bluuebunny/crossref_metadata_2025 huggingface dataset:
PTEN deficiency in mast cells causes a mastocytosis-like proliferative disease that heightens allergic responses and vascular permeability
Authors: Furumoto Yasuko , Charles Nicolas , Olivera Ana , Leung Wai Hang , Dillahunt Sandra , Sargent Jennifer L. , Tinsley Kevin , Odom Sandra , Scott Eric , Wilson Todd M. , Ghoreschi Kamran , Kneilling Manfred , Chen Mei , Lee David M. , Bolland Silvia , Rivera Juan
Published: September 2011

Kit regulation of mast cell proliferation and differentiation has been intimately linked to the activation of phosphatidylinositol 3-OH kinase (PI3K). The activating D816V mutation of Kit, seen in the majority of mastocytosis patients, causes a robust activation of PI3K signals. However, whether increased PI3K signaling in mast cells is a key element for their in vivo hyperplasia remains unknown. Here we report that dysregulation of PI3K signaling in mice by deletion of the phosphatase and tensin homolog (Pten) gene (which regulates the levels of the PI3K product, phosphatidylinositol 3,4,5-trisphosphate) caused mast cell hyperplasia and increased numbers in various organs. Selective deletion of Pten in the mast cell compartment revealed that the hyperplasia was intrinsic to the mast cell. Enhanced STAT5 phosphorylation and increased expression of survival factors, such as Bcl-XL, were observed in PTEN-deficient mast cells, and these were further enhanced by stem cell factor stimulation. Mice carrying PTEN-deficient mast cells also showed increased hypersensitivity as well as increased vascular permeability. Thus, Pten deletion in the mast cell compartment results in a mast cell proliferative phenotype in mice, demonstrating that dysregulation of PI3K signals is vital to the observed mast cell hyperplasia.
CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation
Authors: de Wit Jelle , Souwer Yuri , van Beelen Astrid J. , de Groot Rosa , Muller Femke J. M. , Klaasse Bos Hanny , Jorritsma Tineke , Kapsenberg Martien L. , de Jong Esther C. , van Ham S. Marieke
Published: September 2011

IL-17–producing CD4+ T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via the CD5 or CD6 lymphocyte receptors forms a superior pathway for human Th17-priming. In the presence of the Th17-promoting cytokines IL-1β, IL-6, IL-23, and transforming growth factor-β (TGF-β), CD5 costimulation induces more Th17 cells that produce higher amounts of IL-17, which is preceded by prolonged activation of signal transducer and activator of transcription 3 (STAT3), a key regulator in Th17 differentiation, and enhanced levels of the IL-17–associated transcription factor retinoid-related orphan receptor-γt (ROR-γt). Strikingly, these Th17-promoting signals critically depend on CD5-induced elevation of IL-23 receptor (IL-23R) expression. The present data favor the novel concept that alternative costimulation via CD5, rather than classic costimulation via CD28, primes naive T cells for stable Th17 development through promoting the expression of IL-23R.
HIV envelope-mediated, CCR5/α4β7-dependent killing of CD4-negative γδ T cells which are lost during progression to AIDS
Authors: Li Haishan , Pauza C. David
Published: September 2011

HIV infects and replicates in CD4+ T cells but effects on host immunity and disease also involve depletion, hyper-activation, and modification of CD4-negative cell populations. In particular, the depletion of CD4-negative γδ T cells is common to all HIV+ individuals. We found that soluble or cell-associated envelope glycoproteins from CCR5-tropic strains of HIV could bind, activates the p38-caspase pathway, and induce the death of γδ cells. Envelope binding requires integrin α4β7 and chemokine receptor CCR5 which are at high levels and form a complex on the γδ T cell membrane. This receptor complex facilitated V3 loop binding to CCR5 in the absence of CD4-induced conformational changes. Cell death was increased by antigen stimulation after exposure to envelope glycoprotein. Direct signaling by envelope glycoprotein killed CD4-negative γδ T cells and reproduced a defect observed in all patients with HIV disease.
A polymorphism in the leptin gene promoter is associated with anemia in patients with HIV disease
Authors: Vanasse Gary J. , Jeong Jee-Yeong , Tate Janet , Bathulapalli Harini , Anderson Damon , Steen Hanno , Fleming Mark , Mattocks Kristin , Telenti Amalio , Fellay Jacques , Justice Amy C. , Berliner Nancy
Published: September 2011

To study factors associated with anemia and its effect on survival in HIV-infected persons treated with modern combined antiretroviral therapy (cART), we characterized the prevalence of anemia in the Veterans Aging Cohort Study (VACS) and used a candidate gene approach to identify proinflammatory gene single nucleotide polymorphisms (SNPs) associated with anemia in HIV disease. The study comprised 1597 HIV+ and 865 HIV− VACS subjects with DNA, blood, and annotated clinical data available for analysis. Anemia was defined according to World Health Organization criteria (hemoglobin < 13 g/dL and < 12 g/dL in men and women, respectively). The prevalence of anemia in HIV+ and HIV− subjects was 23.1% and 12.9%, respectively. Independent of HIV status, anemia was present in 23.4% and 8% in blacks and whites, respectively. Analysis of our candidate genes revealed that the leptin −2548 G/A SNP was associated with anemia in HIV+, but not HIV−, patients, with the AA and AG genotypes significantly predicting anemia (P < .003 and P < .039, respectively, logistic regression). This association was replicated in an independent cohort of HIV+ women. Our study provides novel insight into the association between genetic variability in the leptin gene and anemia in HIV+ individuals.
Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias
Authors: Nicolini Franck Emmanuel , Basak Grzegorz W. , Soverini Simona , Martinelli Giovanni , Mauro Michael J. , Müller Martin C. , Hochhaus Andreas , Chuah Charles , Dufva Inge H. , Rege-Cambrin Giovanna , Saglio Giuseppe , Michallet Mauricette , Labussière Hélène , Morisset Stéphane , Hayette Sandrine , Etienne Gabriel , Olavarria Eduardo , Zhou Wei , Peter Senaka , Apperley Jane F. , Cortes Jorge
Published: September 2011

T315I+ Philadelphia chromosome–positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABLT315I mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome–positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABLT315I mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors.
Symmetric strong vector quasiequilibrium problems in Hausdorff locally convex spaces
Authors: Chen Bin , Huang Nan-jing , Cho Yeol Je
Published: September 2011

In this article, a new symmetric strong vector quasiequilibrium problem in real locally convex Hausdorff topological vector spaces is introduced and studied. An existence theorem of solutions for the symmetric strong vector quasiequilibrium problem by using Kakutani-Fan-Glicksberg fixed point theorem is obtained. Moreover, the closedness of the solution set for this problem is derived. The results presented in this article improve and extend some known results according to Long et al. [Math. Comput. Model. 47, 445-451 (2008)], Somyot and Kanokwan [Fixed Point Theory Appl. doi:10.1155/2011/475121], and Wang et al. [Bull. Malays. Math. Sci. Soc. http://www.emis.de/journals/BMMSS/pdf/acceptedpapers/2009-11-022_R1.pdf].

2000 MSC: 49J40; 90C29.
Coma in fatal adult human malaria is not caused by cerebral oedema
Authors: Medana Isabelle M , Day Nicholas PJ , Sachanonta Navakanit , Mai Nguyen TH , Dondorp Arjen M , Pongponratn Emsri , Hien Tran T , White Nicholas J , Turner Gareth DH
Published: September 2011

Background

The role of brain oedema in the pathophysiology of cerebral malaria is controversial. Coma associated with severe Plasmodium falciparum malaria is multifactorial, but associated with histological evidence of parasitized erythrocyte sequestration and resultant microvascular congestion in cerebral vessels. To determine whether these changes cause breakdown of the blood-brain barrier and resultant perivascular or parenchymal cerebral oedema, histology, immunohistochemistry and image analysis were used to define the prevalence of histological patterns of oedema and the expression of specific molecular pathways involved in water balance in the brain in adults with fatal falciparum malaria.

Methods

The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection.

Results

The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02).

Conclusions

Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.
Hop-distance relationship analysis with quasi-UDG model for node localization in wireless sensor networks
Authors: Gao Deyun , Chen Ping , Foh Chuan Heng , Niu Yanchao
Published: September 2011

In wireless sensor networks (WSNs), location information plays an important role in many fundamental services which includes geographic routing, target tracking, location-based coverage, topology control, and others. One promising approach in sensor network localization is the determination of location based on hop counts. A critical priori of this approach that directly influences the accuracy of location estimation is the hop-distance relationship. However, most of the related works on the hop-distance relationship assume the unit-disk graph (UDG) model that is unrealistic in a practical scenario. In this paper, we formulate the hop-distance relationship for quasi-UDG model in WSNs where sensor nodes are randomly and independently deployed in a circular region based on a Poisson point process. Different from the UDG model, quasi-UDG model has the non-uniformity property for connectivity. We derive an approximated recursive expression for the probability of the hop count with a given geographic distance. The border effect and dependence problem are also taken into consideration. Furthermore, we give the expressions describing the distribution of distance with known hop counts for inner nodes and those suffered from the border effect where we discover the insignificance of the border effect. The analytical results are validated by simulations showing the accuracy of the employed approximation. Besides, we demonstrate the localization application of the formulated relationship and show the accuracy improvement in the WSN localization.
Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK
Authors: Lofgren Kristopher A , Ostrander Julie H , Housa Daniel , Hubbard Gregory K , Locatelli Alessia , Bliss Robin L , Schwertfeger Kathryn L , Lange Carol A
Published: September 2011

Introduction

Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear.

Methods

We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents.

Results

Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. Consistent with delayed involution, mammary glands of transgenic animals displayed decreased STAT3 phosphorylation, a marker of early-stage involution. Notably, p38 MAPK, a pro-survival signaling mediator downstream of Brk, was activated in mammary glands of Brk transgenic relative to wt mice. Brk-dependent signaling to p38 MAPK was recapitulated by Brk overexpression in the HC11 murine mammary epithelial cell (MEC) line and human MEC, while Brk knock-down in breast cancer cells blocked EGF-stimulated p38 signaling. Additionally, human or mouse MECs expressing Brk exhibited increased anchorage-independent survival and resistance to doxorubicin. Finally, breast tumor biopsies were subjected to IHC analysis for co-expression of Brk and phospho-p38 MAPK; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK.

Conclusions

These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways.
Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post-hoc analysis of a double-blind, randomized, placebo-controlled study
Authors: Devlin John W , Skrobik Yoanna , Riker Richard R , Hinderleider Eric , Roberts Russel J , Fong Jeffrey J , Ruthazer Robin , Hill Nicholas S , Garpestad Erik
Published: September 2011

Introduction

We hypothesized that delirium symptoms may respond differently to antipsychotic therapy. The purpose of this paper was to retrospectively compare duration and time to first resolution of individual delirium symptoms from the database of a randomized, double-blind, placebo-controlled study comparing quetiapine (Q) or placebo (P), both with haloperidol rescue, for critically ill patients with delirium.

Methods

Data for 10 delirium symptoms from the eight-domain, intensive care delirium screening checklist (ICDSC) previously collected every 12 hours were extracted for 29 study patients. Data between the Q and P groups were compared using a cut-off P- value of ≤0.10 for this exploratory study.

Results

Baseline ICDSC scores (5 (4 to 7) (Q) vs 5 (4 to 6)) (median, interquartile range (IQR)) and % of patients with each ICDSC symptom were similar in the two groups (all P > 0.10). Among patients with the delirium symptom at baseline, use of Q may lead to a shorter time (days) to first resolution of symptom fluctuation (4 (Q) vs. 14, P = 0.004), inattention (3 vs. 8, P = .10) and disorientation (2 vs. 10, P = 0.10) but a longer time to first resolution of agitation (3 vs. 1, P = 0.04) and hyperactivity (5 vs. 1, P = 0.07). Among all patients, Q-treated patients tended to spend a smaller percent of time with inattention (47 (0 to 67) vs. 78 (43 to 100), P = 0.025), hallucinations (0 (0 to 17) vs. 28 (0 to 43), P = 0.10) and symptom fluctuation (47 (19 to 67) vs. 89 (33 to 00), P = 0.04] and there was a trend for Q-treated patients to spend a greater percent of time at an appropriate level of consciousness (26% (13 to 63%) vs. 14% (0 to 33%), P = 0.17].

Conclusions

Our exploratory analysis suggests that quetiapine may resolve several intensive care unit (ICU) delirium symptoms faster than the placebo. Individual symptom resolution appears to differ in association with the pharmacologic intervention (that is, P vs Q, both with as needed haloperidol). Future studies evaluating antipsychotics in ICU patients with delirium should measure duration and resolution of individual delirium symptoms and their relation to long-term outcomes.
An investigation of side-effects and efficacy of foam-based sclerotherapy with carbon dioxide or room air in the treatment of reticular leg veins: a pilot study
Authors: Peterson J D , Goldman M P
Published: September 2011

Objectives

In sclerotherapy, carbon dioxide (CO2) or room air can be employed by phlebologists for foam creation. We compared room air (RA) and carbon dioxide in treating reticular leg veins with foam sclerotherapy.

Methods

Twenty patients were randomly treated with RA- or CO2-created sodium tetradecyl sulphate (STS) foam. Concentration and volume of STS, side-effects and efficacy were determined.

Results

There was no difference in the efficacy, local side-effects or distant side-effects between RA and CO2 foam in the treatment of reticular leg veins. The total volume of foam sclerosant required for treatment was greater with CO2 compared with RA ( P value = 0.01).

Conclusion

No differences were found in efficacy or side-effects between RA- and CO2-foam sclerotherapy for reticular leg veins. CO2 foam's shorter half-life was hypothesized to be responsible for larger total volumes of CO2 foam sclerosant.
Localized superficial femoral vein thrombosis coupled with iatrogenic arteriovenous fistulas presenting as pulmonary emboli
Authors: De Santis F , Zywica M , Mani G , Martini G
Published: September 2011

Introduction

‘Localized’ femoral vein thrombosis (FVT) is a relatively rare condition usually associated with traumas, external compression or iatrogenic etiologies and the consequence can be pulmonary embolism.

Report

This is the case of a 46-year-old woman who presented with pulmonary emboli secondary to ‘localized’ superficial FVT, coupled with post-puncture arteriovenous fistulas (AVFs), two days after trans-femoral vein radio-frequency cardiac ablation. After placing a temporary IVC-filter, the AVFs were sutured directly while the residual FVT was treated conservatively.

Discussion

Close local monitoring and adequate medical and surgical management are mandatory to avoid possible dangerous complications, also in apparently ‘low-risk’ iatrogenic AVFs.
Clinical features of snake bite in southern Iran
Authors: Sagheb Mohammad Mahdi , Sharifian Maryam , Moini Maryam , Salehi Oveis
Published: September 2011

We attempt to describe the clinical features of venomous snake bites in southern Iran. In this study the complication rate has been markedly reduced compared with other developing countries. The availability of antivenom at primary health-care centres and rapid transportation facilities may change the morbidity associated with snake bites.
Three unusual presentations of plasmodium vivax malaria
Authors: Sonkar Satyendra Kumar , Uniyal Ravi , Sonkar Gyanendra Kumar
Published: September 2011

We present three cases of unusual and complicated malaria caused by Plasmodium vivax. Parenteral artemisinin derivatives or quinine should be used, irrespective of chloroquine sensitivity, for treatment of severe malaria.
Fibulin-1 Is a Marker for Arterial Extracellular Matrix Alterations in Type 2 Diabetes
Authors: Cangemi Claudia , Skov Vibe , Poulsen Michael Kjaer , Funder Jonas , Twal Waleed O , Gall Mari-Anne , Hjortdal Vibeke , Jespersen Marie Louise , Kruse Torben A , Aagard Jan , Parving Hans-Henrik , Knudsen Steen , Høilund-Carlsen Poul-Flemming , Rossing Peter , Henriksen Jan Erik , Argraves William Scott , Rasmussen Lars Melholt
Published: September 2011

BACKGROUND

Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined.

METHODS

Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from (a) 70 patients scheduled for vascular surgery, (b) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and (c) 308 patients with type 2 diabetes, followed for 15 years.

RESULTS

The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 (P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A1c (P < 0.001), arterial stiffness indices including pulse pressure (P < 0.001), and carotid compliance (P = 0.004), as well as plasma N-terminal pro–B-type natriuretic peptide concentrations (P < 0.001) and were predictive of 15-year mortality (P = 0.013).

CONCLUSIONS

Fibulin-1 accumulates in the arterial wall and in plasma of patients with type 2 diabetes, and appears to be a factor associated with arterial extracellular matrix changes in type 2 diabetes.
The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses
Authors: Lenhard Miriam , Stieber Petra , Hertlein Linda , Kirschenhofer Angela , Fürst Sophie , Mayr Doris , Nagel Dorothea , Hofmann Karin , Krocker Katja , Burges Alexander
Published: September 2011

Cancer antigen 125 (CA125) is the best known single tumor marker for ovarian cancer (OC). We investigated whether the additional information of the human epididymis protein 4 (HE4) improves diagnostic accuracy.

We retrospectively analyzed preoperative sera of 109 healthy women, 285 patients with benign ovarian masses (cystadenoma: n=78, leimyoma: n=66, endometriosis: n=52, functional ovarian cysts: n=79, other: n=10), 16 low malignant potential (LMP) ovarian tumors and 125 OC (stage I: 22, II: 15, III: 78, IV: 10). CA125 was analyzed using the ARCHITECT system, HE4 using the ARCHITECT(a) system and EIA(e) technology additionally.

The lowest concentrations of CA125 and HE4 were observed in healthy individuals, followed by patients with benign adnexal masses and patients with LMP tumors and OC. The area under the curve (AUC) for the differential diagnosis of adnexal masses of CA125 alone was not significantly different to HE4 alone in premenopausal (CA125: 86.7, HE4(a): 82.6, HE4(e): 81.6% p>0.05) but significantly different in postmenopausal [CA125: 93.4 vs. HE4(a): 88.3 p=0.023 and vs. HE4(e): 87.8% p=0.012] patients. For stage I OC, HE4 as a single marker was superior to CA125, which was the best single marker in stage II-IV. The combination of CA125 and HE4 using risk of malignancy algorithm (ROMA) gained the highest sensitivity at 95% specificity for the differential diagnosis of adnexal masses [CA125: 70.9, HE4(a): 67.4, HE4(e): 66.0, ROMA(a): 76.6 and ROMA(e): 74.5%], especially in stage I OC [CA125: 27.3, HE4(a): 40.9, HE4(e): 40.9, ROMA(a): 45.5 and ROMA(e): 45.5%].

CA125 is still the best single marker in the diagnosis of OC. HE4 alone and even more the combined analysis of CA125 and HE4 using ROMA improve the diagnostic accuracy of adnexal masses, especially in early OC.
Chemical characterization of polymerized products formed in the reactions of matairesinol and pinoresinol with the stable radical 2,2-diphenyl-1-picrylhydrazyl
Authors: Smeds Annika I. , Eklund Patrik C. , Monogioudi Evanthia , Willför Stefan M.
Published: September 2011

Polymerization reactions of the lignans matairesinol and pinoresinol with the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) were studied. The reactions were rapid and almost quantitative. The molecular weight distribution (MWD) of the formed lignan dimers and polymers was determined by high-performance size-exclusion chromatography (HPSEC) combined with evaporative light-scattering detection (ELSD), and the compounds were characterized by HPLC-MS, pyrolysis-GC/MS, NMR, MALDI-ToF-MS, and GC-MS of the monomeric and dimeric units formed by KMnO4oxidation. The yield of high-MW polymers is higher for pinoresinol (69%) than for matairesinol (43%). According to the HPSEC-ELSD analyses, the MWD is also broader for the pinoresinol polymers. The latter seem to consist mainly of hepta-hexacontalignans (MW 2.5–21.4 kDa), whereas the matairesinol polymers are mainly penta-pentadecalignans (MW 1.8–5.3 kDa). The polymers seem to contain mainly unmodified lignan units linked by 5-5′ bonds.
Effect of ammonia addition to alkaline copper quaternary wood preservative solution on the distribution of copper complexes and leaching
Authors: Pankras Sedric , Cooper Paul A.
Published: September 2011

The effects of ammonia (NH3) addition to monoethanolamine (Mea)-based alkaline copper quaternary (ACQ) on the predicted distribution of cupric (Cu2+) species in solution and copper leaching from treated wood were investigated. Addition of ammonia in higher proportions reduced the amount of neutral copper-Mea complex at high pH and increased the amounts of divalent copper-NH3 complexes. At lower pH, the amounts of high-ligand copper-Mea complexes were reduced. These effects should promote better fixation and diminish copper leaching. However, ammonia addition also reduced the monovalent copper-Mea complex and the amount of copper fixed by precipitation at lower pH. This effect could, potentially, reduce fixation and leach resistance. Ammonia addition to the ACQ formulation from a Cu:Mea:NH3 ratio of 1:4:0 (normal Mea formulation, pH=9) to 1:4:2 (pH 10–10.2) and 1:4:4 (pH 10.4–10.5) did not significantly affect the amount of copper leached. However, a further increase in ammonia to 1:4:6 (pH 10.6–10.7) resulted in a significant reduction in copper leaching. At pH 9, an increase in the proportional amount of ammonia increased the amount of copper leached by reducing the amount of monovalent copper-Mea complex and increasing the divalent copper-NH3 complexes. Ammonia addition with a lower amount of Mea, 1:2.5:4 formulation (pH 10.5–10.7), significantly reduced copper leaching as a result of higher amounts of divalent copper-NH3 complexes adsorbed at higher pH (higher cation exchange capacity) without compromising the amount of copper precipitated at lower pH.
Structure of oak wood from the Swedish warship Vasa revealed by X-ray scattering and microtomography
Authors: Svedström Kirsi , Bjurhager Ingela , Kallonen Aki , Peura Marko , Serimaa Ritva
Published: September 2011

The degradation of oak wood of the historical warship Vasa was studied, focusing on cellular structure by X-ray microtomography (μCT) and on the nanostructure of the cell wall by wide- and small-angle X-ray scattering (WAXS, SAXS). Solid samples [polyethylene glycol (PEG)-, impregnated and PEG-extracted] were submitted to X-ray analysis and the results compared to those of recent oak. The cellular structure of the Vasa oak was surprisingly well preserved at the micrometer level, according to the μCT images. As revealed by WAXS, the fraction of crystalline cellulose was lower in the Vasa samples compared with recent oak, but the average length and width of cellulose crystallites (25±2 nm and 3.0±0.1 nm, respectively), and the mean microfibril angles (4–9°), showed no significant differences. Accordingly, the crystalline parts of cellulose microfibrils are well preserved in the Vasa oak. The SAXS results indicated a declined short-range order between the cellulose microfibrils and a higher porosity of the Vasa oak compared with recent oak, which may be explained by modification of the hemicellulose-lignin matrix.
Evidence that release of internal stress contributes to drying strains of wood
Authors: Clair Bruno
Published: September 2011

Wood shrinks during drying, with the departure of bond water. Along the fibre direction, the magnitude of this shrinkage is mainly governed by the orientation of cellulose microfibrils (MF) in the cell wall. However, tension wood has an unexpectedly high longitudinal shrinkage considering the fact that MFs are oriented nearly parallel to the cell direction. This effect is thought to be caused by the gel collapse of the G-layer; however, some species producing a tension wood without a G-layer also exhibit a higher longitudinal shrinkage than normal wood. The aim of this study is to analyse the contribution of maturation stresses to drying shrinkage. Longitudinal and tangential drying shrinkage of tension wood and normal wood were measured on two sets of matched chestnut wood samples. The first set was directly oven-dried, whereas on the second set, a hygrothermal treatment released the maturation stress before oven-drying. The analysis of the strains during each step of the procedure revealed that part of the drying shrinkage is caused by the release of internal stresses during the desorption process. Finally, a tentative schematic model is proposed, taking into account the cumulative contributions to longitudinal drying shrinkage.
Trisomic and Allelic Differences Influence Phenotypic Variability During Development of Down Syndrome Mice
Authors: Deitz Samantha L , Roper Randall J
Published: September 2011

Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the “Down syndrome critical region” or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS.
Experimental Designs for Robust Detection of Effects in Genome-Wide Case–Control Studies
Authors: Ball Roderick D
Published: September 2011

In genome-wide association studies hundreds of thousands of loci are scanned in thousands of cases and controls, with the goal of identifying genomic loci underpinning disease. This is a challenging statistical problem requiring strong evidence. Only a small proportion of the heritability of common diseases has so far been explained. This “dark matter of the genome” is a subject of much discussion. It is critical to have experimental design criteria that ensure that associations between genomic loci and phenotypes are robustly detected. To ensure associations are robustly detected we require good power (e.g., 0.8) and sufficiently strong evidence [i.e., a high Bayes factor (e.g., 106, meaning the data are 1 million times more likely if the association is real than if there is no association)] to overcome the low prior odds for any given marker in a genome scan to be associated with a causal locus. Power calculations are given for determining the sample sizes necessary to detect effects with the required power and Bayes factor for biallelic markers in linkage disequilibrium with causal loci in additive, dominant, and recessive genetic models. Significantly stronger evidence and larger sample sizes are required than indicated by traditional hypothesis tests and power calculations. Many reported putative effects are not robustly detected and many effects including some large moderately low-frequency effects may remain undetected. These results may explain the dark matter in the genome. The power calculations have been implemented in R and will be available in the R package ldDesign.
Drug-Sensitive DNA Polymerase δ Reveals a Role for Mismatch Repair in Checkpoint Activation in Yeast
Authors: Reha-Krantz Linda J , Siddique Md Shahjahan P , Murphy Kelly , Tam Andrea , O’Carroll Michelle , Lou Sam , Schultz Amy , Boone Charles
Published: September 2011

We have used a novel method to activate the DNA damage S-phase checkpoint response in Saccharomyces cerevisiae to slow lagging-strand DNA replication by exposing cells expressing a drug-sensitive DNA polymerase δ (L612M-DNA pol δ) to the inhibitory drug phosphonoacetic acid (PAA). PAA-treated pol3-L612M cells arrest as large-budded cells with a single nucleus in the bud neck. This arrest requires all of the components of the S-phase DNA damage checkpoint: Mec1, Rad9, the DNA damage clamp Ddc1-Rad17-Mec3, and the Rad24-dependent clamp loader, but does not depend on Mrc1, which acts as the signaling adapter for the replication checkpoint. In addition to the above components, a fully functional mismatch repair system, including Exo1, is required to activate the S-phase damage checkpoint and for cells to survive drug exposure. We propose that mismatch repair activity produces persisting single-stranded DNA gaps in PAA-treated pol3-L612M cells that are required to increase DNA damage above the threshold needed for checkpoint activation. Our studies have important implications for understanding how cells avoid inappropriate checkpoint activation because of normal discontinuities in lagging-strand replication and identify a role for mismatch repair in checkpoint activation that is needed to maintain genome integrity.
Emergent Neutrality in Adaptive Asexual Evolution
Authors: Schiffels Stephan , Szöllősi Gergely J , Mustonen Ville , Lässig Michael
Published: September 2011

In nonrecombining genomes, genetic linkage can be an important evolutionary force. Linkage generates interference interactions, by which simultaneously occurring mutations affect each other’s chance of fixation. Here, we develop a comprehensive model of adaptive evolution in linked genomes, which integrates interference interactions between multiple beneficial and deleterious mutations into a unified framework. By an approximate analytical solution, we predict the fixation rates of these mutations, as well as the probabilities of beneficial and deleterious alleles at fixed genomic sites. We find that interference interactions generate a regime of emergent neutrality: all genomic sites with selection coefficients smaller in magnitude than a characteristic threshold have nearly random fixed alleles, and both beneficial and deleterious mutations at these sites have nearly neutral fixation rates. We show that this dynamic limits not only the speed of adaptation, but also a population’s degree of adaptation in its current environment. We apply the model to different scenarios: stationary adaptation in a time-dependent environment and approach to equilibrium in a fixed environment. In both cases, the analytical predictions are in good agreement with numerical simulations. Our results suggest that interference can severely compromise biological functions in an adapting population, which sets viability limits on adaptive evolution under linkage.
The Maize High-Lysine Mutantopaque7Is Defective in an Acyl-CoA Synthetase-Like Protein
Authors: Miclaus Mihai , Wu Yongrui , Xu Jian-Hong , Dooner Hugo K , Messing Joachim
Published: September 2011

Maize (Zea mays) has a large class of seed mutants with opaque or nonvitreous endosperms that could improve the nutritional quality of our food supply. The phenotype of some of them appears to be linked to the improper formation of protein bodies (PBs) where zein storage proteins are deposited. Although a number of genes affecting endosperm vitreousness have been isolated, it has been difficult to clone opaque7 (o7), mainly because of its low penetrance in many genetic backgrounds. The o7-reference (o7-ref) mutant arose spontaneously in a W22 inbred, but is poorly expressed in other lines. We report here the isolation of o7 with a combination of map-based cloning and transposon tagging. We first identified an o7 candidate gene by map-based cloning. The putative o7-ref allele has a 12-bp in-frame deletion of codons 350–353 in a 528-codon-long acyl-CoA synthetase-like gene (ACS). We then confirmed this candidate gene by generating another mutant allele from a transposon-tagging experiment using the Activator/Dissociation (Ac/Ds) system in a W22 background. The second allele, isolated from ∼1 million gametes, presented a 2-kb Ds insertion that resembles the single Ds component of double-Ds, McClintock’s original Dissociation element, at codon 496 of the ACS gene. PBs exhibited striking membrane invaginations in the o7-ref allele and a severe number reduction in the Ds-insertion mutant, respectively. We propose a model in which the ACS enzyme plays a key role in membrane biogenesis, by taking part in protein acylation, and that altered PBs render the seed nonvitreous.
3D contaminant flow imaging in transparent granular porous media
Authors: Serrano R Fernández. , Iskander M. , Tabe K.
Published: September 2011

A physical model based on transparent soil technology is presented as a novel laboratory tool for ground contamination research. The model aims to reproduce both unsaturated and saturated conditions within a Spanish soil formation known as Miga sand. A soil surrogate made of a water-absorbing polymeric gel was employed. Multi-phase flow from a leaking underground storage tank was simulated in both saturated and unsaturated conditions in order to illustrate the usefulness of the technique in simulating a hypothetical spill of a light non-aqueous phase liquid under well-controlled test conditions. The plume observed was found to be spatially variable. The technique permits, for the first time, the simulation of specific grain size distributions in a transparent soil surrogate and visualization of plume development in three dimensions. Preliminary results indicate that the model is a potentially powerful tool for visualising pollutant transport in porous media. A brief description of the test setup, and a summary of the advantages, limitations, and prospective applications are presented.
Explicit Solution for Time-Fractional Batch Reactor System
Authors: Khan Najeeb Alam , Jamil Muhammad , Ara Asmat , Das Subir
Published: September 2011

In this paper, the new homotopy perturbation method (NHPM) has been successively applied for finding approximate analytical solutions of the fractional order batch reactor system. An approximate analytical solution for the concentration of reactants and products that is valid for a time interval. The approximate analytical procedure is depends only on two components. The behavior of the solution and effects of different parameters and fractional index are shown graphically. Numerical solutions of ordinary batch reactor system verify our approximate solution with good agreement.
Kinetic and Thermodynamic Modeling of Cd+2 and Ni+2 Biosorption by Raw Chicken Feathers
Authors: Reynel-Avila Hilda E. , de la Rosa Guadalupe , Rojas-Mayorga Cintia K. , Cano-Aguilera Irene , Bonilla-Petriciolet Adrian
Published: September 2011

Batch experiments were performed to model kinetic and thermodynamic data for Cd+2 and Ni+2 biosorption by raw chicken feathers (CFs) under different conditions. Results indicated that Cd+2 and Ni+2 sorption onto CFs occurred on the external surface of the biosorbent. Ion removal increased with pH, whereas both endothermic and exothermic stages where observed depending on temperature. Our calculated thermodynamic parameters showed that, below the temperature of 30°C, the metal uptake of Cd+2 and Ni+2 ions may be mainly controlled by a chemisorption process. However, for temperatures higher than 30°C, it is likely that sorption of both metals onto CFs is caused by a combination of both physical and chemical processes, especially for Ni+2 ions. Maximum sorption capacities were of 0.039 (Cd+2 ) and 0.065 mmol/g (Ni+2) at pH 5 and 30°C. Using 0.1 M HCl or CH3COOH as desorbing agents, approximately a 50% recovery for Cd+2 was achieved. The pseudo-second order and the general rate law models best fit the sorption kinetics data. The equilibrium metal uptake data was best described by the Sips isotherm.
Aberrant Accumulation of Undifferentiated Myeloid Cells in the Adipose Tissue of CCR2-Deficient Mice Delays Improvements in Insulin Sensitivity
Authors: Gutierrez Dario A. , Kennedy Arion , Orr Jeb S. , Anderson Emily K. , Webb Corey D. , Gerrald William K. , Hasty Alyssa H.
Published: September 2011

OBJECTIVE

Mice with CCR2 deficiency are protected from insulin resistance but only after long periods of high-fat diet (HFD) feeding, despite the virtual absence of circulating inflammatory monocytes. We performed a time course study in mice with hematopoietic and global CCR2 deficiency to determine adipose tissue–specific mechanisms for the delayed impact of CCR2 deficiency on insulin resistance.

RESEARCH DESIGN AND METHODS

Mice with global or hematopoietic CCR2 deficiency (CCR2−/− and BM-CCR2−/−, respectively) and wild-type controls (CCR2+/+ and BM-CCR2+/+, respectively) were placed on an HFD for 6, 12, and 20 weeks. Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed.

RESULTS

Flow cytometry analysis showed that two different populations of F4/80+ myeloid cells (CD11bloF4/80lo and CD11bhiF4/80hi) accumulated in the adipose tissue of CCR2−/− and BM-CCR2−/− mice after 6 and 12 weeks of HFD feeding, whereas only the CD11bhiF4/80hi population was detected in the CCR2+/+ and BM-CCR2+/+ controls. After 20 weeks of HFD feeding, the CD11bloF4/80lo cells were no longer present in the adipose tissue of CCR2−/− mice, and only then were improvements in adipose tissue inflammation detected. Gene expression and histological analysis of the CD11bloF4/80lo cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11bloF4/80lo cells are transiently found in wild-type mice, but CCR2 deficiency leads to the aberrant accumulation of these cells in adipose tissue.

CONCLUSIONS

The discovery of this novel adipose tissue monocytic cell population provides advances toward understanding the pleiotropic role of CCR2 in monocyte/macrophage accumulation and regulation of adipose tissue inflammation.
APPL1 Counteracts Obesity-Induced Vascular Insulin Resistance and Endothelial Dysfunction by Modulating the Endothelial Production of Nitric Oxide and Endothelin-1 in Mice
Authors: Wang Yi , Cheng Kenneth K.Y. , Lam Karen S.L. , Wu Donghai , Wang Yu , Huang Yu , Vanhoutte Paul M. , Sweeney Gary , Li Yiming , Xu Aimin
Published: September 2011

OBJECTIVE

Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)–dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells.

RESEARCH DESIGN AND METHODS

Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1’s physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells.

RESULTS

Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1–dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal–related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.

CONCLUSIONS

APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.