bluuebunny/crossref_metadata_2025 huggingface dataset:
On evaluating boolean expressions
Authors: Gudes E. , Reiter A.
Published: October 2011

An evaluation algorithm for Boolean expressions is efficient if it recognizes when particular conditions cannot affect the value of the result. Of special interest are efficient algorithms which do not expect the conditions to be evaluated in the order in which they appear in the expression. This is important for selective retrieval from a large data base, when the evaluation (retrieval) order depends on the data organization and not on the order in which the qualifiers appear in the query. Another aspect of data retrieval is that we may repeatedly change part (but not all) of the values of the variables, and wish to re‐evaluate part of the expression. Algorithms are given for representing and efficiently evaluating Boolean expressions both for the sequential and random cases; for the latter, an algorithm for partial re‐initialization is also given.
Buffering for sustained, high speed transfers
Authors: Mercer C. A.
Published: October 2011

It is shown that a circular buffering system is more effective than conventional double or treble buffering for handling sustained, high speed data transfers from say analog‐to‐digital converters to disk storage devices.
A high level plotting system
Authors: Hedrick G. E. , Forrest J. R.
Published: October 2011

This paper describes the use of a high level plotting system that has been in use at Oklahoma State University for about one year. The use of this plotting package can save much time and money for installations which use the Calcomp plotter. The program is written in ANSI FORTRAN and permits a user to produce complete graphs on a Calcomp plotter. The plotting system itself uses the assembly routines provided by the plotter manufacturer, thus freeing the user from most of the detail involved in producing two‐dimensional plots. The plotting system plots and labels axes, produces interpolated and/or smoothed curves and performs other common plotting functions.
Computer recreations
Authors: Tanenbaum Andrew S.
Published: October 2011

Jotto is a popular word game for two players. It is of interest here because it unquestionably requires some intellectual ability for people to play it well, and it is a game in which a simple program can beat most human players nearly all the time.
Male infertility: causes and investigations
Authors: Raheem Amr Abdel , Ralph David
Published: October 2011

In the first of a two‐part series, the authors discuss the causes of male infertility and outline the investigations required. Part 2 will cover medical and surgical treatments for male infertility. Copyright © 2011 Wiley Interface Ltd
The state of men's health in Europe: how do we compare in the UK?
Authors: White Alan
Published: October 2011

In this article, Alan White provides an overview of some of the main findings from the State of men's health in Europe report and relates them to the health of men in the UK. Copyright © 2011 Wiley Interface Ltd
Schistosomiasis
Authors: Brightman Christopher
Published: October 2011

With increasing numbers of people travelling to exotic places, exposure to diseases that are rare in the developed world is rising. Christopher Brightman looks at schistosomiasis, a parasitic infection caught by swimming in contaminated fresh water. Copyright © 2011 Wiley Interface Ltd
The Bladder and Bowel Foundation
Authors: Turton Gill
Published: October 2011

The Bladder and Bowel Foundation is the UK's largest, non‐profit‐making, advocacy charity
providing information and support for people living with bladder and bowel control problems. Copyright © 2011 Wiley Interface Ltd
Regulatory gene network circuits underlying T cell development from multipotent progenitors
Authors: Kueh Hao Yuan , Rothenberg Ellen V.
Published: October 2011

Regulatory gene circuits enable stem and progenitor cells to detect and process developmental signals and make irreversible fate commitment decisions. To gain insight into the gene circuits underlying T cell fate decision making in progenitor cells, we generated an updated T‐lymphocyte developmental gene regulatory network from genes and connections found in the literature. This reconstruction allowed us to identify candidate regulatory gene circuit elements underlying T cell fate decision making. Here, we examine the roles of these circuits in facilitating different aspects of the decision making process, and discuss experiments to further probe their structure and function. WIREs Syst Biol Med 2012, 4:79–102. doi: 10.1002/wsbm.162

This article is categorized under:

Developmental Biology > Lineages
Segmentectomy of the liver
Authors: Yoshida Hiroshi , Katayose Yu , Rikiyama Toshiki , Motoi Fuyuhiko , Onogawa Toru , Egawa Shinichi , Unno Michiaki
Published: October 2011

Segmentectomy is anatomical resection of segments based on the classification of Couinaud. This procedure is performed mainly for hepatocellular carcinoma. Invasion of portal vein and intrahepatic metastases often occur with hepatocellular carcinoma. Thus, it is desirable to perform anatomical resection of the cancer‐bearing areas for curative purpose. However, segmentectomy is selected when extensive resection must be avoided to preserve liver function. There are major differences between segmentectomy of the left hemiliver (Sg 2–4) and right hemiliver (Sg 5–8). In the former, the branches (third‐order branches) arising from the umbilical portion of the portal vein can be ligated prior to liver resection. In the latter, manipulation is difficult. Therefore, ultrasonically guided segmental staining is performed by puncturing the portal branch and injecting a dye. This report described techniques for segmentectomy.
Communities of Place, Not Kind: American Technologies of Neighborhood in Postcolonial Delhi
Authors: Hull Matthew S.
Published: October 2011

In 1956 the Indian Government invited the Ford Foundation to assist with a master plan for the Delhi region. Two years later, the invitation was extended to help with a separate urban community development program. Even though the master plan was a comprehensive project covering transportation, water, sewage, housing, industry, and zoning, the creation of community and communities was one of its main goals. TheDraft Master Plan for Delhi(DMPD) declared “in all planning for man's environments,” it was “extremely vital” to “evolve a well integrated new community pattern that would fit the changed living conditions of the new age and promote genuine democratic growth.” Similarly, the primary objective of the urban community development project, as laid out by the Commissioner of Delhi, was that of “giving form to an urban community, which has been drawn from backgrounds varying from one another and trying to achieve a homogeneity.”
The Nature of Sleep
Authors: Wolf-Meyer Matthew
Published: October 2011

In April of 2004, only a few months into my fieldwork, I was struck by the level and variety of doubt expressed by the physicians at the Midwest Sleep Disorder Center (MSDC). The MSDC is a group of physicians recognized in the field as experts in many areas of sleep medicine, especially parasomnias—such as sleepwalking, sleep-related eating, and REM behavior disorder. Dr. Richards, the clinic's senior researcher and a neurologist by training, began the weekly departmental rounds. Generally, these consisted of case studies presented by the assembled clinicians and fellows, but at times rounds wandered into more philosophical discussions or ribald joking. On this day, Dr. Richards asked Dr. Pym if he had seen any patients of note. Pym was trained as a pediatrician, and his patients, at both the MSDC and the neighboring Children's Hospital, were mostly adolescents and young children. Pym had been in Nicaragua for the previous three weeks as part of a volunteer program to provide medical aid to the rural poor, and so had no cases, but he took the opportunity to make some observations on sleep disorders in Central America. He remarked that most of the places he had been to had about eleven hours of night and thirteen of daylight, and with only intermittent electrical lighting in the evening, most people went to bed at nightfall and arose with the sun. As a result, he postulated, most of the sleep disorders that physicians dealt with in the United States were not found there. He went on to blame electric lighting for many of the sleep problems in the United States—including insomnia and advanced and delayed sleep phase disorders—since it negatively affected biological impulses to sleep. Pym claimed that sleep disorders were “rare” in Nicaragua. He said most children there slept with their parents, who attended to their sleep problems as they happened, and so they did not develop into more acute pathological forms. This led into a broader conversation about light and its effects on human sleep patterns, in which some of the discussion revolved around sleeplessness in intensive care units; apparently, Richards reported, many people never entered REM sleep while in the units due to lighting disruptions, which, he said, might account for “ICU psychosis,” as people hallucinated due to sleepiness. At this point, Dr. Blake, a young pediatrician, remarked in relation to the newness of sleep medicine, “We're all flying by the seats of our pants,” to which Richards said, “We don't know anything.”
Dynamics of nanometer-scale foil targets irradiated with relativistically intense laser pulses
Authors: Hörlein R. , Steinke S. , Henig A. , Rykovanov S.G. , Schnürer M. , Sokollik T. , Kiefer D. , Jung D. , Yan X.Q. , Tajima T. , Schreiber J. , Hegelich M. , Nickles P.V. , Zepf M. , Tsakiris G.D. , Sandner W. , Habs D.
Published: October 2011

In this paper we report on an experimental study of high harmonic radiation generated in nanometer-scale foil targets irradiated under normal incidence. The experiments constitute the first unambiguous observation of odd-numbered relativistic harmonics generated by the v × B component of the Lorentz force verifying a long predicted property of solid target harmonics. Simultaneously the observed harmonic spectra allow in-situ extraction of the target density in an experimental scenario which is of utmost interest for applications such as ion acceleration by the radiation pressure of an ultraintense laser.
Complications in immediate breast reconstruction after mastectomy
Authors: Jiménez-Puente Alberto , Prieto-Lara Elisa , Rueda-Domínguez Antonio , Maañón-Di Leo Claudio , Benítez-Parejo Nicolás , Rivas-Ruiz Francisco , Medina-Cano Francisco J. , Perea-Milla Emilio
Published: October 2011

Objectives:Immediate post-mastectomy breast reconstruction (IBR) is a procedure that has proven advantages, but it also entails risks. The aim of this study was to identify risk factors for reconstruction failure.

Methods:A review was made of all the IBR carried out at a general hospital from 2002 to 2009. Retrospective information was obtained about postoperative complications and the characteristics of patients and treatments applied. The minimum follow-up period was 9 months. Cox's regression analysis was performed on the variables related to the reconstruction failure requiring the removal of the prosthesis, with an explanatory model in which all the study variables were introduced and a predictive model that contained only the variables known before the intervention.

Results:A total of 115 IRB interventions carried out on 112 women with breast cancer were analyzed. The mean follow-up period was 25.5 months. In sixty cases (52.2 percent), there were no complications; in sixteen cases (13.9 percent) minor complications appeared, and in 39 (33.9 percent) the complications were moderate. In twenty-six cases (22.6 percent), a reconstruction failure occurred. Cox's regression model revealed that the reconstruction failures were related to the patient's age (Hazard Ratio 1.08), to neoadjuvant chemotherapy (HR 6.24) and to postoperative tamoxifen (HR 3.10). The predictive model included the age of the patient (HR 1.05) and the use of neoadjuvant chemotherapy (HR 5.11).

Conclusions:A significant proportion of the patients receiving IBR developed reconstruction failure. Multivariate analysis identified three variables related to this complication, two of which were known before the intervention.
Innovation in a conservative region: theKentish Sermonsgenitive system
Authors: MYERS SARA
Published: October 2011

The early Middle EnglishKentish Sermonsshows a genitive system which is far advanced towards that of Modern English, an unexpected feature for a text from the conservative region of Kent. In this article I describe this genitive system, and examine how it developed. As the text is a translation from French, the question of French influence is central. Following brief descriptions of the sociolinguistic situation in England at the time (section 2) and of the Old English and Old French genitive systems (section 3), in section 4 I describe in detail the genitive system of theKentish Sermons: genitive forms and functions, as well as the factors which affected their use. In section 5 I compareKentish Sermongenitive phrases to corresponding phrases in the French original. There is evidence that a particular genitive function was strongly influenced by French models, but the system as a whole has its origins in the transition from Old to Middle English.
In search of grammaticalization in synchronic dialect data: general extenders in northeast England
Authors: PICHLER HEIKE , LEVEY STEPHEN
Published: October 2011

In this article, we draw on a socially stratified corpus of dialect data collected in northeast England to test recent proposals that grammaticalization processes are implicated in the synchronic variability of general extenders (GEs), i.e. phrase- or clause-final constructions such asand thatandor something. Combining theoretical insights from the framework of grammaticalization with the empirical methods of variationist sociolinguistics, we operationalize key diagnostics of grammaticalization (syntagmatic length, decategorialization, semantic-pragmatic change) as independent factor groups in the quantitative analysis of GE variability. While multivariate analyses reveal rapid changes in apparent time to the social conditioning of some GE variants in our data, they do not reveal any evidence of systematic changes in the linguistic conditioning of variants in apparent time that would confirm an interpretation of ongoing grammaticalization. These results lead us to question Cheshire's (2007) recent hypothesis that GEs are grammaticalizing in contemporary varieties of British English. They additionally raise caveats with regard to the assumption that the linguistic conditioning of GE variability in contemporary data sets is the product of change.
Toll‐like receptor 9 mediates oral bacteria‐induced IL‐8 expression in gingival epithelial cells
Authors: Kim Youngsook , Jo Ah‐ram , Jang Da Hyun , Cho Yong‐Joon , Chun Jongsik , Min Byung‐Moo , Choi Youngnim
Published: October 2011

Previously, we reported that various oral bacteria regulate interleukin (IL)‐8 production differently in gingival epithelial cells. The aim of this study was to characterize the pattern recognition receptor(s) that mediate bacteria‐induced IL‐8 expression. Among ligands that mimic bacterial components, only a Toll‐like receptor (TLR) 9 ligand enhanced IL‐8 expression as determined by ELISA. Both normal and immortalized human gingival epithelial (HOK‐16B) cells expressed TLR9 intracellularly and showed enhanced IL‐8 expression in response to CpG‐oligonucleotide. The ability of eight strains of four oral bacterial species to induce IL‐8 expression in HOK‐16B cells, and their invasion capacity were examined in the absence or presence of 2% human serum. The ability of purified bacterial DNA (bDNA) to induce IL‐8 was also examined. Six out of eight strains increased IL‐8 production in the absence of serum. Usage of an endosomal acidification blocker or a TLR9 antagonist inhibited the IL‐8 induction by two potent strains. In the presence of serum, many strains lost the ability to induce IL‐8 and presented substantially reduced invasion capacity. The IL‐8‐inducing ability of bacteria in the absence or presence of serum showed a strong positive correlation with their invasion index. The IL‐8‐inducing ability of bacteria in the absence of human serum was also correlated with the immunostimulatory activity of its bDNA. The observed immunostimulatory activity of the bDNA could not be linked to its CpG motif content. In conclusion, oral bacteria induce IL‐8 in gingival epithelial cells through TLR9 and the IL‐8‐inducing ability depends on the invasive capacity and immunostimulating DNA.
Information Technology Project Risk Management: Bridging the Gap between Research and Practice
Authors: Taylor Hazel , Artman Edward , Woelfer Jill Palzkill
Published: October 2011

The gap between research and practice is strikingly evident in the area of information technology (IT) project risk management. In spite of extensive research for over 30 years into IT project risk factors resulting in normative guidance on IT project risk management, adoption of these risk management methods in practice is inconsistent. Managing risk in IT projects remains a key challenge for many organizations. We discuss barriers to the application of normative prescriptions, such as assessments of probability and impact of risk, and suggest a contingency approach, which addresses the uncertainties, complexities, and ambiguities of IT projects and enables early identification of high-risk projects. Specifically, in a case study, we examine how the project management office (PMO) at one organization has bridged the gap between research and practice, developing a contingency-based risk assessment process well founded on research knowledge of project dimensions related to project performance, while also being practical in its implementation. The PMO's risk assessment process, and the risk spider chart that is the primary tool in this assessment, has proven to be effective for surfacing inherent risk at the early stages of IT projects, thereby enabling the recommendation of appropriate management strategies. The PMO's project risk assessment process is a model for other organizations striving to engage in effective and collaborative practices in order to improve project outcomes. The case illustrates the importance of considering the practical constraints of the context of application in order to transform research findings into practices that promote attainment of desired outcomes.
Histo- and cytopathology of trunk phloem necrosis, a form of rubber tree (Hevea brasiliensis Müll. Arg.) tapping panel dryness
Authors: de Faÿ Elisabeth
Published: October 2011

Trunk phloem necrosis (TPN) is a physiological disease of rubber tree (Hevea brasiliensis Müll. Arg.) discovered in the 1980s. It has been distinguished from rubber tree tapping panel dryness (TPD) by its macroscopic symptoms and presumed origin. But little attention has been paid to its microscopic features, and there is now some evidence that both syndromes could be linked to an impaired cyanide metabolism. In order to characterise TPN and compare it with TPD microscopically, the inner phloem of tapping panels was investigated by light and transmission electron microscopy in healthy trees and TPN-affected trees. TPN-affected phloem presented numerous and varied structural and ultrastructural features. There were signs of cellular deterioration in a great number of specialised cells, i.e. laticifers and sieve tubes, and not very specialised cells, i.e. parenchyma cells and companion cells. There were also signs of cellular dedifferentiation in other parenchymatous cells, e.g. in tylosoids and hyperplasic cells. These cells were derived from parenchyma cells that ensheath laticifers in which the latex coagulated. Numerous structural features of TPN are common to TPD, notably tylosoids associated with in situ coagulated latex, which are also known to be early structural markers of TPD and cyanide-induced. It is therefore concluded that TPN is identical to or a variant of TPD, and is a degenerative disease of rubber tree trunk phloem resembling plant stress response, programmed cell death and plant tumourigenesis in some aspects.
Photostability of the UV filter benzophenone-3 and its effect on the photodegradation of benzotriazole in water
Authors: Liu You-Sheng , Ying Guang-Guo , Shareef Ali , Kookana Rai S.
Published: October 2011

Environmental contextThe environmental fate of a particular contaminant can be influenced by the presence of other chemicals. It is shown that the photodegradation in water of benzotriazole, a common household and industrial chemical, is reduced in the presence of a sunscreen compound. Thus, contaminants such as benzotriazole may persist longer in the environment in the presence of chemicals designed to filter ultraviolet rays, such as those used in sunscreens.
AbstractThe presence of co-solutes (e.g. UV filters) can potentially influence the environmental fate of micropollutants. The photolysis of benzotriazole (BT, an anticorrosion agent) and benzophenone-3 (BP-3, a UV filter), as well as their interactions in aqueous solutions under UV and artificial solar light with or without added humic acid (HA) and metal ions (Cu2+ and Fe3+), has been investigated. BT was found to be photosensitive under UV irradiation, but photostable under solar light. The half-lives for the photolysis of BT were 2.8 h in pure aqueous solution and increasing to 4.5 h in the presence of BP-3 (1.0 mg L–1). BP-3 was photostable under both UV and artificial solar light. Solar radiation exposure of 50 days resulted in a small loss of BP-3 (8 %) in pure aqueous solution, and resulted in a greater loss of BP-3 (up to 31 %) at 50 mg L–1 of HA. UV irradiation of the BT solutions containing BP-3 led to formation of five photoproducts, formed mainly by N–N and N–NH bond scission, polymerisation and hydroxylation. In the case of BP-3, one major photoproduct was isolated and tentatively identified as 2,4-dimethylanisole, formed by the loss of hydroxy and benzoyl groups.
Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination
Authors: Nembrini Chiara , Stano Armando , Dane Karen Y. , Ballester Marie , van der Vlies André J. , Marsland Benjamin J. , Swartz Melody A. , Hubbell Jeffrey A.
Published: October 2011

The ability of vaccines to induce memory cytotoxic T-cell responses in the lung is crucial in stemming and treating pulmonary diseases caused by viruses and bacteria. However, most approaches to subunit vaccines produce primarily humoral and only to a lesser extent cellular immune responses. We developed a nanoparticle (NP)-based carrier that, upon delivery to the lung, specifically targets pulmonary dendritic cells, thus enhancing antigen uptake and transport to the draining lymph node; antigen coupling via a disulfide link promotes highly efficient cross-presentation after uptake, inducing potent protective mucosal and systemic CD8
+
T-cell immunity. Pulmonary immunization with NP-conjugated ovalbumin (NP-ova) with CpG induced a threefold enhancement of splenic antigen-specific CD8
+
T cells displaying increased CD107a expression and IFN-γ production compared with immunization with soluble (i.e., unconjugated) ova with CpG. This enhanced response was accompanied by a potent Th17 cytokine profile in CD4
+
T cells. After 50 d, NP-ova and CpG also led to substantial enhancements in memory CD8
+
T-cell effector functions. Importantly, pulmonary vaccination with NP-ova and CpG induced as much as 10-fold increased frequencies of antigen-specific effector CD8
+
T cells to the lung and completely protected mice from morbidity following influenza-ova infection. Here, we highlight recruitment to the lung of a long-lasting pool of protective effector memory cytotoxic T-cells by our disulfide-linked antigen-conjugated NP formulation. These results suggest the reduction-reversible NP system is a highly promising platform for vaccines specifically targeting intracellular pathogens infecting the lung.
Transcriptional modulator
H2A histone family, member Y
(
H2AFY
) marks Huntington disease activity in man and mouse
Authors: Hu Yi , Chopra Vanita , Chopra Raman , Locascio Joseph J. , Liao Zhixiang , Ding Hongliu , Zheng Bin , Matson Wayne R. , Ferrante Robert J. , Rosas H. Diana , Hersch Steven M. , Scherzer Clemens R.
Published: October 2011

Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity
H2A histone family, member Y (H2AFY)
is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces
H2AFY
levels in a randomized phase II clinical trial. This study identifies the chromatin regulator
H2AFY
as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.
Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch
Authors: Haughian James M. , Pinto Mauricio P. , Harrell J. Chuck , Bliesner Brian S. , Joensuu Kristiina M. , Dye Wendy W. , Sartorius Carol A. , Tan Aik Choon , Heikkilä Päivi , Perou Charles M. , Horwitz Kathryn B.
Published: October 2011

Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like “triple negative” cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that more than half of primary ER
+
PR
+
breast cancers contain an ER
−
PR
−
CK5
+
“luminobasal” subpopulation exceeding 1% of cells. Starting from ER
+
PR
+
luminal cell lines, we generated lines with varying luminal to luminobasal cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone-resistant cells matches that of clinical triple negative basal-like and claudin-low disease. Luminobasal cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by γ-secretase inhibitors. Our data establish a previously unrecognized plasticity of ER
+
PR
+
luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition.
Allosteric vs. spontaneous exit-site (E-site) tRNA dissociation early in protein synthesis
Authors: Chen Chunlai , Stevens Benjamin , Kaur Jaskiran , Smilansky Zeev , Cooperman Barry S. , Goldman Yale E.
Published: October 2011

During protein synthesis, deacylated transfer RNAs leave the ribosome via an exit (E) site after mRNA translocation. How the ribosome regulates tRNA dissociation and whether functional linkages between the aminoacyl (A) and E sites modulate the dynamics of protein synthesis have long been debated. Using single molecule fluorescence resonance energy transfer experiments, we find that, during early cycles of protein elongation, tRNAs are often held in the E site until being allosterically released when the next aminoacyl tRNA binds to the A site. This process is regulated by the length and sequence of the nascent peptide and by the conformational state, detected by tRNA proximity, prior to translocation. In later cycles, E-site tRNA dissociates spontaneously. Our results suggest that the distribution of pretranslocation tRNA states and posttranslocation pathways are correlated within each elongation cycle via communication between distant subdomains in the ribosome, but that this correlation between elongation cycle intermediates does not persist into succeeding cycles.
Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74
Authors: Heinrichs Daniel , Knauel Meike , Offermanns Christian , Berres Marie-Luise , Nellen Andreas , Leng Lin , Schmitz Petra , Bucala Richard , Trautwein Christian , Weber Christian , Bernhagen Jürgen , Wasmuth Hermann E.
Published: October 2011

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that has been implicated in various inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis, a leading cause of morbidity worldwide, but the role of MIF in liver scarring has not yet been elucidated. Here we have uncovered an unexpected antifibrotic role for MIF. Mice genetically deleted in
Mif
(
Mif
−/−
) showed strongly increased fibrosis in two models of chronic liver injury. Pronounced liver fibrosis in
Mif
−/−
mice was associated with alterations in fibrosis-relevant genes, but not by a changed intrahepatic immune cell infiltration. Next, a direct impact of MIF on hepatic stellate cells (HSC) was assessed in vitro. Although MIF alone had only marginal effects on HSCs, it markedly inhibited PDGF-induced migration and proliferation of these cells. The inhibitory effects of MIF were mediated by CD74, which we detected as the most abundant known MIF receptor on HSCs. MIF promoted the phosphorylation of AMP-activated protein kinase (AMPK) in a CD74-dependent manner and, in turn, inhibition of AMPK reversed the inhibition of PDGF-induced HSC activation by MIF. The pivotal role of CD74 in MIF-mediated antifibrotic properties was further supported by augmented liver scarring of
Cd74
−/−
mice. Moreover, mice treated with recombinant MIF displayed a reduced fibrogenic response in vivo. In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases.
Larval helpers and age polyethism in ambrosia beetles
Authors: Biedermann Peter H. W. , Taborsky Michael
Published: October 2011

Division of labor among the workers of insect societies is a conspicuous feature of their biology. Social tasks are commonly shared among age groups but not between larvae and adults with completely different morphologies, as in bees, wasps, ants, and beetles (i.e., Holometabola). A unique yet hardly studied holometabolous group of insects is the ambrosia beetles. Along with one tribe of ants and one subfamily of termites, wood-dwelling ambrosia beetles are the only insect lineage culturing fungi, a trait predicted to favor cooperation and division of labor. Their sociality has not been fully demonstrated, because behavioral observations have been missing. Here we present behavioral data and experiments from within nests of an ambrosia beetle,Xyleborinus saxesenii. Larval and adult offspring of a single foundress cooperate in brood care, gallery maintenance, and fungus gardening, showing a clear division of labor between larval and adult colony members. Larvae enlarge the gallery and participate in brood care and gallery hygiene. The cooperative effort of adult females in the colony and the timing of their dispersal depend on the number of sibling recipients (larvae and pupae), on the presence of the mother, and on the number of adult workers. This suggests that altruistic help is triggered by demands of brood dependent on care. Thus, ambrosia beetles are not only highly social but also show a special form of division of labor that is unique among holometabolous insects.
Caenorhabditis elegans
selects distinct crawling and swimming gaits via dopamine and serotonin
Authors: Vidal-Gadea Andrés , Topper Stephen , Young Layla , Crisp Ashley , Kressin Leah , Elbel Erin , Maples Thomas , Brauner Martin , Erbguth Karen , Axelrod Abram , Gottschalk Alexander , Siegel Dionicio , Pierce-Shimomura Jonathan T.
Published: October 2011

Many animals, including humans, select alternate forms of motion (gaits) to move efficiently in different environments. However, it is unclear whether primitive animals, such as nematodes, also use this strategy. We used a multifaceted approach to study how the nematode
Caenorhabditis elegans
freely moves into and out of water. We demonstrate that
C. elegans
uses biogenic amines to switch between distinct crawling and swimming gaits. Dopamine is necessary and sufficient to initiate and maintain crawling after swimming. Serotonin is necessary and sufficient to transition from crawling to swimming and to inhibit a set of crawl-specific behaviors. Further study of locomotory switching in
C. elegans
and its dependence on biogenic amines may provide insight into how gait transitions are performed in other animals.
Translocation of HIV TAT peptide and analogues induced by multiplexed membrane and cytoskeletal interactions
Authors: Mishra Abhijit , Lai Ghee Hwee , Schmidt Nathan W. , Sun Victor Z. , Rodriguez April R. , Tong Rong , Tang Li , Cheng Jianjun , Deming Timothy J. , Kamei Daniel T. , Wong Gerard C. L.
Published: October 2011

Cell-penetrating peptides (CPPs), such as the HIV TAT peptide, are able to translocate across cellular membranes efficiently. A number of mechanisms, from direct entry to various endocytotic mechanisms (both receptor independent and receptor dependent), have been observed but how these specific amino acid sequences accomplish these effects is unknown. We show how CPP sequences can multiplex interactions with the membrane, the actin cytoskeleton, and cell-surface receptors to facilitate different translocation pathways under different conditions. Using “nunchuck” CPPs, we demonstrate that CPPs permeabilize membranes by generating topologically active saddle-splay (“negative Gaussian”) membrane curvature through multidentate hydrogen bonding of lipid head groups. This requirement for negative Gaussian curvature constrains but underdetermines the amino acid content of CPPs. We observe that in most CPP sequences decreasing arginine content is offset by a simultaneous increase in lysine and hydrophobic content. Moreover, by densely organizing cationic residues while satisfying the above constraint, TAT peptide is able to combine cytoskeletal remodeling activity with membrane translocation activity. We show that the TAT peptide can induce structural changes reminiscent of macropinocytosis in actin-encapsulated giant vesicles without receptors.
Mutagenesis of tryptophan199 suggests that hopping is required for MauG-dependent tryptophan tryptophylquinone biosynthesis
Authors: Tarboush Nafez Abu , Jensen Lyndal M. R. , Yukl Erik T. , Geng Jiafeng , Liu Aimin , Wilmot Carrie M. , Davidson Victor L.
Published: October 2011

The diheme enzyme MauG catalyzes the posttranslational modification of the precursor protein of methylamine dehydrogenase (preMADH) to complete biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. Catalysis proceeds through a high valent bis-Fe(IV) redox state and requires long-range electron transfer (ET), as the distance between the modified residues of preMADH and the nearest heme iron of MauG is 19.4 Å. Trp199 of MauG resides at the MauG-preMADH interface, positioned midway between the residues that are modified and the nearest heme. W199F and W199K mutations did not affect the spectroscopic and redox properties of MauG, or its ability to stabilize the bis-Fe(IV) state. Crystal structures of complexes of W199F/K MauG with preMADH showed no significant perturbation of the MauG-preMADH structure or protein interface. However, neither MauG variant was able to synthesize TTQ from preMADH. In contrast, an ET reaction from diferrous MauG to quinone MADH, which does not require the bis-Fe(IV) intermediate, was minimally affected by the W199F/K mutations. W199F/K MauGs were able to oxidize quinol MADH to form TTQ, the putative final two-electron oxidation of the biosynthetic process, but with
k
cat
/
K
m
values approximately 10% that of wild-type MauG. The differential effects of the W199F/K mutations on these three different reactions are explained by a critical role for Trp199 in mediating multistep hopping from preMADH to bis-Fe(IV) MauG during the long-range ET that is required for TTQ biosynthesis.
Animal-specific C-terminal domain links myeloblastosis oncoprotein (Myb) to an ancient repressor complex
Authors: Andrejka Laura , Wen Hong , Ashton Jonathan , Grant Megan , Iori Kevin , Wang Amy , Manak J. Robert , Lipsick Joseph S.
Published: October 2011

Members of the Myb oncoprotein and E2F-Rb tumor suppressor protein families are present within the same highly conserved multiprotein transcriptional repressor complex, named either as Myb and synthetic multivuval class B (Myb-MuvB) or as
Drosophila
Rb E2F and Myb-interacting proteins (dREAM). We now report that the animal-specific C terminus of
Drosophila
Myb but not the more highly conserved N-terminal DNA-binding domain is necessary and sufficient for (
i
) adult viability, (
ii
) proper localization to chromosomes in vivo, (
iii
) regulation of gene expression in vivo, and (
iv
) interaction with the highly conserved core of the MuvB/dREAM transcriptional repressor complex. In addition, we have identified a conserved peptide motif that is required for this interaction. Our results imply that an ancient function of Myb in regulating G2/M genes in both plants and animals appears to have been transferred from the DNA-binding domain to the animal-specific C-terminal domain. Increased expression of
B-MYB/MYBL2
, the human ortholog of
Drosophila Myb
, correlates with poor prognosis in human patients with breast cancer. Therefore, our results imply that the specific interaction of the C terminus of Myb with the MuvB/dREAM core complex may provide an attractive target for the development of cancer therapeutics.
Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)
Authors: Li Guorong , Du Xiaoli , Vass William C. , Papageorge Alex G. , Lowy Douglas R. , Qian Xiaolan
Published: October 2011

The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.
Induction of 9-
cis
-epoxycarotenoid dioxygenase in
Arabidopsis thaliana
seeds enhances seed dormancy
Authors: Martínez-Andújar Cristina , Ordiz M. Isabel , Huang Zhonglian , Nonogaki Mariko , Beachy Roger N. , Nonogaki Hiroyuki
Published: October 2011

Full understanding of mechanisms that control seed dormancy and germination remains elusive. Whereas it has been proposed that translational control plays a predominant role in germination, other studies suggest the importance of specific gene expression patterns in imbibed seeds. Transgenic plants were developed to permit conditional expression of a gene encoding 9-
cis
-epoxycarotenoid dioxygenase 6 (NCED6), a rate-limiting enzyme in abscisic acid (ABA) biosynthesis, using the ecdysone receptor-based plant gene switch system and the ligand methoxyfenozide. Induction of
NCED6
during imbibition increased ABA levels more than 20-fold and was sufficient to prevent seed germination. Germination suppression was prevented by fluridone, an inhibitor of ABA biosynthesis. In another study, induction of the
NCED6
gene in transgenic seeds of nondormant mutants
tt3
and
tt4
reestablished seed dormancy. Furthermore, inducing expression of
NCED6
during seed development suppressed vivipary, precocious germination of developing seeds. These results indicate that expression of a hormone metabolism gene in seeds can be a sole determinant of dormancy. This study opens the possibility of developing a robust technology to suppress or promote seed germination through engineering pathways of hormone metabolism.
Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis
Authors: Cheng Bo , Anea Ciprian B. , Yao Lin , Chen Feng , Patel Vijay , Merloiu Ana , Pati Paramita , Caldwell R. William , Fulton David J. , Rudic R. Daniel
Published: October 2011

The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.
Redox cycling and kinetic analysis of single molecules of solution-phase nitrite reductase
Authors: Goldsmith Randall H. , Tabares Leandro C. , Kostrz Dorota , Dennison Christopher , Aartsma Thijs J. , Canters G. W. , Moerner W. E.
Published: October 2011

Single-molecule measurements are a valuable tool for revealing details of enzyme mechanisms by enabling observation of unsynchronized behavior. However, this approach often requires immobilizing the enzyme on a substrate, a process which may alter enzyme behavior. We apply a microfluidic trapping device to allow, for the first time, prolonged solution-phase measurement of single enzymes in solution. Individual redox events are observed for single molecules of a blue nitrite reductase and are used to extract the microscopic kinetic parameters of the proposed catalytic cycle. Changes in parameters as a function of substrate concentration are consistent with a random sequential substrate binding mechanism.
Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer
Authors: Gillespie Earl , Leeman Susan E. , Watts Luisa A. , Coukos Jennifer A. , O'Brien Michael J. , Cerda Sandra R. , Farraye Francis A. , Stucchi Arthur F. , Becker James M.
Published: October 2011

Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P= 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P= 0.02) in HGD and 80% (P= 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitis-associated cancer.
Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma
Authors: Agemy Lilach , Friedmann-Morvinski Dinorah , Kotamraju Venkata Ramana , Roth Lise , Sugahara Kazuki N. , Girard Olivier M. , Mattrey Robert F. , Verma Inder M. , Ruoslahti Erkki
Published: October 2011

Antiangiogenic therapy can produce transient tumor regression in glioblastoma (GBM), but no prolongation in patient survival has been achieved. We have constructed a nanosystem targeted to tumor vasculature that incorporates three elements: (
i
) a tumor-homing peptide that specifically delivers its payload to the mitochondria of tumor endothelial cells and tumor cells, (
ii
) conjugation of this homing peptide with a proapoptotic peptide that acts on mitochondria, and (
iii
) multivalent presentation on iron oxide nanoparticles, which enhances the proapoptotic activity. The iron oxide component of the nanoparticles enabled imaging of GBM tumors in mice. Systemic treatment of GBM-bearing mice with the nanoparticles eradicated most tumors in one GBM mouse model and significantly delayed tumor development in another. Coinjecting the nanoparticles with a tumor-penetrating peptide further enhanced the therapeutic effect. Both models used have proven completely resistant to other therapies, suggesting clinical potential of our nanosystem.