bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels
Authors: Zhou Pingzheng , Yu Haibo , Gu Min , Nan Fa-jun , Gao Zhaobing , Li Min
Published: May 2013

Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1–KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP
2
) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP
2
may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP
2
site within the S4–S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP
2
.
Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor
Authors: Wiley Devin T. , Webster Paul , Gale Aaron , Davis Mark E.
Published: May 2013

Receptor-mediated transcytosis across the blood–brain barrier (BBB) may be a useful way to transport therapeutics into the brain. Here we report that transferrin (Tf)-containing gold nanoparticles can reach the brain parenchyma from systemic administration in mice through a receptor-mediated transcytosis pathway. This transport is aided by tuning the nanoparticle avidity to Tf receptor (TfR), which is correlated with nanoparticle size and total amount of Tf decorating the nanoparticle surface. Nanoparticles of both 45 nm and 80 nm diameter reach the brain parenchyma, and their accumulation there (visualized by silver enhancement light microscopy in combination with transmission electron microscopy imaging) is observed to be dependent on Tf content (avidity); nanoparticles with large amounts of Tf remain strongly attached to brain endothelial cells, whereas those with less Tf are capable of both interacting with TfR on the luminal side of the BBB and detaching from TfR on the brain side of the BBB. The requirement of proper avidity for nanoparticles to reach the brain parenchyma is consistent with recent behavior observed with transcytosing antibodies that bind to TfR.
p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Authors: Davalos Albert R. , Kawahara Misako , Malhotra Gautam K. , Schaum Nicholas , Huang Jiahao , Ved Urvi , Beausejour Christian M. , Coppe Jean-Philippe , Rodier Francis , Campisi Judith
Published: May 2013

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.
The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A
Authors: Kress Elsa , Schwager Françoise , Holtackers René , Seiler Jonas , Prodon François , Zanin Esther , Eiteneuer Annika , Toya Mika , Sugimoto Asako , Meyer Hemmo , Meraldi Patrick , Gotta Monica
Published: May 2013

Coordination of cell cycle events in space and time is crucial to achieve a successful cell division. Here, we demonstrate that UBXN-2, a substrate adaptor of the AAA ATPase Cdc48/p97, is required to coordinate centrosome maturation timing with mitosis. In UBXN-2–depleted Caenorhabditis elegans embryos, centrosomes recruited more AIR-1 (Aurora A), matured precociously, and alignment of the mitotic spindle with the axis of polarity was impaired. UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 and the spindle alignment defect was partially rescued by co-depleting AIR-1, indicating that UBXN-2 controls these processes via AIR-1. Similarly, depletion in human cells of the UBXN-2 orthologues p37/p47 resulted in an accumulation of Aurora A at centrosomes and a delay in centrosome separation. The latter defect was also rescued by inhibiting Aurora A. We therefore postulate that the role of this adaptor in cell cycle regulation is conserved.
Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2
Authors: Sitrin Jonathan , Ring Aaron , Garcia K. Christopher , Benoist Christophe , Mathis Diane
Published: May 2013

Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK–T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4+ T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4+ T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets.
The Eisenstein family
Authors: Coleman Robert
Published: May 2013

Based on the work of Buzzard, Kilford, and Roe, we state a general conjecture about the family of overconvergent Eisenstein series.
On the Kobayashi hyperbolicity of certain tube domains
Authors: Huckleberry Alan , Isaev Alexander
Published: May 2013

In an article from 2008 the second author introduced three families of tube domains in

C

2

\mathbb {C}^2

with holomorphic automorphism group isomorphic to

R

⋉

R

2

\mathbb {R}\ltimes \mathbb {R}^2

and envelope of holomorphy equal to

C

2

\mathbb {C}^2

. In the present paper we show that every domain in each of these families is Kobayashi-hyperbolic.
Galectin‐3 in heart failure with preserved ejection fraction
Authors: de Boer Rudolf A. , Edelmann Frank , Cohen‐Solal Alain , Mamas Mamas A. , Maisel Alan , Pieske Burkert
Published: May 2013

In the last decades it has been appreciated that many patients with heart failure (HF) suffer from HF with preserved ejection fraction (HFpEF). The diagnosis and treatment of HFpEF is difficult, as we lack specific markers of the disease and no specific treatments have been identified. Galectin‐3 has a strong relationship to several aspects of the pathophysiology of HF, especially myocardial fibrosis, the transition from compensated to decompensated HF, and co‐morbidities such as renal disease and diabetes. Many of these traits are very commonly observed in patients with HFpEF, and this suggests that galectin‐3 may be particularly important and useful in the study of HFpEF. This review summarizes our knowledge of the role of galectin‐3 in fibrosis, specifically in experimental models of HF and HFpEF. Galectin‐3 may be a marker and also a causal factor, and experimental studies suggested that galectin‐3 may be a target for therapy in HFpEF. The detrimental effects of aldosterone may, in part, be conferred via galectin‐3, and there are data to suggest that aldosterone blockers are of more benefit in patients with high levels of galectin‐3. Furthermore, the relationship of galectin‐3 to clinical correlates of developing HFpEF in human subjects is discussed, and the association between increased levels of galectin‐3 and new‐onset HF and mortality in the general population is highlighted. Additionally, the usefulness of galectin‐3 in patients with established HFpEF is described. We conclude that galectin‐3 may be useful for early detection, phenotyping, risk stratification, and therapeutic targeting of individuals with early or established HFpEF in which fibrosis is a major contributor to the disease. Finally, we propose areas of further research that should validate the role of galectin‐3 in HFpEF.
Functional anatomy of distant-acting mammalian enhancers
Authors: Dickel D. E. , Visel A. , Pennacchio L. A.
Published: May 2013

Transcriptional enhancers are a major class of functional element embedded in the vast non-coding portion of the human genome. Acting over large genomic distances, enhancers play critical roles in the tissue and cell type-specific regulation of genes, and there is mounting evidence that they contribute to the aetiology of many human diseases. Methods for genome-wide mapping of enhancer regions are now available, but the functional architecture contained within human enhancer elements remains unclear. Here, we review recent approaches aimed at understanding the functional anatomy of individual enhancer elements, using systematic qualitative and quantitative assessments of mammalian enhancer variants in cultured cells andin vivo. These studies provide direct insight into common architectural characteristics of enhancers including the presence of multiple transcription factor-binding sites and the mixture of both transcriptionally activating and repressing domains within the same enhancer. Despite such progress in understanding the functional composition of enhancers, the inherent complexities of enhancer anatomy continue to limit our ability to predict the impact of sequence changes onin vivoenhancer function. While providing an initial glimpse into the mutability of mammalian enhancers, these observations highlight the continued need for experimental enhancer assessment as genome sequencing becomes routine in the clinic.
CTCF: the protein, the binding partners, the binding sites and their chromatin loops
Authors: Holwerda Sjoerd Johannes Bastiaan , de Laat Wouter
Published: May 2013

CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.
Production of food bodies on the reproductive organs of myrmecophytic Macaranga species (Euphorbiaceae): effects on interactions with herbivores and pollinators
Authors: Yamasaki Eri , Inui Yoko , Sakai Shoko
Published: May 2013

In protective ant–plant mutualisms, plants offer ants food (such as extrafloral nectar and/or food bodies) and ants protect plants from herbivores. However, ants often negatively affect plant reproduction by deterring pollinators. The aggressive protection that mutualistic ants provide to some myrmecophytes may enhance this negative effect in comparison to plant species that are facultatively protected by ants. Because little is known about the processes by which myrmecophytes are pollinated in the presence of ant guards, we examined ant interactions with herbivores and pollinators on plant reproductive organs. We examined eight myrmecophytic and three nonmyrmecophytic Macaranga species in Borneo. Most of the species studied are pollinated by thrips breeding in the inflorescences. Seven of eight myrmecophytic species produced food bodies on young inflorescences and/or immature fruits. Food body production was associated with increased ant abundance on inflorescences of the three species observed. The exclusion of ants from inflorescences of one species without food rewards resulted in increased herbivory damage. In contrast, ant exclusion had no effect on the number of pollinator thrips. The absence of thrips pollinator deterrence by ants may be due to the presence of protective bracteoles that limit ants, but not pollinators, from accessing flowers. This unique mechanism may account for simultaneous thrips pollination and ant defense of inflorescences.
Speaking to the Markets or to the People? A Discursive Institutionalist Analysis of the EU's Sovereign Debt Crisis
Authors: Schmidt Vivien A.
Published: May 2013

Research Highlights and Abstract

Uses ‘discursive institutionalism’ as its analytic framework, by focusing on the wide range of EU leaders’ ideas about the crisis and how they have communicated about them. Examines the different ways in which the scholarly literature analyzes those ideas and discursive interactions, and how they lead one to consider different aspects of the crisis. Argues that there are disconnects between what EU leaders say to one another in the ‘coordinative discourse’ at the EU level and between what they say about those agreements to the markets and to the people in the ‘communicative discourse’. Suggests, with regard to the markets specifically, that EU leaders have proposed solutions that were seen as too little too late; were considered to be the wrong solutions; or raised new contingencies that the markets themselves had not anticipated. Shows, with regard to the people, that EU leaders' communication of the wrong or misleading messages meant that national publics were often not prepared for the reform initiatives taken, and that this has often left the field open to the extremes of the right and left.

The EU's sovereign debt crisis is not just economic; it is also political, resulting from the failure of EU leaders to offer solutions that calm the markets and convince the people. These failures stem from problems with EU leaders' ideas about how to solve the crisis as well as their communication about them. That communication encompasses not just EU leaders talking to one another in negotiations of crisis solutions but also speaking to ‘the markets’ and to ‘the people’ about those solutions, all of which may interact in perverse ways. This article uses the analytic framework of ‘discursive institutionalism’ to consider the different forms, types, levels, rates and mechanisms of change in ideas followed by the EU leaders'discursive interactions in the ‘coordinative’ discourse and their ‘communicative discourse’ to the global markets and European publics. It uses a range of country cases, but in particular Germany and France, in illustration.
Beyond pregnancy – the neglected burden of mortality in young women of reproductive age in Bangladesh: a prospective cohort study
Authors: Labrique AB , Sikder SS , Wu L , Rashid M , Ali H , Ullah B , Shamim AA , Mehra S , Klemm R , Banu H , West KP , Christian P
Published: May 2013

Objective

To describe proportionate mortality and causes of death unrelated to pregnancy.

Design

Prospective cohort study.

Setting

Rural northwest Bangladesh.

Population

A cohort of 133 617 married women of reproductive age.

Methods

Verbal autopsies were conducted for women who died whilst under surveillance in the cohort trial. Physician‐assigned causes of death based on verbal autopsies were used to categorise deaths.

Main outcome measures

The proportion of deaths due to non‐communicable diseases, infectious diseases, injury or pregnancy.

Results

Of the 1107 deaths occurring among women between 2001 and 2007, 48% were attributed to non‐communicable diseases, 22% to pregnancy, 17% to infections, 9% to injury and 4% to other causes.

Conclusions

Although focus on pregnancy‐related mortality remains important, more attention is warranted on non‐communicable diseases among women of reproductive age.
PTSD risk associated with a functional DRD2 polymorphism in heroin‐dependent cases and controls is limited to amphetamine‐dependent individuals
Authors: Nelson Elliot C. , Heath Andrew C. , Lynskey Michael T. , Agrawal Arpana , Henders Anjali K. , Bowdler Lisa M. , Todorov Alexandre A. , Madden Pamela A. F. , Moore Elizabeth , Degenhardt Louisa , Martin Nicholas G. , Montgomery Grant W.
Published: May 2013

Posttraumatic stress disorder (PTSD), a pathologic response to severe stress, is a common co‐morbid disorder in substance‐dependent individuals. Evidence from twin studies suggests that PTSD is moderately heritable. Genetic association studies to date have reported a limited number of replicated findings. We conducted a candidate gene association study in trauma‐exposed individuals within the Comorbidity and Trauma Study's sample (1343 heroin‐dependent cases and 406 controls from economically disadvantaged neighborhoods). After data cleaning, the 1430 single nucleotide polymorphisms (SNPs) retained for analyses provided coverage of 72 candidate genes and included additional SNPs for which association was previously reported as well as 30 ancestry‐informative markers. We found a functional DRD2 promoter polymorphism (rs12364283) to be most highly associated with PTSD liability [odds ratio (OR) 1.65 (1.27–2.15); P = 1.58 × 10−4]; however, this association was not significant, with a stringent Bonferroni correction for multiple comparisons. The top hits include SNPs from other dopaminergic system genes: DRD2 DRD3, TH and DBH. Additional analyses revealed that the association involving rs12364283 is largely limited to amphetamine‐dependent individuals. Substantial risk is observed in amphetamine‐dependent individuals, with at least one copy of this SNP [OR 2.86 (1.92–4.27); P = 2.6 × 10−7]. Further analyses do not support extensive mediation of PTSD risk via self‐reported impulsivity (BIS total score). These findings suggest roles for impairment in inhibitory control in the pathophysiology of PTSD and raise questions about stimulant use in certain populations (e.g. those in combat).
Case–control study and mRNA expression analysis reveal the MyD88 gene is associated with digestive disorders in rabbit
Authors: Chen Shi‐Yi , Zhang Wen‐Xiu , Zhang Gong‐Wei , Peng Jin , Zhao Xiao‐Bing , Lai Song‐Jia
Published: May 2013

As in humans, significant associations between Toll‐like receptor 4 (TLR4) and digestive disorders have been identified in rabbit and dog. However, as an essential adaptor downstream of TLR4, the genetic variation of myeloid differentiating factor 88 (MyD88) and its association with digestive disorders have remained unknown. In this study, we detected 10 single nucleotide polymorphisms (SNPs) in the entire genomic region of rabbit MyD88. The genetic variation in susceptibility to digestive disorders for the only coding SNP (synonymous c.699T>C) was studied in Yaan (183 cases and 142 controls) and Chengdu populations (145 cases and 140 controls). A case–control association study revealed that individuals with the C allele had significant protection against digestive disorders in the Yaan population (OR = 0.71; 95% CI, 0.51–0.99; P < 0.05), the Chengdu population (OR = 0.55; 95% CI, 0.39–0.78; P < 0.01) and for joint analysis (OR = 0.62; 95% CI, 0.49–0.79; P < 0.01). We also experimentally induced digestive disorders by feeding a fiber‐deficient diet and found that increased susceptibility was significantly associated with higher MyD88 mRNA expression (P < 0.05). The lowest MyD88 mRNA expression was observed in individuals carrying the protective CC genotype. These results suggest that MyD88 is one of the most plausible candidate genes in relation to digestive disorders in rabbit. Further studies are required to explore the biological implications of MyD88 in the pathogenesis of digestive disorders.
Feasibility of multifocal intra‐ocular lens exchange and conversion to the bag‐in‐the‐lens implantation
Authors: Tassignon Marie‐José , Bartholomeeusen Ellen , Rozema Jos J. , Jongenelen Sien , Mathysen Danny G. P.
Published: May 2013

Purpose:  Our purpose was to evaluate the surgical outcome after intra‐ocular lens exchange in patients who presented impairing visual complaints after primary multifocal intra‐ocular lens (MIOL) implantation. In particular, the study was undertaken to look at the number of eyes that could be equipped with the bag‐in‐the‐lens (BIL) IOL after MIOL exchange.

Methods:  This series consisted of 30 eyes of 21 consecutive patients scheduled for MIOL exchange. In 15 out of the 30 eyes, IOL misalignment was measured on slit lamp anterior segment photo’s after defining the mathematical centres of the IOL optic, pupil and limbus.

Results:  Diffractive MIOL was more frequently explanted (25; 83%) when compared with refractive MIOL (4; 13%) and progressive optic IOL (1; 4%). In 21 out of the 30 eyes (70%) a bag‐in‐the‐lens could be implanted. In 7 out of the 30 eyes (23%), the capsule was not considered sufficiently stable to accommodate an IOL. An iris‐fixated IOL or a sulcus‐fixated IOL was then implanted. In 2 out of the 30 eyes (6%) the remaining capsular bag could accommodate a traditional lens‐in‐the‐bag only. Eyes that underwent Nd:YAG laser capsulotomy prior to the MIOL exchange needed anterior vitrectomy peroperatively (11 eyes; 37%). Visual acuity improved postoperatively in 13 out of the 30 eyes and remained stable in 17 out of the 30 eyes.

Conclusions:  Since the BIL technique requires a very well‐preserved capsular bag for the purpose of the IOL implantation, the success rate of BIL implantation after MIOL is a good indicator to evaluate the degree of difficulty to exchange MIOL.
Pseudophakic monovision: optimal distribution of refractions
Authors: Næser Kristian , Hjortdal Jesper Ø. , Harris William F.
Published: May 2013

Purpose:  To determine the optimal distribution of refractions in monofocal, pseudophakic monovision.

Methods:  A previously reported mathematical method for describing defocus for a single eye (Acta Ophthalmol, 89, 2011, 111) is expanded to the binocular situation. The binocular distribution of refractions yielding the least defocus over the most extended fixation intervals is identified by mathematical optimization. The results are tested in a group of 22 pseudophakic patients.

Results:  For the fixation interval 0.25–6.0 m, the optimal refractions are pure spheres of −0.27 D for the distance eye and −1.15 D for near eye. The mathematically derived defocus structure is confirmed in the clinical series.

Conclusions:  The reported mathematical method enables identification of the optimal distribution of refractions over any fixation interval. Monovision with refractions of approximately −0.25 and −1.25 D may lead to spectacle independence for distance and intermediate vision. Binocular problems – such as monovision suppression, reduced stereoacuity and binocular inhibition – are likely to be minimal with the suggested anisometropia of 1.0 D. This moderate monovision is fully reversible with spectacle correction, as the induced aniseikonia is minimal and it therefore represents a safe alternative to multifocal intraocular lenses (IOLs).
Attention‐deficit/hyperactivity disorder increased the risk of injury: a population‐based follow‐up study
Authors: Kang Jiunn‐Horng , Lin Herng‐Ching , Chung Shiu‐Dong
Published: May 2013

Aim

To explore the frequency and risk for injury among children with Attention‐deficit/hyperactivity Disorder (ADHD) in Taiwan through a population‐based study.

Methods

A total of 3616 subjects aged between four and twelve years diagnosed with ADHD were selected along with a comparison cohort comprising 18 080 subjects. Each subject was individually traced for a three‐year period from their index date to identify those subjects who subsequently received a diagnosis of injury. We used stratified Cox proportional hazards regressions to examine the three‐year injury‐free survival rates between the two cohorts.

Results

Of the subjects, the incidence rate of injury during the three‐year follow‐up period was 7.97 (95% CI = 7.45–8.51) and 5.36 (95% CI = 5.17–5.56) for the study and comparison cohort, respectively. After adjusting for geographic region, the hazard ratio (HR) of injury for subjects with ADHD was 1.64 (95% CI = 1.50–1.79) that of comparison subjects. In addition, we found children with ADHD aged between four and 6 years to demonstrate a greater HR (1.98, 95% CI = 1.72–2.28) than those aged between seven and twelve (HR = 1.46, 95% CI = 1.31–1.63).

Conclusions

Children with ADHD appear to be at a higher risk for injury than children that are not diagnosed with ADHD.
Treating Fragile X syndrome with the diuretic bumetanide: a case report
Authors: Lemonnier Eric , Robin Gaëlle , Degrez Céline , Tyzio Roman , Grandgeorge Marine , Ben‐Ari Yehezkel
Published: May 2013

We report that daily administration of the diuretic NKCC1 chloride co‐transporter, bumetanide, reduces the severity of autism in a 10‐year‐old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double‐blind clinical trial is warranted to test the efficacy of bumetanide in FRX.

Conclusion: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double‐blind clinical trials are warranted to test the efficacy of bumetanide in FRX.
Characterization of ion currents of murine CD117pos stem cells in vitro and their modulation under AT2R stimulation
Authors: Ludwig M. , Skorska A. , Tölk A. , Hopp H.‐H. , Patejdl R. , Li J. , Steinhoff G. , Noack T.
Published: May 2013

Aim

Hematopoietic stem cells, especially CD117pos cells, have been found to possess a regenerative potential in various tissues, in particular cardiac muscle. However, the characterization of the relevant ion currents of stem cells prior to implantation lacks documentation. Activation of angiotensin II type 2 receptor (AT2R) can lead to further cell differentiation and receptor auto‐expression and might thus influence electrophysiological properties of CD117pos stem cells. This study was designed to functionally characterize membrane currents of CD117pos cells under normal and AT2R‐stimulated conditions.

Methods

CD117pos murine bone marrow stem cells were isolated with MACS technique and stimulated for the AT2R with angiotensin II and losartan for 3–5 days prior to patch‐clamp measurements. RT‐PCR was used to determine channel expression. Endothelial properties were analysed with immunocytochemistry and acLDL uptake assay.

Results

A well‐expressed inward rectifying current (IKir) was identified in cultured CD117pos cells. Furthermore, a ZD 7288 (HCN channel blocker)‐sensitive current component was isolated. Voltage‐dependent potassium currents and chloride currents were less expressed. A small fraction of cells demonstrated voltage‐ and time‐dependent inward currents. In AT2R‐stimulated cells inward rectifying the hyperpolarization‐induced inward currents were slightly attenuated on the translational level but showed increased mRNA expression. Cultured CD117pos cells express CD31 and VEGFR‐2 and significantly increased the uptake of acLDL.

Conclusions

CD117pos cells do not have properties of action potential–generating cells and moderately change their excitability during AT2R stimulation. Electrophysiological and molecular properties of control and AT2R‐stimulated cells point to a differentiation to vascular endothelial cells. This could increase beneficial vascularization in injured tissues.
An Estimating Function Approach to the Analysis of Recurrent and Terminal Events
Authors: Kalbfleisch John D. , Schaubel Douglas E. , Ye Yining , Gong Qi
Published: May 2013

In clinical and observational studies, the event of interest can often recur on the same subject. In a more complicated situation, there exists a terminal event (e.g., death) which stops the recurrent event process. In many such instances, the terminal event is strongly correlated with the recurrent event process. We consider the recurrent/terminal event setting and model the dependence through a shared gamma frailty that is included in both the recurrent event rate and terminal event hazard functions. Conditional on the frailty, a model is specified only for the marginal recurrent event process, hence avoiding the strong Poisson‐type assumptions traditionally used. Analysis is based on estimating functions that allow for estimation of covariate effects on the recurrent event rate and terminal event hazard. The method also permits estimation of the degree of association between the two processes. Closed‐form asymptotic variance estimators are proposed. The proposed method is evaluated through simulations to assess the applicability of the asymptotic results in finite samples and the sensitivity of the method to its underlying assumptions. The methods can be extended in straightforward ways to accommodate multiple types of recurrent and terminal events. Finally, the methods are illustrated in an analysis of hospitalization data for patients in an international multi‐center study of outcomes among dialysis patients.
A phase I first‐in‐human study with tefinostat – a monocyte/macrophage targeted histone deacetylase inhibitor – in patients with advanced haematological malignancies
Authors: Ossenkoppele Gert J. , Lowenberg Bob , Zachee Pierre , Vey Norbert , Breems Dimitri , Van de Loosdrecht Arjan A. , Davidson Alan H. , Wells Graham , Needham Lindsey , Bawden Lindsay , Toal Martin , Hooftman Leon , Debnam Phillip M.
Published: May 2013

Summary

Tefinostat (CHR‐2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first‐in‐human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20–640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti‐proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte‐targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose‐limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug‐related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte‐targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non‐targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508).
Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly
Authors: Madsen Michael , Fisker Sanne , Feldt‐Rasmussen Ulla , Andreassen Mikkel , Kristensen Lars Østergaard , Ørskov Hans , Jørgensen Jens Otto L.
Published: May 2013

Objective

To investigate whether pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and whether serum pegvisomant levels predict the therapeutic outcome.

Patients and Methods

Seventeen patients (6 women), mean age 46·3 years (range: 23·2–76·2), were studied. For each patient, four hospital visits were identified including ‘active disease’ (no treatment) and last follow‐up. At each visit, 12 blood samples were drawn during 3 h including an oral glucose tolerance test (OGTT). Eight patients received a somatostatin analogue in addition to pegvisomant on the last visit.

Results

Median (range) pegvisomant doses (mg/day) were 10 (10–10), 15 (10–15) and 15 (10–15) at visits 2, 3 and 4, respectively, and the mean duration of pegvisomant treatment was 17·5 ± 3·2 (SEM) months. Serum IGF‐I changed significantly during the treatment period with the highest level at baseline and lowest levels at visits 3 and 4. GH levels increased in a dose‐dependent manner during pegvisomant treatment and decreased at visit 4. Changes in IGF‐I levels correlated negatively with changes in serum pegvisomant levels between visits. Serum pegvisomant at each visit correlated with baseline growth hormone levels, whereas no associations between serum pegvisomant and either dose, gender, age or body weight were found.

Conclusions

(1) Serum GH levels increased initially, but remained stable during prolonged pegvisomant treatment in patients with acromegaly, (2) serum pegvisomant levels predicted the reduction in serum IGF‐I during treatment and (3) the interindividual variation in serum pegvisomant levels seems not predicted by either age, gender or body composition.
Preventive therapy and resilience promotion: an evaluation of social work led skills development group work
Authors: Sheppard Michael , Clibbens John
Published: May 2013

Concerns have been expressed for some time about a decline in emphasis on therapeutic work in social work, notably articulated in the Munro Review. Further concerns have been expressed in child care that social workers have increasingly had to focus on child protection work rather than earlier stages of prevention. However, there remain opportunities for social workers through the development of new programmes. One development has been that of Behaviour and Education Support Teams: multi‐professional teams, containing as a key element social workers, and encouraging novel practices designed to help emotional stability and improved behaviour and education performance. This study reports on an evaluation of a social worker delivered school‐based social skills programme, which can contribute to the important area of resilience. This showed significant and sustained improvements in pro‐social behaviour and friendships. The implications of this for the therapeutic potential and professional role of social work are discussed.
Circular Arc Snakes and Kinematic Surface Generation
Authors: Bartoň M. , Shi L. , Kilian M. , Wallner J. , Pottmann H.
Published: May 2013

We discuss the theory, discretization, and numerics of curves which are evolving such that part of their shape, or at least their curvature as a function of arc length, remains unchanged. The discretization of a curve as a smooth sequence of circular arcs is well suited for such purposes, and allows us to reduce evolution of curves to the evolution of a control point collection in a certain finite‐dimensional shape space. We approach this evolution by a 2‐step process: linearized evolution via optimized velocity fields, followed by optimization in order to exactly fulfill all geometric side conditions. We give applications to freeform architecture, including “rationalization” of a surface by congruent arcs, form finding and, most interestingly, non‐static architecture.
Accurate Binary Image Selection from Inaccurate User Input
Authors: Subr Kartic , Paris Sylvain , Soler Cyril , Kautz Jan
Published: May 2013

Selections are central to image editing, e.g., they are the starting point of common operations such as copy‐pasting and local edits. Creating them by hand is particularly tedious and scribble‐based techniques have been introduced to assist the process. By interpolating a few strokes specified by users, these methods generate precise selections. However, most of the algorithms assume a 100% accurate input, and even small inaccuracies in the scribbles often degrade the selection quality, which imposes an additional burden on users. In this paper, we propose a selection technique tolerant to input inaccuracies. We use a dense conditional random field (CRF) to robustly infer a selection from possibly inaccurate input. Further, we show that patch‐based pixel similarity functions yield more precise selection than simple point‐wise metrics. However, efficiently solving a dense CRF is only possible in low‐dimensional Euclidean spaces, and the metrics that we use are high‐dimensional and often non‐Euclidean. We address this challenge by embedding pixels in a low‐dimensional Euclidean space with a metric that approximates the desired similarity function. The results show that our approach performs better than previous techniques and that two options are sufficient to cover a variety of images depending on whether the objects are textured.
Path Space Regularization for Holistic and Robust Light Transport
Authors: Kaplanyan Anton S. , Dachsbacher Carsten
Published: May 2013

We propose a simple yet powerful regularization framework for robust light transport simulation. It builds on top of existing unbiased methods and resorts to a consistent estimation using regularization only for paths which cannot be sampled in an unbiased way. To introduce as little bias as possible, we selectively regularize individual interactions along paths, and also derive the regularization consistency conditions. Our approach is compatible with the majority of unbiased methods, e.g. (bidirectional) path tracing and Metropolis light transport (MLT), and only a simple modification is required to adapt existing renderers. We compare to recent unbiased and consistent methods and show examples of scenes with difficult light paths, where regularization is required to account for all illumination features. When coupled with MLT we are able to sample all phenomena, like recent consistent methods, while achieving superior convergence.
Locally Adaptive Products for All‐Frequency Relighting
Authors: Inger Yaron , Farbman Zeev , Lischinski Dani
Published: May 2013

Triple product integrals evaluate the shading at a point by factoring the reflection equation into incident illumination, visibility, and BRDF. By densely sampling the space of incident directions, this approach is capable of highly accurate rendering scenes lit by high‐frequency environment lighting, containing complex materials and featuring intricate shadows. Efficient evaluation of triple product integrals using Haar wavelets enables near‐interactive rendering of such scenes, while dynamically changing the lighting and the view. Although faster methods have been proposed in the recent real‐time rendering literature, the approximations employed in these methods typically limit them to lower frequency phenomena.

In this paper, we present a new approach for high‐frequency scene relighting within the triple product framework. Our approach breaks the computation to smaller solid angles (blocks) over most of which the triple product degenerates to a dot product. We introduce a lossless, yet compact, differential representation of the visibility function over each block, and sample the BRDF on the fly, eliminating the need to store multiple rotated copies of each BRDF. By combining these ideas, we are able to achieve true interactive performance even when running on a CPU, while supporting high frequency effects in scenes with high vertex counts.
Global Selection of Stream Surfaces
Authors: Esturo Janick Martinez , Schulze Maik , Rössl Christian , Theisel Holger
Published: May 2013

Stream surfaces are well‐known and widely‐used structures for 3D flow visualization. A single surface can be sufficient to represent important global flow characteristics. Unfortunately, due to the huge space of possible stream surfaces, finding the globally most representative stream surface turns out to be a hard task that is usually performed by time‐consuming manual trial and error exploration using slight modifications of seed geometries. To assist users we propose a new stream surface selection method that acts as an automatic preprocessing step before data analysis. We measure stream surface relevance by a novel surface‐based quality measure that prefers surfaces where the flow is aligned with principal curvature directions. The problem of seed structure selection can then be reduced to the computation of simple minimal paths in a weighted graph spanning the domain. We apply a simulated annealing‐based optimization method to find smooth seed curves of globally near‐optimal stream surfaces. We illustrate the effectiveness of our method on a series of synthetic and real‐world data sets.
Mesh‐Free Discrete Laplace–Beltrami Operator
Authors: Petronetto F. , Paiva A. , Helou E. S. , Stewart D. E. , Nonato L. G.
Published: May 2013

In this work we propose a new discretization method for the Laplace–Beltrami operator defined on point‐based surfaces. In contrast to the existing point‐based discretization techniques, our approach does not rely on any triangle mesh structure, turning out truly mesh‐free. Based on a combination of Smoothed Particle Hydrodynamics and an optimization procedure to estimate area elements, our discretization method results in accurate solutions while still being robust when facing abrupt changes in the density of points. Moreover, the proposed scheme results in numerically stable discrete operators. The effectiveness of the proposed technique is brought to bear in many practical applications. In particular, we use the eigenstructure of the discrete operator for filtering and shape segmentation. Point‐based surface deformation is another application that can be easily carried out from the proposed discretization method.
Graft macrosteatosis and time of T‐tube removal as risk factors for biliary strictures after liver transplantation
Authors: Lattanzi Barbara , Lai Quirino , Guglielmo Nicola , Giannelli Valerio , Merli Manuela , Giusto Michela , Melandro Fabio , Ginanni Corradini Stefano , Mennini Gianluca , Berloco Pasquale Bartolomeo , Rossi Massimo
Published: May 2013

Biliary strictures (BS) remain a significant problem following liver transplantation (LT), representing an important cause of morbidity. The purpose of this follow‐up study was to evaluate the incidence and risk factors associated with BS after LT. From 2001 to 2009, 244 consecutive patients underwent LT at our center. Multiple donor and recipient variables were collected for each patient. Exclusion criteria were hepaticojejunostomy, living‐donor LT, and follow‐up less than three months. We reviewed 177 patients, all of whom underwent an end‐to‐end choledochocholedochostomy and T‐tube placement. BS occurred in 23% of patients. Multivariate analysis revealed that graft macrovesicular steatosis >25% (p = 0.05, OR 3.38) and time of T‐tube removal less than six months (p = 0.02, OR 2.53) were independent risk factors for BS. Biliary strictures did not affect patient and graft survival. Donor macrovesicular steatosis represents a risk factor for BS, contributing to liver damage through a reduction in hepatic blood flow. Time of T‐tube removal seems to play a role in the development of BS, although it is unclear whether it represents the cause or the consequence of the development of BS.
Species distribution modelling for the people: unclassified landsat TM imagery predicts bird occurrence at fine resolutions
Authors: Shirley S. M. , Yang Z. , Hutchinson R. A. , Alexander J. D. , McGarigal K. , Betts M. G.
Published: May 2013

Aim

Assessing the influence of land cover in species distribution modelling is limited by the availability of fine‐resolution land‐cover data appropriate for most species responses. Remote‐sensing technology offers great potential for predicting species distributions at large scales, but the cost and required expertise are prohibitive for many applications. We test the usefulness of freely available raw remote‐sensing reflectance data in predicting species distributions of 40 commonly occurring bird species in western Oregon.

Location

Central Coast Range, Cascade and Klamath Mountains Oregon, USA.

Methods

Information on bird observations was collected from 4598 fixed‐radius point counts. Reflectance data were obtained using 30‐m resolution Landsat imagery summarized at scales of 150, 500, 1000 and 2000 m. We used boosted regression tree (BRT) models to analyse relationships between distributions of birds and reflectance values and evaluated prediction performance of the models using area under the receiver operating characteristic curve (AUC) values.

Results

Prediction success of models using all reflectance values was high (mean AUC = 0.79 ± 0.10 SD). Further, model performance using individual reflectance bands exceeded those that used only Normalized Difference Vegetation Index (NDVI). The relative influence of band 4 predictors was highest, indicating the importance of variables associated with vegetation biomass and photosynthetic activity. Across spatial scales, the average influence of predictors at the 2000 m scale was greatest.

Main Conclusions

We demonstrate that unclassified remote‐sensing imagery can be used to produce species distribution models with high prediction success. Our study is the first to identify general patterns in the usefulness of spectral reflectances for species distribution modelling of multiple species. We conclude that raw Landsat Thematic Mapper data will be particularly useful in species distribution models when high‐resolution predictions are required, including habitat change detection studies, identification of fine‐scale biodiversity hotspots and reserve design.
Temporary site selection and decision‐making methods: a case study of Tehran, Iran
Authors: Omidvar Babak , Baradaran‐Shoraka Mohammad , Nojavan Mehdi
Published: May 2013

Decisions on selecting an appropriate site for temporary shelter used to be taken in a limited amount of time after a disaster. The need for a systematic method in this area inspired the MADM (multi‐attribute decision making) for complex disaster management decisions. This research proposes a model for appropriate and systematic site selection for temporary shelters, before an earthquake, using a geographical information system and MADM based on an earthquake damage assessment. After the effective criteria for site selection of temporary shelters are determined, the geographical layers of these criteria are prepared for Municipal District No.1 of Greater Tehran, the capital of Iran. Given these attributes and the required shelter area (415–610 hectares), 14 zones are proposed initially. Various MADM methods are used for the final selection. The mean of the aggregated ranking results are determined, and 10 of the 14 initial zones are ranked.