bluuebunny/crossref_metadata_2025 huggingface dataset:
Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters
Authors: King Andrew J. , Brown Geoffrey D. , Gilday Alison D. , Larson Tony R. , Graham Ian A.
Published: August 2014

The Euphorbiaceae produce a diverse range of diterpenoids, many of which have pharmacological activities. These diterpenoids include ingenol mebutate, which is licensed for the treatment of a precancerous skin condition (actinic keratosis), and phorbol derivatives such as resiniferatoxin and prostratin, which are undergoing investigation for the treatment of severe pain and HIV, respectively. Despite the interest in these diterpenoids, their biosynthesis is poorly understood at present, with the only characterized step being the conversion of geranylgeranyl pyrophosphate into casbene. Here, we report a physical cluster of diterpenoid biosynthetic genes from castor (Ricinus communis), including casbene synthases and cytochrome P450s from the CYP726A subfamily. CYP726A14, CYP726A17, and CYP726A18 were able to catalyze 5-oxidation of casbene, a conserved oxidation step in the biosynthesis of this family of medicinally important diterpenoids. CYP726A16 catalyzed 7,8-epoxidation of 5-keto-casbene and CYP726A15 catalyzed 5-oxidation of neocembrene. Evidence of similar gene clustering was also found in two other Euphorbiaceae, including Euphorbia peplus, the source organism of ingenol mebutate. These results demonstrate conservation of gene clusters at the higher taxonomic level of the plant family and that this phenomenon could prove useful in further elucidating diterpenoid biosynthetic pathways.
microARPES and nanoARPES at diffraction-limited light sources: opportunities and performance gains
Authors: Rotenberg Eli , Bostwick Aaron
Published: August 2014

The scientific opportunities for microARPES and nanoARPES techniques are discussed, and the benefits to these techniques at diffraction-limited light sources are presented, in particular the impact on spectromicroscopic ARPES (angle-resolved photoemission spectroscopy) of upgrading the Advanced Light Source to diffraction-limited performance. The most important consideration is whether the space-charge broadening, impacting the energy and momentum resolution, will limit the possible benefits for ARPES. Calculations of energy broadening due to space-charge effects will be presented over a wide range of parameters, and optimum conditions for ARPES will be discussed. The conclusion is that spectromicroscopic ARPES will greatly benefit from the advent of diffraction-limited light sources; space-charge broadening effects will not be a limiting factor.
Prospects of high-resolution resonant X-ray inelastic scattering studies on solid materials, liquids and gases at diffraction-limited storage rings
Authors: Schmitt Thorsten , de Groot Frank M. F. , Rubensson Jan-Erik
Published: August 2014

The spectroscopic technique of resonant inelastic X-ray scattering (RIXS) will particularly profit from immensely improved brilliance of diffraction-limited storage rings (DLSRs). In RIXS one measures the intensities of excitations as a function of energy and momentum transfer. DLSRs will allow for pushing the achievable energy resolution, signal intensity and the sampled spot size to new limits. With RIXS one nowadays probes a broad range of electronic systems reaching from simple molecules to complex materials displaying phenomena like peculiar magnetism, two-dimensional electron gases, superconductivity, photovoltaic energy conversion and heterogeneous catalysis. In this article the types of improved RIXS studies that will become possible with X-ray beams from DLSRs are envisioned.
Pixel detectors for diffraction-limited storage rings
Authors: Denes Peter , Schmitt Bernd
Published: August 2014

Dramatic advances in synchrotron radiation sources produce ever-brighter beams of X-rays, but those advances can only be used if there is a corresponding improvement in X-ray detectors. With the advent of storage ring sources capable of being diffraction-limited (down to a certain wavelength), advances in detector speed, dynamic range and functionality is required. While many of these improvements in detector capabilities are being pursued now, the orders-of-magnitude increases in brightness of diffraction-limited storage ring sources will require challenging non-incremental advances in detectors. This article summarizes the current state of the art, developments underway worldwide, and challenges that diffraction-limited storage ring sources present for detectors.
Diffraction-limited storage rings – a window to the science of tomorrow
Authors: Eriksson Mikael , van der Veen J. Friso , Quitmann Christoph
Published: August 2014

This article summarizes the contributions in this special issue on Diffraction-Limited Storage Rings. It analyses the progress in accelerator technology enabling a significant increase in brightness and coherent fraction of the X-ray light provided by storage rings. With MAX IV and Sirius there are two facilities under construction that already exploit these advantages. Several other projects are in the design stage and these will probably enhance the performance further. To translate the progress in light source quality into new science requires similar progress in aspects such as optics, beamline technology, detectors and data analysis. The quality of new science will be limited by the weakest component in this value chain. Breakthroughs can be expected in high-resolution imaging, microscopy and spectroscopy. These techniques are relevant for many fields of science; for example, for the fundamental understanding of the properties of correlated electron materials, the development and characterization of materials for data and energy storage, environmental applications and bio-medicine.
Overview of the methods available for biomechanical testing of the uterine cervix in vivo
Authors: Hee Lene
Published: August 2014

Objective

To give an overview of the methods available for biomechanical testing of the non‐pregnant and pregnant uterine cervix in vivo.

Methods

The following databases were searched. PubMed, Embase, and Cochrane Library. Additional studies were identified from reference lists. Only studies on in vivo biomechanical testing on both pregnant and non‐pregnant women were included.

Main outcome measures

Estimation of distensibility, compressibility, and biochemical composition of the uterine cervix.

Results

The distensibility methods evaluated a physiologic variable and might serve as a gold standard; however, they may never be clinically useful as they involve instrumentation of the cervical canal. The compression methods evaluated an unphysiological variable but despite that, they seemed to evaluate biologically relevant figures and were non‐invasive. Of the methods evaluating the biomechanical properties indirectly, those based on ultrasound may be clinically useful. Other indirect methods only measured variables within the most superficial layer of the distal uterine cervix, so further studies are needed to evaluate whether these measurements reflect the entire organ. Both compression methods and indirect methods were similar or superior to the Bishop score and to cervical length measurements regarding prediction of spontaneous preterm delivery and successful induction of labor in small studies.

Conclusion

The methods may have the potential to detect the biomechanical changes in the uterine cervix before the cervical length has shortened. The most promising methods need large‐scale clinical testing regarding induction of labor and preterm delivery before they can be used in the clinic.
Amplification of 3q26 and 5p15 regions in cervical intraepithelial neoplasia
Authors: Kudela Erik , Farkasova Anna , Visnovsky Jozef , Balharek Tomas , Sumichrastova Petra , Sivakova Jana , Plank Lukas , Danko Jan
Published: August 2014

Objective

To analyze different amplification patterns of 3q26 and 5p15 regions in low‐grade and high‐grade cervical intraepithelial neoplasia.

Design

Experimental research.

Setting

Department of Obstetrics and Gynecology at a medical faculty in Slovakia.

Population

A group of 83 patients referred for colposcopic examination.

Methods

Amplification of 3q26 and 5p15 regions was analyzed on the 100 most atypical cells from a cervical cytology slide by fluorescent in situ hybridization using a multicolor hybridization probe. Chi‐squared and Man–Whitney U‐tests were used for statistical analysis.

Main outcome measures

Liquid‐based cytology samples and biopsy samples obtained during colposcopic examination correlated with high‐risk human papillomavirus status and with amplification patterns of selected regions analyzed by fluorescent in situ hybridization.

Results

The number of cells with 3q26 and 5p15 gain rises with the severity of the lesion p < 0.01. The sensitivity of 3q26 amplification for CIN2+ lesions was 72.1% (95% confidence interval 56.3–84.7) and specificity was 90.0% (95% confidence interval 76.3–97.1). The sensitivity of 5p15 amplification for CIN2+ lesions was 69.8% (95% confidence interval 53.9–82.8) and specificity was 85.0% (95% confidence interval 70.2–94.3).

Conclusion

Evaluation of telomerase components can help in differential diagnosis of low‐grade and high‐grade cervical lesions and in individualized management of these patients.
Laparoscopic management of bowel endometriosis: resection margins as a predictor of recurrence
Authors: Nirgianakis Konstantinos , McKinnon Brett , Imboden Sara , Knabben Laura , Gloor Beat , Mueller Michael D.
Published: August 2014

Objective

To evaluate possible predictive factors for recurrence after laparoscopic segmental bowel resection for bowel endometriosis.

Design

Cohort study.

Setting

Academic tertiary referral center.

Methods

95 symptomatic women with bowel endometriosis who underwent laparoscopic segmental bowel resection at the Endometriosis clinic, University of Berne, between 2002 and 2012 were enrolled. Since 14 women were lost to follow‐up, 81 formed the final cohort. Clinical and histological characteristics were examined as possible predictive factors for disease recurrence.

Main outcome measures

Recurrence, defined as a subsequent operation due to recurrent endometriosis‐associated pain with a histologically confirmed endometriotic lesion.

Results

Recurrence was observed in 13 (16%) patients. Variables that were significantly associated to recurrence by the Cox regression analysis were positive bowel resection margins (hazard ratio 6.5, 95% confidence interval 1.8–23.5, p = 0.005), age <31 years (hazard ratio 5.6, 95% confidence interval 1.7–18.6, p = 0.005) and body mass index ≥23 kg/m2 (hazard ratio 11.0, 95% confidence interval 2.7–44.6, p = 0.001).

Conclusions

Positive bowel resection margins as well as age <31 years and body mass index ≥23 kg/m2 appear to be independent predictors of disease recurrence.
The contribution of general cognitive abilities and approximate number system to early mathematics
Authors: Passolunghi Maria Chiara , Cargnelutti Elisa , Pastore Massimiliano
Published: August 2014

Background

Math learning is a complex process that entails a wide range of cognitive abilities to be fulfilled. There is sufficient evidence that both general and specific cognitive skills assume a fundamental role, despite the absence of shared consensus about the relative extent of their involvement. Moreover, regarding general abilities, there is no agreement about the recruitment of the different memory components or of intelligence. In relation to specific factors, great debate subsists regarding the role of the approximate number system (ANS).

Aims

Starting from these considerations, we wanted to conduct a wide assessment of memory components and ANS, by controlling for the effects associated with intelligence and also exploring possible relationships between all precursors.

Sample and Method

To achieve this purpose, a sample of 157 children was tested at both beginning and end of their Grade 1. Both general (memory and intelligence) and specific (ANS) precursors were evaluated by a wide battery of tests and put in relation to concurrent and subsequent math skills. Memory was explored in passive and active aspects involving both verbal and visuo‐spatial components.

Results

Path analysis results demonstrated that memory, and especially the more active processes, and intelligence were the strongest precursors in both assessment times. ANS had a milder role which lost significance by the end of the school year. Memory and ANS seemed to influence early mathematics almost independently.

Conclusion

Both general and specific precursors seemed to have a crucial role in early math competences, despite the lower involvement of ANS.
Cell death, cavitation and spontaneous multi‐differentiation of dental pulp stem cells‐derived spheroids in vitro: A journey to survival and organogenesis
Authors: Xiao Li , Kumazawa Yasuo , Okamura Hisashi
Published: August 2014

Background information

During embryonic development, cell death transforms the solid embryonic cell mass into a hollow structure (cavitation), which allows the surviving cells to differentiate into varied tissues and organs around the cavity. This process can be partly reproduced with embryonic stem cells. However, it is unknown if adult stem cell masses have the same ability to cavitate and then differentiate into organs. In this study, we assessed the capacity of human dental pulp stem cells (DPSCs)‐derived spheroids to mimic the above‐mentioned cavitation and spontaneous differentiation in vitro.

Results

DPSCs were able to form large‐sized spheroids on matrigel in osteogenic medium. Inside the spheroids, cells in the centre showed positive stain to stem cell markers, alkaline phosphatase and STRO‐1. Hypoxia and massive cell death were observed in the core of the spheroids. Cavities were formed when the spheroids were cultivated in the osteogenic medium for about 14 days. After 28 days of cultivation, the surviving cells around the cavity spontaneously differentiated into neuronal (28.8%), vascular (33.3%), osteogenic (46.7%) and cartilaginous (72.0%) tissues under the osteogenic medium only. In contrast, when DPSCs‐formed cell sheets were folded into giant‐sized lumps and cultivated under the same conditions, the folded cell sheets became an entire lumenal structure and failed to differentiate into neuronal, osteogenic and cartilaginous cells. Marker analysis showed that cavitation‐related molecules BMP7 and FGF3 expressed on the wall of the cavity in the spheroids, suggesting that the cavitation was functional, whereas cavitation‐related molecules were absent in the folded cell sheets.

Conclusions

DPSC‐derived spheroids can mimic the developmental process of cell survival, cavitation and spontaneous multi‐differentiation on matrigel under certain conditions. This work allows for functional studies to investigate organ regeneration with human DPSCs in vitro.
Ecosystem engineering effects on species diversity across ecosystems: a meta‐analysis
Authors: Romero Gustavo Q. , Gonçalves‐Souza Thiago , Vieira Camila , Koricheva Julia
Published: August 2014

Ecosystem engineering is increasingly recognized as a relevant ecological driver of diversity and community composition. Although engineering impacts on the biota can vary from negative to positive, and from trivial to enormous, patterns and causes of variation in the magnitude of engineering effects across ecosystems and engineer types remain largely unknown. To elucidate the above patterns, we conducted a meta‐analysis of 122 studies which explored effects of animal ecosystem engineers on species richness of other organisms in the community. The analysis revealed that the overall effect of ecosystem engineers on diversity is positive and corresponds to a 25% increase in species richness, indicating that ecosystem engineering is a facilitative process globally. Engineering effects were stronger in the tropics than at higher latitudes, likely because new or modified habitats provided by engineers in the tropics may help minimize competition and predation pressures on resident species. Within aquatic environments, engineering impacts were stronger in marine ecosystems (rocky shores) than in streams. In terrestrial ecosystems, engineers displayed stronger positive effects in arid environments (e.g. deserts). Ecosystem engineers that create new habitats or microhabitats had stronger effects than those that modify habitats or cause bioturbation. Invertebrate engineers and those with lower engineering persistence (<1 year) affected species richness more than vertebrate engineers which persisted for >1 year. Invertebrate species richness was particularly responsive to engineering impacts. This study is the first attempt to build an integrative framework of engineering effects on species diversity; it highlights the importance of considering latitude, habitat, engineering functional group, taxon and persistence of their effects in future theoretical and empirical studies.
Historical ecology: past, present and future
Authors: Szabó Péter
Published: August 2014

The term ‘historical ecology’ has been used with various meanings since the first half of the 20th century. Studies labelled as historical ecology have been produced in at least four academic disciplines: history, ecology, geography and anthropology. Although all those involved seem to agree that historical ecology concerns the historical interconnectedness of nature and human culture, this field of study has no unified methodology, specialized institutional background and common publication forums. Knowledge of the development of historical ecology is also limited. As a result, the current multitude of definitions of historical ecology is accompanied by divergent opinions as to where the origins of the field are to be sought. In this review, I follow the development of historical ecology from the 18th century to the present. In the first part, I briefly describe some early examples of historical ecological investigations, followed by a description of the various scientific strands in the 20th century that contributed to the formation of historical ecology. In the second part, I discuss the past five decades of historical ecological investigations in more detail, focusing mostly (but not exclusively) on works that their respective authors identified as historical ecology. I also examine the appearance and interconnectedness of the two main trends (ecological and anthropological) in historical ecological research. In the last part, I attempt to outline the future of historical ecology based on common features in existing research. It appears that at present historical ecology is at a crossroads. With rapidly growing interest in historical ecological research, it may move towards institutionalization or remain an umbrella term.
Contextualizing Gay‐Straight Alliances: Student, Advisor, and Structural Factors Related to Positive Youth Development Among Members
Authors: Poteat V. Paul , Yoshikawa Hirokazu , Calzo Jerel P. , Gray Mary L. , DiGiovanni Craig D. , Lipkin Arthur , Mundy‐Shephard Adrienne , Perrotti Jeff , Scheer Jillian R. , Shaw Matthew P.
Published: August 2014

Gay‐straight alliances (GSAs) may promote resilience. Yet, what GSA components predict well‐being? Among 146 youth and advisors in 13 GSAs (58% lesbian, gay, bisexual, or questioning; 64% White; 38% received free/reduced‐cost lunch), student (demographics, victimization, attendance frequency, leadership, support, control), advisor (years served, training, control), and contextual factors (overall support or advocacy, outside support for the GSA) that predicted purpose, mastery, and self‐esteem were tested. In multilevel models, GSA support predicted all outcomes. Racial/ethnic minority youth reported greater well‐being, yet lower support. Youth in GSAs whose advisors served longer and perceived more control and were in more supportive school contexts reported healthier outcomes. GSA advocacy also predicted purpose. Ethnographic notes elucidated complex associations and variability as to how GSAs operated.
Verbal Positional Memory in 7‐Month‐Olds
Authors: Benavides‐Varela Silvia , Mehler Jacques
Published: August 2014

Verbal memory is a fundamental prerequisite for language learning. This study investigated 7‐month‐olds' (N = 62) ability to remember the identity and order of elements in a multisyllabic word. The results indicate that infants detect changes in the order of edge syllables, or the identity of the middle syllables, but fail to encode the order of middle syllables. This suggests that the representational format of multisyllabic words is determined by core mnemonic biases, which favor accurate encoding of edges and limits the encoding of temporal order for internal segments. The studies support accounts proposing that content and order are encoded separately; in addition, the data show that this dissociation occurs early in development.
Language and Cognitive Predictors of Text Comprehension: Evidence From Multivariate Analysis
Authors: Kim Young‐Suk
Published: August 2014

Using data from children in South Korea (N = 145, Mage = 6.08), it was determined how low‐level language and cognitive skills (vocabulary, syntactic knowledge, and working memory) and high‐level cognitive skills (comprehension monitoring and theory of mind [ToM]) are related to listening comprehension and whether listening comprehension and word reading mediate the relations of language and cognitive skills to reading comprehension. Low‐level skills predicted comprehension monitoring and ToM, which in turn predicted listening comprehension. Vocabulary and syntactic knowledge were also directly related to listening comprehension, whereas working memory was indirectly related via comprehension monitoring and ToM. Listening comprehension and word reading completely mediated the relations of language and cognitive skills to reading comprehension.
Household Income and Preschool Attendance in China
Authors: Gong Xin , Xu Di , Han Wen‐Jui
Published: August 2014

This article draws upon the literature showing the benefits of high‐quality preschools on child well‐being to explore the role of household income on preschool attendance for a cohort of 3‐ to 6‐year‐olds in China using data from the China Health and Nutrition Survey, 1991–2006. Analyses are conducted separately for rural (N = 1,791) and urban (N = 633) settings. Estimates from a probit model with rich controls suggest a positive association between household income per capita and preschool attendance in both settings. A household fixed‐effects model, conducted only on the rural sample, finds results similar to, although smaller than, those from the probit estimates. Policy recommendations are discussed.
Cerebral haemorrhagic risk in children with sickle‐cell disease
Authors: Kossorotoff Manoelle , Brousse Valentine , Grevent David , Naggara Olivier , Brunelle Francis , Blauwblomme Thomas , Gaussem Pascale , Desguerre Isabelle , De Montalembert Mariane
Published: August 2014

Aim

To address risk of first or recurrent cerebral haemorrhage in children with sickle‐cell disease (SCD) who are being managed with modern stroke prevention strategies.

Method

A systematically followed SCD paediatric cohort was retrospectively studied over a 9‐year period. Haemorrhagic risk was defined as intracranial haemorrhage occurrence or intracranial aneurysm diagnosis during the study period. Ischaemic risk was defined as cerebrovascular ischaemic event occurrence or transcranial Doppler/magnetic resonance imaging hallmarks of ischaemic risk finding during the study period.

Results

Among the 251 patients in the cohort, 36 patients were included in the ischaemic group. Seven patients were included in the haemorrhagic group, of which five also met the criteria for the ischaemic group. Age at first haemorrhagic symptom/hallmark of risk was older (10.4 vs 6.2 years old, p=0.036). Nine intracranial saccular aneurysms were found, mostly on the posterior circulation. Two patients had endovascular embolization.

Interpretation

The ratio of ischaemic to haemorrhagic risk was not modified with modern management compared with historical series. Intracranial aneurysm in children with SCD had specific characteristics, close to intracranial aneurysms described in adults with SCD. Data favoured concurrent development of intracranial SCD‐associated anterior stenosis and posterior dilation, suggesting common pathophysiology and management strategies.
Taking steps towards improving the mobility of children with cerebral palsy
Authors: Kurz Max J , Reelfs Heidi
Published: August 2014

This commentary is on the original article by Schroeder et al. on pages 1172–1179 of this issue.
First report on the association of Pestalotiopsis mangiferae with leaf blight disease of Canthium dicoccum in India
Authors: Mahadevakumar S. , Janardhana G. R.
Published: August 2014

The multi‐use tree Canthium dicoccum (Rubiaceae) growing in shrub forests of Mysore, Mandya and Chamarajanagar (India) was severely affected by a leaf blight disease. The ascomycete Pestalotiopsis mangiferae was consistently isolated from symptomatic leaves and identified by micromorphology and ITS rDNA sequencing analysis. Pathogenicity test was performed and Koch's postulates were fulfilled. This is the first report of P. mangiferae causing leaf blight of C. dicoccum in India.
Ecosystem models for fisheries management: finding the sweet spot
Authors: Collie Jeremy S , Botsford Louis W , Hastings Alan , Kaplan Isaac C , Largier John L , Livingston Patricia A , Plagányi Éva , Rose Kenneth A , Wells Brian K , Werner Francisco E
Published: August 2014

The advent of an ecosystem‐based approach dramatically expanded the scope of fisheries management, creating a critical need for new kinds of data and quantitative approaches that could be integrated into the management system. Ecosystem models are needed to codify the relationships among drivers, pressures and resulting states, and to quantify the trade‐offs between conflicting objectives. Incorporating ecosystem considerations requires moving from the single‐species models used in stock assessments, to more complex models that include species interactions, environmental drivers and human consequences. With this increasing model complexity, model fit can improve, but parameter uncertainty increases. At intermediate levels of complexity, there is a ‘sweet spot’ at which the uncertainty in policy indicators is at a minimum. Finding the sweet spot in models requires compromises: for example, to include additional component species, the models of each species have in some cases been simplified from age‐structured to logistic or bioenergetic models. In this paper, we illuminate the characteristics, capabilities and short‐comings of the various modelling approaches being proposed for ecosystem‐based fisheries management. We identify key ecosystem needs in fisheries management and indicate which types of models can meet these needs. Ecosystem models have been playing strategic roles by providing an ecosystem context for single‐species management decisions. However, conventional stock assessments are being increasingly challenged by changing natural mortality rates and environmentally driven changes in productivity that are observed in many fish stocks. Thus, there is a need for more tactical ecosystem models that can respond dynamically to changing ecological and environmental conditions.
Minimizing the biodiversity impact of Neotropical oil palm development
Authors: Gilroy James J. , Prescott Graham W. , Cardenas Johann S. , Castañeda Pamela González del Pliego , Sánchez Andrés , Rojas‐Murcia Luis E. , Medina Uribe Claudia A. , Haugaasen Torbjørn , Edwards David P.
Published: August 2014

Oil palm agriculture is rapidly expanding in the Neotropics, at the expense of a range of natural and seminatural habitats. A key question is how this expansion should be managed to reduce negative impacts on biodiversity. Focusing on the Llanos of Colombia, a mixed grassland–forest system identified as a priority zone for future oil palm development, we survey communities of ants, dung beetles, birds and herpetofauna occurring in oil palm plantations and the other principal form of agriculture in the region – improved cattle pasture – together with those of surrounding natural forests. We show that oil palm plantations have similar or higher species richness across all four taxonomic groups than improved pasture. For dung beetles, species richness in oil palm was equal to that of forest, whereas the other three taxa had highest species richness in forests. Hierarchical modelling of species occupancy probabilities indicated that oil palm plantations supported a higher proportion of species characteristic of forests than did cattle pastures. Across the bird community, occupancy probabilities within oil palm were positively influenced by increasing forest cover in a surrounding 250 m radius, whereas surrounding forest cover did not strongly influence the occurrence of other taxonomic groups in oil palm. Overall, our results suggest that the conversion of existing improved pastures to oil palm has limited negative impacts on biodiversity. As such, existing cattle pastures of the Colombian Llanos could offer a key opportunity to meet governmental targets for oil palm development without incurring significant biodiversity costs. Our results also highlight the value of preserving remnant forests within these agricultural landscapes, protecting high biodiversity and exporting avian ‘spill‐over’ effects into oil palm plantations.
The actin‐bundling protein L‐plastin supports T‐cell motility and activation
Authors: Morley Sharon Celeste
Published: August 2014

Tight regulation of actin dynamics is essential for T‐cell trafficking and activation. Recent studies in human and murine T cells reveal that T‐cell motility and full T‐cell activation require the hematopoietic‐specific, actin‐bundling protein L‐plastin (LPL). T cells lackingLPLdo not form fully mature synapses and thus demonstrate reduced cytokine production and proliferation. Reduction or loss ofLPLexpression also reduces the velocity of T cells and impairs thymic egress and intranodal motility. Whereas dispensable for proximal T‐cell receptor and chemokine receptor signaling,LPLis critical to the later stages of synapse maturation and cellular polarization. Serine phosphorylation, calcium, and calmodulin binding regulate the bundling activity and localization ofLPLfollowing T‐cell receptor and chemokine receptor engagement. However, the interaction between these regulatory domains and resulting changes in local control of actin cytoskeletal structures has not been fully elucidated. Circumstantial evidence suggests a function forLPLin either the formation or maintenance of integrin‐associated adhesion structures. AsLPLmay be a target of the commonly used immunosuppressive agent dexamethasone, full elucidation of the regulation and function ofLPLin T‐cell biology may illuminate new pathways for clinically useful immunotherapeutics.
The actin‐driven spatiotemporal organization of T‐cell signaling at the system scale
Authors: Roybal Kole T. , Sinai Parisa , Verkade Paul , Murphy Robert F. , Wülfing Christoph
Published: August 2014

T cells are activated through interaction with antigen‐presenting cells (APCs). During activation, receptors and signaling intermediates accumulate in diverse spatiotemporal distributions. These distributions control the probability of signaling interactions and thus govern information flow through the signaling system. Spatiotemporally resolved system‐scale investigation of signaling can extract the regulatory information thus encoded, allowing unique insight into the control of T‐cell function. Substantial technical challenges exist, and these are briefly discussed herein. While much of the work assessing T‐cell spatiotemporal organization uses planar APC substitutes, we focus here on B‐cell APCs with often stark differences. Spatiotemporal signaling distributions are driven by cell biologically distinct structures, a large protein assembly at the interface center, a large invagination, the actin‐supported interface periphery as extended by smaller individual lamella, and a newly discovered whole‐interface actin‐driven lamellum. The more than 60 elements of T‐cell activation studied to date are dynamically distributed between these structures, generating a complex organization of the signaling system. Signal initiation and core signaling prefer the interface center, while signal amplification is localized in the transient lamellum. Actin dynamics control signaling distributions through regulation of the underlying structures and drive a highly undulating T‐cell/APC interface that imposes substantial constraints on T‐cell organization. We suggest that the regulation of actin dynamics, by controlling signaling distributions and membrane topology, is an important rheostat of T‐cell signaling.
Re‐defining ERM function in lymphocyte activation and migration
Authors: Parameswaran Neetha , Gupta Neetu
Published: August 2014

Lymphocyte activation and migration involve large‐scale actin cytoskeletal remodeling. The Ezrin–Radixin–Moesin (ERM) family proteins reversibly link the plasma membrane and cortical actin meshwork and mediate the dynamic nature of the membrane‐cytoskeletal interface to facilitate remodeling. The reversibility of this linkage is controlled by the conformation of ERM proteins and depends on the phosphorylation of a conserved threonine residue in the actin‐binding domain. Disruption of the phospho‐cycling nature of ERM proteins through dominant negative and constitutively active mutants results in impaired lymphocyte migration and activation. In recent years, a novel role has emerged for ERM proteins as signaling scaffolds that can modulate B and T‐cell activation through additional posttranslational modifications at tyrosine residues. Here, we highlight recent studies that have redefined the role of ERM proteins in lymphocyte activation and migration. We discuss how lymphocyte‐specific knockouts of ERM proteins and high resolution imaging techniques have identified a novel function for them as rheostats that modulate the strength of antigen receptor signaling in B cells. Finally, we describe scenarios in which ERM protein function is coopted by pathogens for their own transmission and speculate on the potential of ERM proteins for regulating undesirable lymphocyte behaviors such as autoimmunity and malignancy.
Class I myosins in B‐cell physiology: functions in spreading, immune synapses, motility, and vesicular traffic
Authors: Santos‐Argumedo Leopoldo , Maravillas‐Montero José Luis , López‐Ortega Orestes
Published: August 2014

Myosins comprise a family of motor proteins whose role in muscle contraction and motility in a large range of eukaryotic cells has been widely studied. Although these proteins have been characterized extensively and much is known about their function in different cellular compartments, little is known about these molecules in hematopoietic cells. Myosins expressed by cells from the immune response are involved in maintaining plasma membrane tension, moving and secreting vesicles, endo‐ and exocytotic processes, and promoting the adhesion and motility of cells. Herein, we summarize our current understanding of class I myosins in B cells, with an emphasis on the emerging roles of these molecular motors in immune functions.
Novel anti‐HIV therapeutics targeting chemokine receptors and actin regulatory pathways
Authors: Spear Mark , Guo Jia , Wu Yuntao
Published: August 2014

The human immunodeficiency virus‐1 (HIV‐1) infects helper CD4+ T cells, and causes CD4+ T‐cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV‐dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4+ T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post‐entry migration has led to the nascent model of virus‐host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway‐based anti‐HIV drugs that are currently in development or testing.
The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse
Authors: Lagrue Kathryn , Carisey Alex , Oszmiana Anna , Kennedy Philippa R. , Williamson David J. , Cartwright Adam , Barthen Charlotte , Davis Daniel M.
Published: August 2014

Natural killer (NK) cells discriminate between healthy and unhealthy target cells through a balance of activating and inhibitory signals at direct intercellular contacts called immune synapses. Rearrangements in the cellular cytoskeleton have long been known to be critical in assembly of immune synapses. Here, through bringing together the vast literature on this subject, the number of different ways in which the cytoskeleton is important becomes evident. The dynamics of filamentous actin are critical in (i) creating the nanometer‐scale organization of NK cell receptors, (ii) establishing cellular polarity, (iii) coordinating immune receptor and integrin‐mediated signaling, and (iv) directing secretion of lytic granules and cytokines. The microtubule network also is important in the delivery of lytic granules and vesicles containing cytokines to the immune synapse. Together, these data establish that the cytoskeleton acts as a central regulator of this complex and dynamic process – and an enormous amount of NK cell biology is controlled through the cytoskeleton.
Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses
Authors: Soares Helena , Lasserre Rémi , Alcover Andrés
Published: August 2014

Immunological synapses are specialized cell–cell contacts formed between T lymphocytes and antigen‐presenting cells. They are induced upon antigen recognition and are crucial for T‐cell activation and effector functions. The generation and function of immunological synapses depend on an active T‐cell polarization process, which results from a finely orchestrated crosstalk between the antigen receptor signal transduction machinery, the actin and microtubule cytoskeletons, and controlled vesicle traffic. Although we understand how some of these particular events are regulated, we still lack knowledge on how these multiple cellular elements are harmonized to ensure appropriate T‐cell responses. We discuss here our view on how T‐cell receptor signal transduction initially commands cytoskeletal and vesicle traffic polarization, which in turn sets the immunological synapse molecular design that regulates T‐cell activation. We also discuss how the human immunodeficiency virus (HIV‐1) hijacks some of these processes impairing immunological synapse generation and function.
Actin‐mediated feedback loops in B‐cell receptor signaling
Authors: Song Wenxia , Liu Chaohong , Seeley‐Fallen Margaret K. , Miller Heather , Ketchum Christina , Upadhyaya Arpita
Published: August 2014

Upon recognizing cognate antigen, B cells mobilize multiple cellular apparatuses to propagate an optimal response. Antigen binding is transduced into cytoplasmic signaling events through B‐cell antigen receptor (BCR)‐based signalosomes at the B‐cell surface. BCR signalosomes are dynamic and transient and are subsequently endocytosed for antigen processing. The function of BCR signalosomes is one of the determining factors for the fate of B cells: clonal expansion, anergy, or apoptosis. Accumulating evidence underscores the importance of the actin cytoskeleton in B‐cell activation. We have begun to appreciate the role of actin dynamics in regulating BCR‐mediated tonic signaling and the formation of BCR signalosomes. Our recent studies reveal an additional function of the actin cytoskeleton in the downregulation of BCR signaling, consequently contributing to the generation and maintenance of B‐cell self‐tolerance. In this review, we discuss how actin remodels its organization and dynamics in close coordination with BCR signaling and how actin remodeling in turn amplifies the activation and subsequent downregulation process of BCR signaling, providing vital feedback for optimal BCR activation.
Actin cytoskeletal defects in immunodeficiency
Authors: Moulding Dale A. , Record Julien , Malinova Dessislava , Thrasher Adrian J.
Published: August 2014

The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin‐related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott‐Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.
Cofilin: a redox sensitive mediator of actin dynamics during T‐cell activation and migration
Authors: Samstag Yvonne , John Isabel , Wabnitz Guido H.
Published: August 2014

Cofilin is an actin‐binding protein that depolymerizes and/or severs actin filaments. This dual function of cofilin makes it one of the major regulators of actin dynamics important for T‐cell activation and migration. The activity of cofilin is spatio‐temporally regulated. Its main control mechanisms comprise a molecular toolbox of phospho‐, phospholipid, and redox regulation. Phosphorylated cofilin is inactive and represents the dominant cofilin fraction in the cytoplasm of resting human T cells. A fraction of dephosphorylated cofilin is kept inactive at the plasma membrane by binding to phosphatidylinositol 4,5‐bisphosphate. Costimulation via the T‐cell receptor/CD3 complex (signal 1) together with accessory receptors (signal 2) or triggering through the chemokine SDF1α (stromal cell‐derived factor 1α) induce Ras‐dependent dephosphorylation of cofilin, which is important for immune synapse formation, T‐cell activation, and T‐cell migration. Recently, it became evident that cofilin is also highly sensitive for microenvironmental changes, particularly for alterations in the redox milieu. Cofilin is inactivated by oxidation, provoking T‐cell hyporesponsiveness or necrotic‐like programmed cell death. In contrast, in a reducing environment, even phosphatidylinositol 4,5‐bisphosphate ‐bound cofilin becomes active, leading to actin dynamics in the vicinity of the plasma membrane. In addition to the well‐established three signals for T‐cell activation, this microenvironmental control of cofilin delivers a modulating signal for T‐cell‐dependent immune reactions. This fourth modulating signal highly impacts both initial T‐cell activation and the effector phase of T‐cell‐mediated immune responses.
From lipid second messengers to molecular motors: microtubule‐organizing center reorientation in T cells
Authors: Huse Morgan , Le Floc'h Audrey , Liu Xin
Published: August 2014

In T lymphocytes, polarization of the microtubule‐organizing center (MTOC) to the immunological synapse enables the directional secretion of cytokines, cytolytic factors, and other soluble molecules toward the antigen‐presenting cell. This is likely to be crucial for maintaining the specificity of T‐cell effector responses. Here, we review recent advances in our understanding of MTOC reorientation in T cells, focusing first on the importance of diacylglycerol and protein kinase C isozymes and then on the molecular motor proteins that function downstream to drive MTOC movement.
The role of the cytoskeleton at the immunological synapse
Authors: Ritter Alex T. , Angus Karen L. , Griffiths Gillian M.
Published: August 2014

It has been over 30 years since the reorganization of both the microtubule network and a ‘peculiar actin polarization’ was reported at the contact area of cytotoxic T lymphocytes interacting with target cells. Since that time, hundreds of studies have been published in an effort to elucidate the structure and function of the microtubule network and the actin cytoskeleton in T‐cell activation, migration, and effector function at the interface between a T cell and its cognate antigen‐presenting cell or target cell. This interface has become known as the immunological synapse, and this review examines some of the roles played by the cytoskeleton at the synapse.
Generation of membrane structures during phagocytosis and chemotaxis of macrophages: role and regulation of the actin cytoskeleton
Authors: Rougerie Pablo , Miskolci Veronika , Cox Dianne
Published: August 2014

Macrophages are best known for their protective search and destroy functions against invading microorganisms. These processes are commonly known as chemotaxis and phagocytosis. Both of these processes require actin cytoskeletal remodeling to produce distinct F‐actin‐rich membrane structures called lamellipodia and phagocytic cups. This review will focus on the mechanisms by which macrophages regulate actin polymerization through initial receptor signaling and subsequent Arp2/3 activation by nucleation‐promoting factors like the WASP/WAVE family, followed by remodeling of actin networks to produce these very distinct structures.
RhoGTPases control specific cytoskeleton‐dependent functions of hematopoietic stem cells
Authors: Nayak Ramesh C. , Chang Kyung‐Hee , Vaitinadin Nataraja‐Sarma , Cancelas Jose A.
Published: August 2014

The Rho family of guanosine triphosphatases (GTPases) is composed of members of the Ras superfamily of proteins. They areGTP‐bound molecules with a modest intrinsicGTPase activity that can be accelerated upon activation/localization of specialized guanine nucleotide exchange factors. Members of this family act as molecular switches and are required for coordinated cytoskeletal rearrangements that are crucial in a set of specialized functions of mammalian stem cells. These functions include self‐renewal, adhesion, and migration. Mouse gene‐targeting studies have provided convincing evidence of the indispensable and dispensable roles of individual members of the RhoGTPase family and the putative upstream and downstream mediators in stem cell‐specific functions. The role of RhoGTPases and related signaling pathways previously seen in other cell types and organisms have been confirmed in mammalian hematopoietic stem cells (HSCs), and new signaling pathways and unexpected functions unique toHSCs have been identified and dissected. This review summarizes our current understanding of the role of Rho family ofGTPases onHSCand progenitor activity through cytoskeleton‐mediated signaling pathways, providing insight about relevant signaling pathways that regulate mammalian stem cell self‐renewal, adhesion, and migration.