness. The degree of chiral asymmetry depends on the wavelength, the abundance of the gauge field, and the strength of the gauge coupling. An asymmetry in the gravitational wave spectrum would be imprinted on the photon polarization pattern of the cosmic microwave background at last scattering. In this scenario, cosmic parity violation is written on the sky, as we predict nonzero correlation of the curl polarization with the temperature, as well as curl with gradient polarization. We compare this phenomena with parity violation in models of chiral gravity, in which the chiral asymmetry is primordial, and with models of quintessence cosmic birefringence, in which parity-violating correlations are induced along the line of sight.
Development of the CA Robot Finger with a Novel Coupled and Active Grasping Mode
Authors: Yang Sicheng , Song Jiuya , Li Guoxuan , Zhang Wenzeng , Sun Zhenguo , Du Dong , Chen Qiang
Published: May 2016

This paper proposes a novel coupled and active (CA) grasping mode for robot finger. While coupled grasping mode enables the phalanges of the finger to rotate in an anthropomorphic way, the active grasping mode enables the finger to adapt to the object’s shape automatically. Combination of these grasping modes can greatly reduce the controlling complexity and enlarge the application of coupled hands. The CA finger is developed based on the pulley-belt mechanism. It is composed of a finger base and two mobile phalanges. The control process of the finger is also introduced in this paper. Grasping capabilities is validated by experiments. Theoretical and experimental results show that the CA grasping mode is effective.
Towards real-time earthquake impact alerting in Indonesia
Authors: Pramono Sigit , Allen Trevor I. , Bugden Craig , Pandhu Rakhindro , Nindya Isabella , Ghasemi Hadi , Masturyono
Published: May 2016

The Government of Indonesia has committed to deploying a network of 500 strong-motion sensors throughout the nation. The data from these sensors have the potential to provide critical near-real-time information on the level of ground shaking and potential impact from Indonesian earthquakes near communities. We describe the implementation of real-time ‘ShakeMaps’ within Indonesia's Agency of Meteorology, Climatology and Geophysics (BMKG). These ShakeMaps are intended to underpin real-time earthquake situational awareness tools.

The use of the new strong-motion network is demonstrated for two recent earthquakes in northern Sumatra: the 2 July 2013 M
w
6.1 Bener Meriah, Sumatra and the 10 October 2013 M
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5.4 Aceh Besar earthquakes. The former earthquake resulted in 35 fatalities, with a further 2400 reported injuries. The recently integrated ShakeMap system automatically generated shaking estimates calibrated by BMKG's strong-motion network within 7 min of the Bener Meriah earthquake's origin, which assisted the emergency response efforts. Recorded ground motions are generally consistent with theoretical models. However, more analysis is required to fully characterize the attenuation of strong ground motion in Indonesia.
High serum creatinine nonlinearity: a renal vital sign?
Authors: Palant Carlos E. , Chawla Lakhmir S. , Faselis Charles , Li Ping , Pallone Thomas L. , Kimmel Paul L. , Amdur Richard L.
Published: May 2016

Patients with chronic kidney disease (CKD) may have nonlinear serum creatinine concentration (SC) trajectories, especially as CKD progresses. Variability in SC is associated with renal failure and death. However, present methods for measuring SC variability are unsatisfactory because they blend information about SC slope and variance. We propose an improved method for defining and calculating a patient's SC slope and variance so that they are mathematically distinct, and we test these methods in a large sample of US veterans, examining the correlation of SC slope and SC nonlinearity (SCNL) and the association of SCNL with time to stage 4 CKD (CKD4) and death. We found a strong correlation between SCNL and rate of CKD progression, time to CKD4, and time to death, even in patients with normal renal function. We therefore argue that SCNL may be a measure of renal autoregulatory dysfunction that provides an early warning sign for CKD progression.