bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic potential of histamine H4 receptor agonists in triple‐negative human breast cancer experimental model
Authors: Martinel Lamas Diego J , Croci Maximo , Carabajal Eliana , Crescenti Ernesto J V , Sambuco Lorena , Massari Noelia A , Bergoc Rosa M , Rivera Elena S , Medina Vanina A
Published: February 2013

Background and Purpose

The presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model.

Experimental Approach

Xenograft tumours of the highly invasive human breast cancer cell line MDA‐MB‐231 were established in immune deficient nude mice. The following H4R agonists were employed: histamine (5 mg kg−1), clozapine (1 mg kg−1) and the experimental compound JNJ28610244 (10 mg kg−1).

Results

Data indicate that developed tumours were highly undifferentiated, expressed H4R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H4R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel‐Cox Test, P = 0.0025; Gehan‐Breslow‐Wilcoxon Test, P = 0.0158) and tumoural apoptosis.

Conclusions and Implications

Histamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
Low molecular weight heparin suppresses receptor for advanced glycation end products‐mediated expression of malignant phenotype in human fibrosarcoma cells
Authors: Takeuchi Akihiko , Yamamoto Yasuhiko , Munesue Seiichi , Harashima Ai , Watanabe Takuo , Yonekura Hideto , Yamamoto Hiroshi , Tsuchiya Hiroyuki
Published: February 2013

The receptor for advanced glycation end products (RAGE) is a pattern‐recognition receptor and its engagement by ligands such as high mobility group box 1 (HMGB1) is implicated in tumor growth and metastasis. Low molecular weight heparin (LMWH) has an antagonistic effect on the RAGE axis and is also reported to exert an antitumor effect beyond the known activity of anticoagulation. However, the link between the anti‐RAGE and antitumor activities of LMWH has not yet to be fully elucidated. In this study, we investigated whether LMWH could inhibit tumor cell proliferation, invasion, and metastasis by blocking the RAGE axis using in vitro and in vivo assay systems. Stably transformed HT1080 human fibrosarcoma cell lines were obtained, including human full‐length RAGE‐overexpressing (HT1080RAGE), RAGE dominant‐negative, intracellular tail‐deleted RAGE‐overexpressing (HT1080dnRAGE), and mock‐transfected control (HT1080mock) cells. Confocal microscopy showed the expression of HMGB1 and RAGE in HT1080 cells. The LMWH significantly inhibited HMGB1‐induced NFκB activation through RAGE using an NFκB‐dependent luciferase reporter assay and the HT1080 cell lines. Overexpression of RAGE significantly accelerated, but dnRAGE expression attenuated HT1080 cell proliferation and invasion in vitro, along with similar effects on local tumor mass growth and lung metastasis in vivo. Treatment with LMWH significantly inhibited the migration, invasion, tumor formation, and lung metastasis of HT1080RAGE cells, but not of HT1080mock or HT1080dnRAGE cells. In conclusion, this study revealed that RAGE exacerbated the malignant phenotype of human fibrosarcoma cells, and that this exacerbation could be ameliorated by LMWH. It is suggested that LMWH has therapeutic potential in patients with certain types of malignant tumors.
Rational Discovery of Dengue Type 2 Non‐Competitive Inhibitors
Authors: Heh Choon H. , Othman Rozana , Buckle Michael J. C. , Sharifuddin Yusrizam , Yusof Rohana , Rahman Noorsaadah A.
Published: February 2013

Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti‐dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti‐dengue agents based on non‐competitive inhibition of DEN‐2 NS2B/NS3 protease. A homology model of the DEN‐2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13 341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top‐ranking compounds against DEN‐2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti‐dengue agents.
Calmodulin as a Potential Target by Which Berberine Induces Cell Cycle Arrest in Human Hepatoma Bel7402 Cells
Authors: Ma Chao , Tang Kailin , Liu Qi , Zhu Ruixin , Cao Zhiwei
Published: February 2013

Berberine is an isoquinoline alkaloid that has drawn extensive attention because it possesses various biological activities. Several mechanisms have been proposed to interpret the anticancer activity of berberine. However, these explanations are mostly based on its downstream‐regulated genes or proteins; information on the direct target proteins that mediate the antiproliferative action of berberine remains unclear. In this study, a computational pipeline based on a ligand–protein inverse docking program and mining of the ‘Connectivity MAP’ data was adopted to explore the potential target proteins for berberine. The results showed that four proteins, that is calmodulin, cytochrome P450 3A4, sex hormone‐binding globulin, and carbonic anhydrase II, were suggested to be the potential targets of berberine. The anticalmodulin property of berberine was demonstrated with an in vitro phosphodiesterase activity assay. Flow cytometric analysis found that G1 cell cycle arrest induced by berberine in Bel7402 cells was enhanced by cotreatment with calmodulin inhibitors. Western blotting results indicated that berberine treatment decreased phosphorylation of calmodulin kinase II and blocked subsequent MEK1 activation as well as p27 protein degradation. These results suggested that calmodulin might play crucial roles in berberine‐induced cell cycle arrest in cancer cells.
Incidence rate and clinical features of hyperthyroidism in a long‐term iodine sufficient area of Sweden (Gothenburg) 2003–2005
Authors: Nyström Helena Filipsson , Jansson Svante , Berg Gertrud
Published: February 2013

Objectives

To study hyperthyroidism in long‐term iodine sufficiency (IS), as iodine supply affects its occurrence.

Design

Prospective descriptive study.

Patients

In 2003–2005, all referred cases of subclinical (SH) and overt hyperthyroidism (OH) were registered at diagnosis from a population (n = 631 239) in Gothenburg, Sweden.

Measurements

Information on age, gender, smoking, thyroid associated ophthalmopathy (TAO), thyroid hormones and TSH receptor antibodies (TRab) was collected. Incidences were calculated. SH and OH cases with Graves' disease (GD), toxic multinodular goiter (TMNG) and solitary toxic adenoma (STA) were compared. In GD, TRab+ and TRab− cases and patients with (TAO+) and without TAO (TAO−) were compared.

Results

The total incidence (n/100 000/year) of hyperthyroidism was 27·6; OH 23·8; SH 3·8; GD 21·4; TMNG 4·3; and STA 1·8. SH was more common among TMNG (40·2%) and STA (45·7%) than in GD (5·9%). SH‐GD patients were older, more often smokers and had lower TRab levels than OH‐GD patients. FreeT4 and T3 levels in GD were higher than in TMNG and STA. FreeT4, T3 and TRab decreased with age in patients with GD, P < 0·0001. TRab‐ patients had lower T3 than TRab+ patients, P < 0·001. TRab was positively correlated to FreeT4, P < 0·0001. TAO occured in 20% of patients with GD. TAO+ patients were younger than TAO‐ patients. Smokers did not have more TAO.

Conclusion

The total incidence of hyperthyroidism was low. GD dominated with an age‐related decline of thyroid hormones and TRab levels. The spectrum of hyperthyroidism in this long‐term IS area may represent the future situation for countries with shorter history of IS.
Conometric retention for complete fixed prosthesis supported by four implants: 2‐years prospective study
Authors: Bressan Eriberto , Lops Diego
Published: February 2013

Objective

The aim of this study was to verify the reliability of a conometric system for a fixed retention of complete prostheses (CPs) on four implants followed for 2 years.

Material and methods

Twenty‐five patients received four implants and only one CPs for a total of 100 implants followed. Each prosthesis was supported by four implants. An immediate loading surgical protocol was used. The CPs were provided to be fixed to conometric abutments without prostheses removal by the patients, to test this retention for a fixed instead of a removable rehabilitation. Clinical and radiographical parameters were assessed at the yearly follow‐up visit. A follow‐up of 2 years was observed for each patient. Moreover, biological and technical complications were recorded. Changes overtime of clinical and radiographic parameters were analyzed as well as the satisfaction degree for each patient.

Results

No patient was classified as “dropout.” The following results were observed after 2 years of follow‐up: all the implants supporting the 25 CPs completed the follow‐up examination. No implant, reconstruction, and abutment failure were recorded; therefore, the prosthetic survival was 100% for all the abutments and restorations. No significant differences in biological indexes were observed when compared with the baseline. No significant change of the mean marginal bone level (MBL) was found between the baseline and the last follow‐up. No loss of retention was recorded for the CPs. No technical complications referred to abutments and frameworks were observed: a prosthetic survival rate of 100% can be recorded. Mucositis was recorded for two implants and successfully treated with interceptive supportive therapy.

No significant differences (P < 0.05) were found between plaque index and MBi parameters at baseline and after 2 years of function. Similar results were recorded for the mean probing pocket depth Index at baseline (1.2 mm with SD of 0.3 mm) and after 2 years of function (1.2 mm with SD of 0.2 mm).

Conclusions

The present implant‐supported conometric retention system can be used to give a fixed retention to a CPs supported by four implants immediately loaded. Furthermore, costs reduction and simplified treatment procedures were provided by such a clinical approach.
Marginal bone loss around implants placed in maxillary native bone or grafted sinuses: a retrospective cohort study
Authors: Galindo‐Moreno P. , Fernández‐Jiménez A. , Avila‐Ortiz G. , Silvestre F.J. , Hernández‐Cortés P. , Wang H.L.
Published: February 2013

Objectives

To assess differences in marginal bone loss around implants placed in maxillary pristine bone and implants placed following maxillary sinus augmentation over a period of 3 years after functional loading.

Material and methods

Two cohorts of subjects (Group 1: Subjects who received sinus augmentation with simultaneous implant placement; Group 2: Subjects who underwent conventional implant placement in posterior maxillary pristine bone) were included in this retrospective study. Radiographic marginal bone loss was measured around one implant per patient on digitized panoramic radiographs that were obtained at the time of prosthesis delivery (baseline) and 12, 24, and 36 months later. The influence of age, gender, smoking habits, history of periodontal disease, and type of prosthetic connection (internal or external) on marginal bone loss was analyzed in function of the type of osseous support (previously grafted or pristine).

Results

A total of 105 subjects were included in this study. Cumulative radiographic marginal bone loss ranged from 0 mm to 3.9 mm after 36 months of functional loading. There were statistically significant differences in marginal bone loss between implants placed in grafted and pristine bone at the 12‐month assessment, but not in the subsequent progression rate. External prosthetic connection, smoking, and history of periodontitis negatively influenced peri‐implant bone maintenance, regardless of the type of osseous substrate.

Conclusions

Implants placed in sites that received maxillary sinus augmentation exhibited more marginal bone loss than implants placed in pristine bone, although marginal bone loss mainly occurred during the first 12 months after functional loading. Implants with external implant connection were strongly associated with increased marginal bone loss overtime.
The LRRK2 R1628P Variant Plays a Protective Role in Han Chinese Population with Alzheimer's Disease
Authors: Li Hong‐Lei , Lu Shen‐Ji , Sun Yi‐Min , Guo Qi‐Hao , Sadovnick Adele Dessa , Wu Zhi‐Ying
Published: February 2013

Aims

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative disorders that may share some overlapping etiologies. Mutations within leucine‐rich repeat kinase 2 (LRRK2) have been reported to be responsible for PD, and the location of LRRK2 is within a linkage peak for sporadic AD (SAD). The aim of this study was to investigate two Asian‐specific LRRK2 variants, R1628P and G2385R, with the association of Han Chinese SAD.

Methods

Genotyping of R1628P and G2385R was performed by PCR‐restriction fragment length polymorphism (RFLP) analysis in 390 patients with SAD and 545 unrelated age‐ and sex‐matched healthy controls.

Results

The frequency of the C allele within R1628P was more than three times higher in control group (1.7%) than in patients with SAD (0.5%) (OR 0.264; 95% CI, 0.088–0.792, P = 0.018). After stratification by the presence of one or two apolipoprotein E ε4 alleles, the protective effect becomes stronger (ε44: OR 0.028; 95% CI, 0.003–0.303, P = 0.003; ε4: OR 0.104; 95% CI, 0.013–0.818, P = 0.031). However, no difference was found in G2385R variant.

Conclusion

Our study suggested that R1628P variant within LRRK2 plays a protective role in Han Chinese population with SAD and such effect has an interaction with the APOE genotype.
From “Special K” to “Special M”: The Evolution of the Recreational Use of Ketamine and Methoxetamine
Authors: Corazza Ornella , Assi Sulaf , Schifano Fabrizio
Published: February 2013

This article reviews the recreational use of ketamine (“Special K”; KET) and explores the recent diffusion of its new derivative methoxetamine (“Special M”; MXE). The literature search on the nonclinical/recreational use of KET and MXE was carried out in a range of medical databases. Considering the limitations of peer‐reviewed information, data were integrated with a qualitative assessment of a range of websites, drug fora, and other online resources including e‐newsgroups, chat rooms, mailing lists, e‐newsletters, and bulletin boards. The recreational use of KET has started since its discovery in 1962. This was due to its rapid onset, short duration of action, and peculiar psychotropic effects (“K‐hole”). The latter effect ranges from confusion to dissociation and depersonalization (near‐death experience). However, KET abuse is often associated with physical and psychological side effects, of which the worst is urological/bladder toxicity. Recently, MXE has emerged as a legal and “bladder‐friendly” KET alternative. MXE presents with the same dissociative effect of KET, but with slower onset and longer duration of action. However, MXE seems to be associated with worse side effects than KET, ranging from mood disturbances/suicidal attempts to acute cerebellar toxicity. After 50 years of its discovery, KET has led to the emergence of MXE. However, this latter derivative does not appear to be a safer alternative to KET itself.
A Zn isotope perspective on the rise of continents
Authors: Pons M.‐L. , Fujii T. , Rosing M. , Quitté G. , Télouk P. , Albarède F.
Published: February 2013

Zinc isotope abundances are fairly constant in igneous rocks and shales and are left unfractionated by hydrothermal processes at pH < 5.5. For that reason, Zn isotopes in sediments can be used to trace the changing chemistry of the hydrosphere. Here, we report Zn isotope compositions in Fe oxides from banded iron formations (BIFs) and iron formations of different ages. Zinc from early Archean samples is isotopically indistinguishable from the igneous average (δ66Zn ~0.3‰). At 2.9–2.7 Ga, δ66Zn becomes isotopically light (δ66Zn < 0‰) and then bounces back to values >1‰ during the ~2.35 Ga Great Oxygenation Event. By 1.8 Ga, BIF δ66Zn has settled to the modern value of FeMn nodules and encrustations (~0.9‰). The Zn cycle is largely controlled by two different mechanisms: Zn makes strong complexes with phosphates, and phosphates in turn are strongly adsorbed by Fe hydroxides. We therefore review the evidence that the surface geochemical cycles of Zn and P are closely related. The Zn isotope record echoes Sr isotope evidence, suggesting that erosion starts with the very large continental masses appearing at ~2.7 Ga. The lack of Zn fractionation in pre‐2.9 Ga BIFs is argued to reflect the paucity of permanent subaerial continental exposure and consequently the insignificant phosphate input to the oceans and the small output of biochemical sediments. We link the early decline of δ66Zn between 3.0 and 2.7 Ga with the low solubility of phosphate in alkaline groundwater. The development of photosynthetic activity at the surface of the newly exposed continents increased the oxygen level in the atmosphere, which in turn triggered acid drainage and stepped up P dissolution and liberation of heavy Zn into the runoff. Zinc isotopes provide a new perspective on the rise of continents, the volume of carbonates on continents, changing weathering conditions, and compositions of the ocean through time.
Variation of first‐order root traits across climatic gradients and evolutionary trends in geological time
Authors: Chen Weile , Zeng Hui , Eissenstat David M. , Guo Dali
Published: February 2013

Aim

Plant roots are crucial for water and nutrient absorption, but large‐scale patterns and underlying mechanisms of root trait variation and evolution are poorly understood. Here we quantify the degree of variation in functional traits for the first‐order roots across large geographical scales and examine the potential mechanisms underlying these patterns.

Location

China.

Methods

We collected first‐order roots (stream‐based ordering system) and leaf samples of 65 tree species in six forests from subtropical to temperate zones and determined the key morphological, architectural and chemical traits.

Results

We found wider variation in root morphology in the subtropical zone, where species with very thick and very thin first‐order roots coexisted, in contrast with narrower variation among species in the temperate zone. Inconsistent with the predictions of trait economics spectrum, root nitrogen concentration was uncorrelated with root morphology. Furthermore, average root diameter at the plant family level decreased markedly with their divergence time in both piecewise and phylogenetic independent contrast regression analyses.

Main conclusions

Higher variation in root morphology in the subtropical zone appears to result from the coexistence of tree species with thick and thin roots, probably because of a more favourable water supply. Patterns of root evolution towards thinner roots were driven by both phylogeny and possible adaptation of newly diverged species to drier habitats from mid to late Cretaceous. Our findings reveal contrasting selection pressures at the root and leaf level in different climatic zones during plant evolution, and suggest that a single vector of variation linking morphology to resource acquisition or life span (‘trait economics’) remains elusive in roots.
Where lynx prevail, foxes will fail – limitation of a mesopredator in Eurasia
Authors: Pasanen‐Mortensen Marianne , Pyykönen Markku , Elmhagen Bodil
Published: February 2013

Aim

Climate change and loss of apex predators can affect ecosystem structure and function through modified limitation processes. We investigated, on a continental scale, whether mesopredator abundance is limited from the top down by large predators, as predicted by the mesopredator release hypothesis, or by bottom‐up factors. The mesopredator in focus is the red fox Vulpes vulpes, a key predator in many ecosystems due to its strong effects on prey abundance.

Location

Europe and northern Asia.

Methods

Data on red fox density were compiled from published papers and reports. For each site, we collated presence–absence data on large carnivores (Lynx lynx, Canis lupus, Canis aureus) and remote sensing data for factors potentially related to bottom‐up limitation (winter severity, summer temperature, human density, primary productivity, tree cover). The data were analysed through structural equation modelling.

Results

The presence of lynx had a direct negative effect on red foxes, suppressing fox abundance. Also winter severity had a negative effect on red fox abundance, and in Eurasia as a whole this effect was partially mediated through lynx. Within the lynx distribution range, winter severity was the only bottom‐up factor significantly affecting red fox abundance. Outside the lynx distribution range, primary productivity, summer temperature and human density had a positive effect on red fox abundance.

Main conclusions

Our results show that apex predators can limit mesopredator abundance on a continental scale, thus supporting the mesopredator release hypothesis. Winter severity also affected red fox abundance, partially due to an interaction between lynx and winter conditions. On the continental scale a complex network of processes operates with varying effects depending on mediation processes. Our results imply that apex predators can have an important effect on ecosystem structure by limiting mesopredator abundance, and we suggest that apex predators may dampen increases in mesopredator abundance driven by global warming.
Genetic similarity analysis within Pyropia yezoensis blades developed from both conchospores and blade archeospores using AFLP1
Authors: He Linwen , Zhu Jianyi , Lu Qinqin , Niu Jianfeng , Zhang Baoyu , Lin Apeng , Wang Guangce
Published: February 2013

Pyropia yezoensis (Ueda) M. S. Hwang et H. G. Choi (previously called Porphyra yezoensis) is an economically important alga. The blades generated from conchospores are genetic chimeras, which are not suitable for genetic similarity analysis. In this study, two types of blades from a single filament of P. yezoensis sporophyte filament were obtained. One type, ConB, consisted of 40 blades that had germinated from conchospores. The other type, ArcB, consisted of 88 blades that had germinated from archeospores released from ConB. Both of them were analyzed by amplified fragment length polymorphism. The low genetic similarity levels for both conchospore‐germinated and archeospore‐germinated blades demonstrated that the conchcelis we used was cross‐fertilized. Furthermore, a higher polymorphic loci ratio (98.6%) was detected in ArcB than in ConB (80.7%), and the average genetic similarity of ArcB (average 0.61) was lower than that of ConB (average 0.71). These differences indicated that genetic analysis using ArcB gives more accurate results.
Bacterial Contamination of Stethoscope Chest Pieces and the Effect of Daily Cleaning
Authors: Fujita H. , Hansen B. , Hanel R.
Published: February 2013

Background

Stethoscopes are a potential source of nosocomial infection for hospitalized humans, a phenomenon not previously studied in companion animals.

Objectives

To determine if daily cleaning of stethoscope chest pieces reduces bacterial contamination between cleanings.

Animals

Client‐owned dogs and cats.

Methods

Prospective observational study. In phase 1, bacterial cultures were obtained from the chest pieces of 10 participant stethoscopes once weekly for 3 weeks. In phase 2, stethoscopes were cleaned daily and 2 culture samples were obtained once weekly, immediately before and after cleaning with 70% isopropyl alcohol, for 3 weeks.

Results

Daily cleaning eliminated bacteria immediately after each cleaning (P = .004), but did not reduce the rate of positive cultures obtained before cleaning in phase 2. Cultures were positive for 20/30 (67%) samples during phase 1 and 18/30 (60%) obtained before daily cleaning during phase 2. Recovered organisms included normal skin flora, agents of opportunistic infections, and potential pathogens. The only genus that was repeatedly recovered from the same stethoscope for 2 or more consecutive weeks was Bacillus sp.

Conclusions and Clinical Importance

Daily cleaning was highly effective at removing bacteria, but provided no reduction in precleaning contamination. Cleaning stethoscopes after use on dogs or cats infected with pathogenic bacteria and before use on immunocompromised animals should be considered.
Dealing with change: the different microenvironments faced by the malarial parasite
Authors: Chitnis Chetan E. , Staines Henry M.
Published: February 2013

In a new paper, Pillai et al. () report that in vitro asexual blood‐stage Plasmodium falciparum parasite cultures are able to grow unhindered in media with surprisingly broad ranges of ionic constituents. In doing so, the authors demonstrate that long known changes in the cationic composition of the cytosol of host erythrocytes induced by developing intra‐erythrocytic parasites are not essential for growth. Moreover, their results also suggest that besides a low K+ environment, which has been shown to trigger key processes such as microneme secretion and merozoite egress, there must be alternative signals that can regulate these processes and allow normal growth in diverse ionic environments. Given these findings, mechanisms by which the parasite is able to sense and tolerate different ionic environments are worthy of further study in an effort to identify urgently needed novel anti‐malarial strategies.
Functional insights into the Shigella type III needle tip IpaD in secretion control and cell contact
Authors: Schiavolin Lionel , Meghraoui Alaeddine , Cherradi Youness , Biskri Latéfa , Botteaux Anne , Allaoui Abdelmounaaïm
Published: February 2013

Type III secretion apparatus (T3SA) are complex nanomachines that insert a translocation pore into the host cell membrane through which effector proteins are injected into the cytosol. In Shigella, the pore is inserted by a needle tip complex that also controls secretion. IpaD is the key protein that rules the composition of the tip complex before and upon cell contact or Congo red (CR) induction. However, how IpaD is involved in secretion control and translocon insertion remains not fully understood. Here, we report the phenotypic analysis of 20 10‐amino acids deletion variants all along the coiled‐coil and the central domains of IpaD (residues 131–332). Our results highlight three classes of T3S phenotype; (i) wild‐type secretion, (ii) constitutive secretion of all classes of effectors, and (iii) constitutive secretion of translocators and early effectors, but not of late effectors. Our data also suggest that the composition of the tip complex defines both the T3SA inducibility state and late effectors secretion. Finally, we shed light on a new aspect regarding the contact of the needle tip with cell membrane by uncoupling the Shigella abilities to escape macrophage vacuole, and to insert the translocation pore or to invade non‐phagocytic cells.
Ubiquilin‐1 immunoreactivity is concentrated on Hirano bodies and dystrophic neurites in Alzheimer's disease brains
Authors: Satoh J. , Tabunoki H. , Ishida T. , Saito Y. , Arima K.
Published: February 2013

Aims

Ubiquilin‐1 acts as an adaptor protein that mediates the translocation of polyubiquitinated proteins to the proteasome for degradation. Although previous studies suggested a key role of ubiquilin‐1 in the pathogenesis of Alzheimer's disease (AD), a direct relationship between ubiquilin‐1 and Hirano bodies in AD brains remains unknown.

Methods

By immunohistochemistry, we studied ubiquilin‐1 and ubiquilin‐2 expression in the frontal cortex and the hippocampus of six AD and 13 control cases.

Results

Numerous Hirano bodies, accumulated in the hippocampal CA1 region of AD brains, expressed intense immunoreactivity for ubiquilin‐1. They were much less frequently found in control brains. However, Hirano bodies did not express a panel of markers for proteasome, autophagosome or pathogenic proteins, such as ubiquilin‐2, ubiquitin, p62, LC3, beclin‐1, HDAC6, paired helical filament (PHF)‐tau, protein‐disulphide isomerase (PDI) and phosphorylated TDP‐43, but some of them expressed C9orf72. Ubiquilin‐1‐immunoreactive deposits were classified into four distinct morphologies, such as rod‐shaped structures characteristic of Hirano bodies, dystrophic neurites contacting senile plaques, fragmented structures accumulated in the lesions affected with severe neuronal loss, and thread‐shaped structures located mainly in the molecular layer of the hippocampus.

Conclusions

Ubiquilin‐1 immunoreactivity is concentrated on Hirano bodies and dystrophic neurites in AD brains, suggesting that aberrant expression of ubiquilin‐1 serves as one of pathological hallmarks of AD.
Contrasting arbuscular mycorrhizal communities colonizing different host plants show a similar response to a soil phosphorus concentration gradient
Authors: Gosling Paul , Mead Andrew , Proctor Maude , Hammond John P. , Bending Gary D.
Published: February 2013

High soil phosphorus (P) concentration is frequently shown to reduce root colonization by arbuscular mycorrhizal (AM) fungi, but the influence of P on the diversity of colonizing AM fungi is uncertain.

We used terminal restriction fragment length polymorphism (T‐RFLP) of 18S rDNA and cloning to assess diversity of AM fungi colonizing maize (Zea mays), soybean (Glycene max) and field violet (Viola arvensis) at three time points in one season along a P gradient of 10–280 mg l−1 in the field.

Percentage AM colonization changed between sampling time points but was not reduced by high soil P except in maize. There was no significant difference in AM diversity between sampling time points. Diversity was reduced at concentrations of P > 25 mg l−1, particularly in maize and soybean. Both cloning and T‐RFLP indicated differences between AM communities in the different host species. Host species was more important than soil P in determining the AM community, except at the highest P concentration.

Our results show that the impact of soil P on the diversity of AM fungi colonizing plants was broadly similar, despite the fact that different plants contained different communities. However, subtle differences in the response of the AM community in each host were evident.
Is self‐fertilization an evolutionary dead end?
Authors: Igic Boris , Busch Jeremiah W.
Published: February 2013

A compound hypothesis positing that self‐fertilization is an evolutionary dead end conflates two distinct claims: the transition from outcrossing to selfing is unidirectional; and the diversification rate, or the balance of the speciation and extinction rate, is negative for selfing species. Both claims have enjoyed widespread informal support for decades, but have recently come under suspicion. Sources of data that apparently contradict strongly asymmetric mating system transitions often rely on statistical phylogenetic tests plagued by profound flaws. Although recently developed models mend preceding approaches, they have been employed sparingly, and many problems remain. Theoretical investigations, genetic data and applications of new phylogenetic methods provide indirect support for an association of selfing with negative diversification rates. We lack direct tests of reversals from selfing to outcrossing, and require data concerning the genetic basis and complexity of independently evolved outcrossing adaptations. The identification of the mechanisms that limit the longevity of selfing lineages has been difficult. Limitations may include brief and variable durations of selfing lineages, as well as ongoing difficulties in relating additive genetic and nucleotide variation. Furthermore, a common line of evidence for the stability of mixed mating – based simply on its frequent occurrence – is misleading. We make specific suggestions for research programs that aim to provide a richer understanding of mating system evolution and seriously challengeStebbins’ venerable hypothesis.

ContentsSummary386I.Introduction387II.Microevolutionary perspectives on SEDE388III.Macroevolutionary perspectives on SEDE390IV.SEDE and the distribution of outcrossing rates in angiosperms393V.Redirection of study to challenge Stebbins’ claims394Acknowledgements395References395
Ancestral stomatal control results in a canalization of fern and lycophyte adaptation to drought
Authors: McAdam Scott A. M. , Brodribb Timothy J.
Published: February 2013

Little is known about how a predominantly passive hydraulic stomatal control in ferns and lycophytes might impact water use under stress. Ferns and lycophytes occupy a diverse array of habitats, from deserts to rainforest canopies, raising the question of whether stomatal behaviour is the same under all ecological strategies and imposes ecological or functional constraints on ferns and lycophytes.

We examined the stomatal response of a diverse sample of fern and lycophyte species to both soil and atmospheric water stress, assessing the foliar level of the hormone abscisic acid (ABA) over drought and recovery and the critical leaf water potential (Ψl) at which photosynthesis in droughted leaves failed to recover.

The stomata of all ferns and lycophytes showed very predictable responses to soil and atmospheric water deficit via Ψl, while stomatal closure was poorly correlated with changes in ABA. We found that all ferns closed stomata at very low levels of water stress and their survival afterwards was limited only by their capacitance and desiccation tolerance.

Ferns and lycophytes have constrained stomatal responses to soil and atmospheric water deficit as a consequence of a predominantly passive stomatal regulation. This results in a monotypic strategy in ferns and lycophytes under water stress.
Alterations in inflammatory, antiviral and regulatory cytokine responses in peripheral blood mononuclear cells from pregnant women with asthma
Authors: Vanders Rebecca L. , Gibson Peter G. , Wark Peter A. B. , Murphy Vanessa E.
Published: February 2013

Background & objective

Severe asthma exacerbations during pregnancy are a common complication leading to poor health outcomes for both the mother and the baby. Asthma exacerbations are caused most frequently by respiratory viruses. A balance between antiviral and inflammatory immune responses is critical during pregnancy; the balance may be altered by asthma and respiratory virus infection.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from (i) non‐pregnant healthy controls, (ii) pregnant non‐asthmatics, (iii) post‐partum non‐asthmatics, (iv) non‐pregnant asthmatics (v) pregnant asthmatics, and (vi) post‐partum asthmatics. Cells were culturedin vitrowith the mitogen phytohaemagglutinin or with a strain of the 2009 pandemic swine influenza. Interferon(IFN)‐γ, interleukin (IL)‐10 andIL‐17 protein were measured from culture supernatant. Neutrophil counts were obtained in samples from pregnant and post‐partum women.

Results

Following the phytohaemagglutinin stimulation ofPBMCs, pregnant asthmatics had significantly higherIL‐17 and significantly lowerIFN‐γ responses compared with healthy non‐pregnant women. Following infection with influenza, a significant reduction was also observed inIFN‐γandIL‐10production fromPBMCof pregnant asthmatics. TheIL‐17response to phytohaemagglutinin correlated with the neutrophil percentage. Differences inIFN‐γ,IL‐10andIL‐17were found to persist for at least 6 months post‐partum.

Conclusions

A reduction in antiviral and regulatory immunity with increased inflammation during pregnancy occurs inPBMCfrom pregnant women with asthma. This novel information may relate to the increased susceptibility and disease severity to respiratory virus infections observed during pregnancy.
Social judgment of aggressive language: Effects of target and sender sex on the evaluation of slurs
Authors: Bendixen Mons , Gabriel Ute
Published: February 2013

We investigated the influence of the sex of the target and the sex of the sender on the judgment of slurs (verbal derogation). From previous research, we selected and clustered slurs into seven categories and respondents rated their degree of perceived insult in two consecutive questionnaire surveys (N = 281 and N = 224, respectively). Results confirm that slurs are generally judged as being more insulting when directed towards females than towards males. In comparison, differences in sex of sender were small. When directed towards females, slurs referring to “being loose” were rated as the most insulting. For both target sexes, remarks referring to homosexuality and physical unattractiveness were among those rated as the most insulting. Least insulting were slurs referring to unethical acts, lack of intelligence and cowardliness. A sex of respondent effect was found, suggesting that women rated slurs generally more insulting than men. The pattern of results showed considerable stability across surveys attesting for the reliability of the method for measuring the social evaluation of slurs.
An optimization approach for making causal inferences
Authors: Tam Cho Wendy K. , Sauppe Jason J. , Nikolaev Alexander G. , Jacobson Sheldon H. , Sewell Edward C.
Published: February 2013

To make causal inferences from observational data, researchers have often turned to matching methods. These methods are variably successful. We address issues with matching methods by redefining the matching problem as a subset selection problem. Given a set of covariates, we seek to find two subsets, a control group and a treatment group, so that we obtain optimal balance, or, in other words, the minimum discrepancy between the distributions of these covariates in the control and treatment groups. Our formulation captures the key elements of the Rubin causal model and translates nicely into a discrete optimization framework.
Light and the E3 ubiquitin ligase COP1/SPA control the protein stability of the MYB transcription factors PAP1 and PAP2 involved in anthocyanin accumulation in Arabidopsis
Authors: Maier Alexander , Schrader Andrea , Kokkelink Leonie , Falke Christian , Welter Bastian , Iniesto Elisa , Rubio Vicente , Uhrig Joachim F. , Hülskamp Martin , Hoecker Ute
Published: February 2013

Anthocyanins are natural pigments that accumulate only in light‐grown and not in dark‐grown Arabidopsis plants. Repression of anthocyanin accumulation in darkness requires the CONSTITUTIVELY PHOTOMORPHOGENIC1/SUPPRESSOR OF PHYA‐105 (COP1/SPA) ubiquitin ligase, as cop1 and spa mutants produce anthocyanins also in the dark. Here, we show that COP1 and SPA proteins interact with the myeloblastosis (MYB) transcription factors PRODUCTION OF ANTHOCYANIN PIGMENT1 (PAP)1 and PAP2, two members of a small protein family that is required for anthocyanin accumulation and for the expression of structural genes in the anthocyanin biosynthesis pathway. The increased anthocyanin levels in cop1 mutants requires the PAP1 gene family, indicating that COP1 functions upstream of the PAP1 gene family. PAP1 and PAP2 proteins are degraded in the dark and this degradation is dependent on the proteasome and on COP1. Hence, the light requirement for anthocyanin biosynthesis results, at least in part, from the light‐mediated stabilization of PAP1 and PAP2. Consistent with this conclusion, moderate overexpression of PAP1 leads to an increase in anthocyanin levels only in the light and not in darkness. Here we show that SPA genes are also required for reducing PAP1 and PAP2 transcript levels in dark‐grown seedlings. Taken together, these results indicate that the COP1/SPA complex affects PAP1 and PAP2 both transcriptionally and post‐translationally. Thus, our findings have identified mechanisms via which the COP1/SPA complex controls anthocyanin levels in Arabidopsis that may be useful for applications in biotechnology directed towards increasing anthocyanin content in plants.
Modeling of Piezoelectric Bimorph Nano-Actuators With Surface Effects
Authors: Zhang Chunli , Zhang Chuanzeng , Chen Weiqiu
Published: February 2013

Two-dimensional (2D) equations of piezoelectric bimorph nano-actuators are presented which take account of the surface effect. The surface effect of the bimorph structure is treated as a surface layer with zero thickness. The influence on the plate's overall properties resulted from the surface elasticity and piezoelectricity is modeled by a spring force exerting on the boundary of the bulk core. Using the derived 2D equations, the anti-parallel piezoelectric bimorph nano-actuators of both cantilever and simply supported plate type are investigated theoretically. Numerical results show that the effective properties and the deflections of the antiparallel bimorph nano-actuators are size-dependent. The deflection at the resonant frequency achieves nearly 50 times as that under the static driving voltage.
An Analytical Approach to Study the Intraoperative Fractures of Femoral Shaft During Total Hip Arthroplasty
Authors: Malekmotiei Leila , Farahmand Farzam , Shodja Hossein M. , Samadi-Dooki Aref
Published: February 2013

An analytical approach which is popular in micromechanical studies has been extended to the solution for the interference fit problem of the femoral stem in cementless total hip arthroplasty (THA). The multiple inhomogeneity problem of THA in transverse plane, including an elliptical stem, a cortical wall, and a cancellous layer interface, was formulated using the equivalent inclusion method (EIM) to obtain the induced interference elastic fields. Results indicated a maximum interference fit of about 210 μm before bone fracture, predicted based on the Drucker–Prager criterion for a partially reamed section. The cancellous layer had a significant effect on reducing the hoop stresses in the cortical wall; the maximum press fit increased to as high as 480 μm for a 2 mm thick cancellous. The increase of the thickness and the mechanical quality, i.e., stiffness and strength, of the cortical wall also increased the maximum interference fit before fracture significantly. No considerable effect was found for the implant material on the maximum allowable interference fit. It was concluded that while larger interference fits could be adapted for younger patients, care must be taken when dealing with the elderly and those suffering from osteoporosis. A conservative reaming procedure is beneficial for such patients; however, in order to ensure sufficient primary stability without risking bone fracture, a preoperative analysis might be necessary.
Mechanical Response of the Herniated Human Abdomen to the Placement of Different Prostheses
Authors: Hernández-Gascón Belén , Peña Estefanía , Grasa Jorge , Pascual Gemma , Bellón Juan M. , Calvo Begoña
Published: February 2013

This paper describes a method designed to model the repaired herniated human abdomen just after surgery and examine its static mechanical response to the maximum intra-abdominal pressure provoked by a physiological movement (standing cough). The model is based on the real geometry of the human abdomen bearing a large incisional hernia with several anatomical structures differentiated by MRI. To analyze the outcome of hernia repair, the surgical procedure was simulated by modeling a prosthesis placed over the hernia. Three surgical meshes with different mechanical properties were considered: an isotropic heavy-weight mesh (Surgipro®), a slightly anisotropic light-weight mesh (Optilene®), and a highly anisotropic medium-weight mesh (Infinit®). Our findings confirm that anisotropic implants need to be positioned such that the most compliant axis of the mesh coincides with the craneo-caudal direction of the body.
Causes and elimination of pyramidal defects in GaSb-based epitaxial layers
Authors: Murray Lee M. , Yildirim Asli , Provence Sydney R. , Norton Dennis T. , Boggess Thomas F. , Prineas John P.
Published: February 2013

Here, the authors report on the occurrence, cause, and elimination of pyramidal defects in layers of GaSb grown by molecular beam epitaxy on GaSb substrates. These defects are typically 3–8 nm high, 1–3 μm in diameter, and shaped like pyramids. Their occurrence in the growth of GaSb buffer layers can propagate into subsequent layers such as GaSb, GaInAsSb, and GaSb/InAs superlattices. Defects are nucleated during the early stages of growth after the thermal desorption of native oxide from the GaSb substrate. These defects grow into pyramids due to a repulsive Ehrlich–Schwoebel potential on atomic step edges leading to an upward adatom current. The defects reduce in density with growth of GaSb. The insertion of a thin AlAsSb layer into the early stages of the GaSb buffer increases the rate of elimination of the defects, resulting in a smooth surface within 500 nm. The acceleration of defect reduction is due to the temporary interruption of step-flow growth induced by the AlAsSb layer. This leads to a reduced isolation of the pyramids from the GaSb epitaxial layer and allows the pyramidal defects to smooth out.
Caught in the Web: Informed Consent for Online Health Research
Authors: Vayena Effy , Mastroianni Anna , Kahn Jeffrey
Published: February 2013

Context-specific informed consent for Web-based health research can promote a dynamic research enterprise and maintain the public trust.
Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction
Authors: Seif-Naraghi Sonya B. , Singelyn Jennifer M. , Salvatore Michael A. , Osborn Kent G. , Wang Jean J. , Sampat Unatti , Kwan Oi Ling , Strachan G. Monet , Wong Jonathan , Schup-Magoffin Pamela J. , Braden Rebecca L. , Bartels Kendra , DeQuach Jessica A. , Preul Mark , Kinsey Adam M. , DeMaria Anthony N. , Dib Nabil , Christman Karen L.
Published: February 2013

A hydrogel derived from myocardial extracellular matrix mitigates negative left ventricular remodeling and improves heart function after myocardial infarction in pigs.
With Age Comes Improved Memory
Authors: Yipp Bryan G.
Published: February 2013

Specific immune memory develops with age in the absence of microbial exposure.