bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonin and the 5‐HT7 receptor: The link between hepatocytes, IGF‐1 and small intestinal neuroendocrine tumors
Authors: Svejda Bernhard , Kidd Mark , Timberlake Andrew , Harry Kathy , Kazberouk Alexander , Schimmack Simon , Lawrence Ben , Pfragner Roswitha , Modlin Irvin M.
Published: April 2013

Platelet‐derived serotonin (5‐HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell “carcinoid” (neuroendocrine) neoplasms, the principal cellular source of 5‐HT. We hypothesized that 5‐HT produced by metastatic EC cells played a role in the hepatic tumor‐microenvironment principally via 5‐HT7 receptor‐mediated activation of hepatocyte IGF‐1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5‐HT7 receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5‐HT‐mediated signaling pathways (pCREB, AKT and ERK). IGF‐1 synthesis/secretion was evaluated using QPCR and ELISA. IGF‐1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF‐1 production and 5‐HT7 expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5‐HT7 receptor. 5‐HT activated cAMP/PKA activity, pCREB (130–205%, P < 0.05) and pERK/pAKT (1.2–1.75, P < 0.05). Signaling was reversed by the 5‐HT7 receptor antagonist SB269970. IGF‐1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC50: 7–70 pg/mL) and could be reversed by the small molecule inhibitor BMS‐754807. IGF‐1 and 5‐HT were elevated (40–300×) in peri‐tumoral hepatic tissue in nude mice, while 5‐HT7 was increased fourfold compared to sham‐operated animals. We conclude that hepatocytes express a cAMP‐coupled 5‐HT7 receptor, which, at elevated 5‐HT concentrations that occur in liver metastases, signals via CREB/AKT and is linked to IGF‐1 synthesis and secretion. Because IGF‐1 regulates NEN proliferation, identification of a role for 5‐HT7 in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine‐producing mid‐gut tumors.
Sunitinib induces cellular senescence via p53/Dec1 activation in renal cell carcinoma cells
Authors: Zhu Yu , Xu Le , Zhang Jianping , Hu Xiaoyi , Liu Yujun , Yin Hankun , Lv Tao , Zhang Heng , Liu Li , An Huimin , Liu Haiou , Xu Jiejie , Lin Zongming
Published: April 2013

Although multitargeted tyrosine kinase inhibitor sunitinib has been used as first‐line therapeutic agent against metastatic renal cell carcinoma (mRCC), the molecular mechanism and functional role per se for its therapeutic performance remains obscure. Our present study revealed that sunitinib‐treated RCC cells exhibit senescence characteristics including increased SA‐β‐gal activity, DcR2 and Dec1 expression, and senescence‐associated secretary phenotype (SASP) such as proinflammatory cytokines interleukin (IL)‐1α, IL‐6 and IL‐8 secretion. Moreover, sunitinib administration also led to cell growth inhibition, G1‐S cell cycle arrest and DNA damage response in RCC cells, suggesting therapeutic significance of sunitinib‐induced RCC cellular senescence. Mechanistic investigations indicated that therapy‐induced senescence (TIS) following sunitinib treatment mainly attributed to p53/Dec1 signaling activation mediated by Raf‐1/NF‐κB inhibition in vitro. Importantly, in vivo study showed tumor growth inhibition and prolonged overall survival were associated with increased p53 and Dec1 expression, decreased Raf‐1 and Ki67 staining, and upregulated SA‐β‐gal activity after sunitinib treatment. Immunohistochemistry analysis of tumor tissues from RCC patients receiving sunitinib neoadjuvant therapy confirmed the similar treating phenotype. Taken together, our findings suggested that sunitinib treatment performance could be attributable to TIS, depending on p53/Dec1 activation via inhibited Raf‐1/nuclear factor (NF)‐κB activity. These data indicated potential insights into therapeutic improvement with reinforcing TIS‐related performance or overcoming SASP‐induced resistance.
Are Nouns Learned Before Verbs? Infants Provide Insight Into a Long‐Standing Debate
Authors: Waxman Sandra , Fu Xiaolan , Arunachalam Sudha , Leddon Erin , Geraghty Kathleen , Song Hyun‐joo
Published: April 2013

For decades, a spirited debate has existed over whether infants’ remarkable capacity to learn words is shaped primarily by universal features of human language or by specific features of the particular native language they are acquiring. A strong focus for this debate has been a well‐documented difference in early word learning: Infants’ success in learning verbs lags behind their success in learning nouns. In this review, we articulate both sides of the debate and summarize new cross‐linguistic evidence from infants that underscores the role of universal features and begins to clarify the impact of distinctly different languages on early language and conceptual development.
Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists
Authors: Howlett Trevor A. , Willis Debbie , Walker Gillian , Wass John A. H. , Trainer Peter J. ,   UK Acromegaly Register Study Group (UKAR‐3)
Published: April 2013

Objective

We investigated the control of GH and IGF1 in acromegaly in routine clinical practice in the UK on and off medical treatment.

Design

The UK Acromegaly Register collected routine biochemical and clinical data on patients with acromegaly from 31 UK centres with GH data covering >30y.

Patients

We identified 2572 patients. Somatostatin analogues (SMS) were used in 40·6% and dopamine agonists (DA) in 41·4%.

Measurements

We identified 29,181 GH records linked to data on IGF1, surgery, radiotherapy and medical treatment and derived data on 9900 distinct Periods of Care including 4206 courses of medical treatment. We considered GH controlled when ≤2 μg/l.

Results

Control of GH and IGF1 improved over time, particularly on medical treatment. Control on medical treatment was better after prior surgery and/or radiotherapy. On long‐term SMS, GH was controlled in 75%, IGF1 in 69% and both in 55%; on long‐term DA, GH control was similar but IGF1 worse (77%/55%/45%). Responses to long‐term treatment with octreotide LAR and lanreotide autogel were broadly similar, but we noted a failure to escalate SMS to maximal effective dose. Increasing precourse GH levels were associated with a decreasing proportion who achieved control, despite greater suppression from baseline.

Conclusions

Control of acromegaly in the UK is improving, but ‘safe’ GH levels are still only achieved in 75% on long‐term medical treatment, with GH and IGF1 both normalized in no more than 55% on SMS and 36% on cabergoline. It remains unclear whether the control of GH, but not IGF1, observed in many patients is sufficient to restore long‐term morbidity and mortality to normal.
‘I Was Quite Amazed’: Donor Conception and Parent–Child Relationships from the Child's Perspective
Authors: Blake Lucy , Casey Polly , Jadva Vasanti , Golombok Susan
Published: April 2013

Donor conception and parent–child relationships were explored from the child's perspective. At ages 7 and 10, interview data were obtained from children in 31 donor insemination, 28 egg donation and 51 natural conception families. Children were also administered the MacArthur Story Stem Battery and a family map. Children in all family types reported close and affectionate relationships with their parents, irrespective of the lack of a genetic link between the parent and the child. Of those children who were aware of their donor conception at age 10, most demonstrated an understanding of, and had positive feelings about their donor conception.
Compatibility of a disperse dye mixture in supercritical carbon dioxide dyeing
Authors: Huang Gang , Dai Jinjin , Dong Fengchun , Wang Junhua , Jia Yongtang
Published: April 2013

The compatibility of three disperse dyes, CI Disperse Orange 30, CI Disperse Red 167 and CI Disperse Blue 79, which are commonly used as a trichromatic combination for conventional dyeing, was studied in supercritical carbon dioxide dyeing. Both the dyeing rate and the build‐up of the selected dyes were measured. Experimental results showed that they were quite compatible. The dyeings of a binary combination (CI Disperse Orange 30 and CI Disperse Blue 79, mass ratio 1:1) and a ternary combination (CI Disperse Orange 30, CI Disperse Red 167 and CI Disperse Blue 79, mass ratio 1:1:1) at different dye concentrations showed an on‐tone uptake and presented the same metric hue angles. This proved that the selected dyes could form a useful trichromatic combination in supercritical carbon dioxide dyeing. Furthermore, the uptake and exhaustion of the single dyes in supercritical carbon dioxide dyeing were similar to those in aqueous dyeing, implying that the dyeing media play only a minor role in the dyeing of polyester fibres with disperse dyes.
A clear case of chronic aspiration of starch (potato)
Authors: Andreani Alessandro , Cappiello Gaia , Valli Michele , Businarolo Elisa , Melara Rosita , Giovannini Michele , Rossi Giulio
Published: April 2013

One of the known agent that causes an organizing pneumonia could be the chronic inhalation of food, but generally we can't find the specific food that caused this pattern.

We show a case where, with an accurate medical history, supported by the various histological investigation steps, we could reach the specific cause of it.
A rare indication for video‐assisted thoracoscopic surgery: headscarf needle aspiration
Authors: Ghanim Bahil , Ankersmit Hendrik Jan , Prosch Helmut , Klikovits Thomas , Marta Gabriel , Klepetko Walter , Lang Gyorgy
Published: April 2013

Headscarf needle aspiration is a rare event, especially in Middle and Western European countries. Here, we report the case of a 37‐year‐old Austrian woman of Turkish origin who accidentally aspirated a turban pin. Repeated bronchoscopy was not successful in removing the aspirated foreign body, which extended past the right middle lobe to the interlobar fissure. The needle was finally removed by video‐assisted thoracoscopic surgery.
Cutaneous metastatic breast carcinoma with clear cell features
Authors: Shinohara Michi M. , Tozbikian Gary , Wolfe Jonathan T. , Shin Sandra J. , Mies Carolyn , Elenitsas Rosalie
Published: April 2013

Breast carcinoma remains one of the most common sources of skin metastases in women. Cutaneous breast carcinoma metastases have variable clinical and histopathologic presentations that can make diagnosis challenging. We report a unique case of metastatic breast carcinoma with prominent clear cell features, thus mimicking a xanthomatous process. Dermatopathologists should be aware of this entity given its resemblance to other clear cell infiltrates and neoplasms.
Solitary epidermolytic acanthoma
Authors: Kazlouskaya Viktoryia , Lambe Jennifer , Elston Dirk
Published: April 2013

Background

Solitary epidermolytic acanthoma is thought to be an uncommon lesion. It can present as a solitary, localized or disseminated process that is unrelated to the genetic form of icthyosis.

Methods

A retrospective review of solitary epidermolytic acanthomas was performed at the Ackerman Academy of Dermatopathology, NY, over a 2 year period. The clinical and histopathological features of solitary epidermolytic acanthomas were described in 64 biopsies from 60 individuals. In situ hybridization for human papillomavirus (HPV) was performed on all genital lesions.

Results

The incidence of epidermolytic acanthomas in our series was higher than previously reported (27.8/100,000). Genital location was the most common and the incidence of genital lesions was 8/100,000. In situ hybridization showed no evidence of genital HPV types within the lesions. The histological features of solitary epidermolytic acanthoma were re‐evaluated.

Conclusions

Genital skin was the most common location for solitary epidermolytic acanthoma, but we found no evidence to suggest a role for genital HPV types. A strong male predominance was noted, and the lesions demonstrate a wide range of clinical and pathological findings.
High and variable prevalence does matter in reviews of diagnostic accuracy in cerebral palsy
Authors: Hanna Steven E
Published: April 2013

This commentary is on the review by Bosanquet et al. on pages 418–426 of this issue.
A systematic review of tests to predict cerebral palsy in young children
Authors: Bosanquet Margot , Copeland Lisa , Ware Robert , Boyd Roslyn
Published: April 2013

Aim

This systematic review evaluates the accuracy of predictive assessments and investigations used to assist in the diagnosis of cerebral palsy (CP) in preschool‐age children (<5y).

Method

Six databases were searched for studies that included a diagnosis of CP validated after 2 years of age. The validity of the studies meeting the criteria was evaluated using the Standards for Reporting Diagnostic Accuracy criteria. Where possible, results were pooled and a meta‐analysis was undertaken.

Results

Nineteen out of 351 studies met the full inclusion criteria, including studies of general movements assessment (GMA), cranial ultrasound, brain magnetic resonance imaging (MRI), and neurological examination. All studies assessed high‐risk populations including preterm (gestational range 23–41wks) and low‐birthweight infants (range 500–4350g). Summary estimates of sensitivity and specificity of GMA were 98% (95% confidence interval [CI] 74–100%) and 91% (95% CI 83–93%) respectively; of cranial ultrasound 74% (95% CI 63–83%) and 92% (95% CI 81–96%) respectively; and of neurological examination 88% (95% CI 55–97%) and 87% (95% CI 57–97%) respectively. MRI performed at term corrected age (in preterm infants) appeared to be a strong predictor of CP, with sensitivity ranging in individual studies from 86 to 100% and specificity ranging from 89 to 97% There was inadequate evidence for the use of other predictive tools.

This review found that the assessment with the best evidence and strength for predictive accuracy is the GMA. MRI has a good predictive value when performed at term‐corrected age. Cranial ultrasound is as specific as MRI and has the advantage of being readily available at the bedside. Studies to date have focused on high‐risk infants. The accuracy of these tests in low‐risk infants remains unclear and requires further research.
A TaqMan real‐time PCR assay for the detection of Phytophthora ‘taxon Agathis’ in soil, pathogen of Kauri in New Zealand
Authors: Than D. J. , Hughes K. J. D. , Boonhan N. , Tomlinson J. A. , Woodhall J. W. , Bellgard S. E.
Published: April 2013

Kauri Agathis australis, an iconic tree of New Zealand, is under threat from an introduced disease‐causing pathogen provisionally named Phytophthora ‘taxon Agathis’ (referred to as PTA). This soilborne, Pythiaceous species belongs to the Chromista and causes a collar rot resulting in yellowing of the foliage and thinning of the canopy, which eventually causes death of the infected tree. The management and containment of this pathogen requires rapid and reliable detection in the soil. The current method for soil detection utilizes a soil bioassay involving lupin baits and soil flooding in a process that takes between ten and twenty days. We describe a real‐time PCR assay based on TaqMan chemistry for the specific detection of PTA, which targets the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA. This TaqMan real‐time PCR assay could be used with DNA extracted directly from bulk soil samples to enable rapid quantification of PTA within soil. The detection limit was 2 fg of PTA DNA from pure culture, or 20 fg in the presence of DNA extracted from soil. The assay was validated using soil samples taken from a PTA‐infested site and soil spiked with a known concentration of oospores. We conclude that the TaqMan real‐time PCR assay offers a more time‐efficient method for detection of PTA in soil than existing methods.
You can't spell schizophrenia without an ‘I’: how does theEarlyIntervention inPsychosis approach relate to the concept of schizophrenia as an ipseity disturbance?
Authors: Akroyd Michael John
Published: April 2013

Background and Aim

Operational approaches to psychiatric diagnosis have increased reliability, but the cost has been the reduction of diagnostic concepts to tick‐box lists of objective symptoms. Some blame this for growing disillusionment among younger clinicians in mental health. A renewed emphasis on the human subject and subjective experience could be one way to remedy this. While true for psychiatry in general, it is particularly true in psychiatry's ‘sacred symbol’ of psychiatry, schizophrenia. Greater understanding of schizophrenia will be of most relevance to those who have yet to develop the disorder, such as those targeted byEarlyIntervention inPsychosis services. A promising direction in the understanding of schizophrenia is the notion of fundamental disturbance in the sense of self (‘ipseity disturbance’).

Method

I intend to examine the relationship between the concept of schizophrenia as an ipseity disturbance and theEarlyIntervention inPsychosis service model through consideration of three main areas: symptoms of schizophrenia as understood by the ipseity disturbance concept; implications of the ipseity disturbance concept for the notion of a schizophrenia prodrome; and the ways in which theEarlyIntervention inPsychosis service model reflects or could be informed by the ipseity disturbance concept.

Results and Conclusions

I argue that explicit consideration of schizophrenia as an ipseity disturbance could lead to better identification of those at highest risk, and more appropriately tailored interventions.
Heidegger on Assertion, Method and Metaphysics
Authors: Golob Sacha
Published: April 2013

In Sein und Zeit Heidegger makes several claims about the nature of ‘assertion’ [Aussage]. These claims are of particular philosophical interest: they illustrate, for example, important points of contact and divergence between Heidegger's work and philosophical movements including Kantianism, the early Analytic tradition and contemporary pragmatism. This article provides a new assessment of one of these claims: that assertion is connected to a ‘present‐at‐hand’ ontology. I also indicate how my analysis sets the stage for a new reading of Heidegger's further claim that assertion is an explanatorily derivative phenomenon. I begin with a loose overview of Heidegger's position and then develop a sharper formulation of the key premises. I go on to argue that existing treatments of the supposed link between assertion and the ‘present‐at‐hand’ are unsatisfactory, and advance a new, ‘methodological’, interpretation of that link. Finally, I sketch the implications of my interpretation for the further claim that assertion is explanatorily derivative.
Comparison of the low‐cycle and medium‐cycle fatigue behaviour of ferritic, pearlitic, isothermed and austempered ductile irons
Authors: Meneghetti G. , Ricotta M. , Masaggia S. , Atzori B.
Published: April 2013

In this paper, the fatigue behaviour of some ductile irons for structural applications is analysed in terms of strain–life, stress–life and cyclic stress–strain curves. Push–pull, strain‐controlled fatigue tests were carried out on ferritic, pearlitic, isothermed and austempered ductile irons. The same tests were executed on a structural steel for comparison purposes. The experimental data were processed according to the common practice as well as to a recent procedure proposed by the authors, which ensures the compatibility conditions are satisfied in a strict sense. Conversely, if the common practice is applied, compatibility conditions are satisfied only approximately. Finally, the results of the experimental fatigue tests on the different materials are compared and discussed in view of application to structural components.
Carbon payback period and carbon offset parity point of wood pellet production in the South‐easternUnited States
Authors: Jonker Jan Gerrit Geurt , Junginger Martin , Faaij Andre
Published: April 2013

This study examines the effect of methodological choices to determine the carbon payback time and the offset parity point for wood pellet production from softwood plantations in the South‐easternUnited States. Using the carbon accounting modelGORCAMwe model low‐, medium‐ and high‐intensity plantation management scenarios for a single stand level, an increasing stand level and a landscape level. Other variables are the fossil‐fuel reference system and the electrical conversion efficiency. Due to the large amount of possible methodological choices and reference systems, there is a wide range of payback times (≤1 year at landscape to 27 years at stand level) and offset parity points (2–106 years). Important aspects impacting on the carbon balances are yield, carbon replacement factor, system boundaries and the choice of reference scenario used to determine the parity point. We consider the landscape‐level carbon debt approach more appropriate for the situation in the South‐easternUnited States, where softwood plantation is already in existence, and under this precondition, we conclude that the issue of carbon payback is basically nonexistent. If comparison against a protection scenario is deemed realistic and policy relevant, and assuming that wood pellets directly replace coal in an average coal power plant, the carbon offset parity point is in the range 12–46 years; i.e. one or two rotations. Switching to intensively managed plantations yields most drastic reduction in the time to parity points (≤17 years in 9 of 12 cases).
Which Birds of a Feather Flock Together? Clustering and Avoidance Patterns of Similar Retail Outlets
Authors: Krider Robert E. , Putler Daniel S.
Published: April 2013

A key factor in a retailer's location decision is whether to avoid direct competitors or to join them in a cluster. A review of theoretical research provides reasons why some types of stores should locate together while others should avoid one another. Although application of the theory is straightforward for some store types, the somewhat stylized theory is ambiguous for many store types. Empirical work, which could reduce this ambiguity, faces methodological difficulties and is very limited. Few store types have been studied, and findings often are inconsistent. First, we address this problem by assessing the degree of avoidance or clustering of 54 different store types in two cities using a rich, intuitive measure that avoids common methodological difficulties encountered in previous research. We find both theoretically expected and unexpected location behavior, as well as some surprisingly complex location patterns. Second, we explore two unexpected and intriguing configurations. Finally, we discuss our results and propose further research opportunities.

Un factor clave para determinar la ubicación de un local de ventas es decidir si se evitará establecerlo junto a la competencia directa o, más bien, conviene agruparse junto a ella. Si se revisa la investigación teórica del tema, encontramos motivos por los que a algunos tipos de tiendas deberían estar juntos, mientras que otros deberían evitarse completamente. Si bien la aplicación de la teoría es directa y simple para algunas clases de tiendas, en muchos otros casos, esta teoría ‐relativamente estilizada ‐, se vuelve algo ambigua. Por su parte, el trabajo empírico, que podría reducir esta ambigüedad, se enfrenta a problemas metodológicos y es muy limitado. Son pocos los casos de tipos de tiendas que se han estudiado, y los resultados son, a menudo, inconsistentes. En el presente trabajo, en primer lugar, nos referimos a este problema, evaluando el nivel de evasión o agrupamiento de 54 diferentes tipos de tiendas, en dos ciudades. Para ello utilizamos una nutrida medición intuitiva, que sortea las dificultades metodológicas de anteriores investigaciones. De este modo, encontramos tanto comportamientos de ubicación esperados como inesperados para la teoría. En segundo lugar, exploramos el caso de dos interesante configuraciones inesperadas. Finalmente, discutimos los resultados y proponemos nuevas oportunidades de investigación en el tema.

零售区位确定的一个重要因素在于是否能避免直接竞争或加入集聚。理论研究综述分析了某些类型商店应集聚分布而其他商店分布应趋于分散的原因。虽然可直接将现有理论应用于某些类型商店的研究，但程式化的理论模式在解释许多类型商店的区位选择时却模糊不清。实证工作可降低模糊性，但操作方法比较困难且应用非常有限，因为通常只有少数类型商店被用于实证分析，且其结果时常不一致。为避免这些问题，我们首先采用一种丰富、直观的方法来评估两个案例城市中54种不同商店类型的集聚度或分散度，发现了理论预期与不可预期的区位行为以及一些令人惊讶的复杂区位模式。然后，我们进一步探讨了两种不可预期的和有趣的区位配置模式。最后，讨论了本文的研究结果并给出了后续研究展望。
Identifying Critical Facilities in Hub‐and‐Spoke Networks: A Hub Interdiction Median Problem
Authors: Lei Ting L.
Published: April 2013

The hub location problem has been widely used in analyzing hub‐and‐spoke systems. The basic assumption is that a large number of demands exist to travel from origins to destinations via a set of intermediate transshipment nodes. These intermediate nodes can be lost, due to reasons such as natural disasters, outbreaks of disease, labor strikes, and intentional attacks. This article presents a hub interdiction median (HIM) problem. It can be used to identify the set of critical facilities in a hub‐and‐spoke system that, if lost, leads to the maximal disruption of the system's service. The new model is formulated using integer linear programming. Special constraints are constructed to account for origin‐to‐destination demand following the least‐cost route via the remaining hubs. Based on the HIM problem, two hub protection problems are defined that aim to minimize the system cost associated with the worst‐case facility loss. Computational experiment results are presented along with a discussion of possible future work.

El problema de la ubicación de la central (hub) ha sido ampliamente analizado para el caso de los sistemas de sistemas radiales (hub‐and‐spoke). La presunción inicial es que existe un gran número de demandas que viajan desde puntos de origen hasta sus puntos de destino a través de un set de nodos intermedios de trasbordo. Estos nodos intermedios pueden perderse por diferentes motivos, como desastres naturales, brotes de enfermedades, huelgas de trabajadores, o ataques intencionales. Este artículo presenta un problema de tipo mediana de interdicción de hub, conocido como hub interdiction median‐HIM. Puede usarse para identificar un set de instalaciones críticas de un sistema tipo hub‐and‐spoke que, si se pierde, conduce a la máxima interrupción del servicio del sistema. El nuevo modelo se ha formulado utilizando programación entera lineal, (integer linear programming‐ILP). El modelo construye restricciones especiales para dar cuenta de la demanda de “origen‐a‐destino” (O‐D), siguiendo la ruta de menor costo, a través de los hubs restantes. Basándonos en el problema de HIM, se definen dos problemas de protección de hub que buscan minimizar el costo asociado al peor caso posible de pérdida de instalaciones. Se presentan además, resultados de experimentos computacionales, así como a una discusión sobre posibles futuros trabajos en la materia.

枢纽区位研究已广泛应用于中枢辐射型系统分析，其基本假设条件为起始点到目的地之间存在大量旅行需求的中间转运节点。但自然灾害、突发疾病、劳务罢工和蓄意攻击等因素可能导致中间转运节点的丧失。本文提出了一种枢纽封闭中心模型（HIM），可用于识别中枢辐射型系统的重要节点，一旦这些节点丧失，将导致整个系统服务最大程度的瓦解。新模型通过整数线性规划公式建立。模型特殊约束条件的建立基于最小成本路径通过余下枢纽的花费来解释始发到目的地（ origin‐to‐destination）需求量。基于HIM问题，双枢纽保护问题被定义为旨在最小化系统花费及其与之关联的最坏情况下节点丢失问题。最后，根据计算的经验结果讨论未来可能深入的研究。
Efficient identification of TALEN‐mediated genome modifications using heteroduplex mobility assays
Authors: Ota Satoshi , Hisano Yu , Muraki Michiko , Hoshijima Kazuyuki , Dahlem Timothy J. , Grunwald David J. , Okada Yasushi , Kawahara Atsuo
Published: April 2013

The heteroduplex mobility assay (HMA) is widely used to characterize strain variants of human viruses. To determine whether it can detect small sequence differences in homologous templates, we constructed a series of deletion constructs (1–10 bp deletions) in the multiple cloning site (MCS) of pBluescript II. After PCR amplification of the MCS using a mixture of wild‐type and one of the deletion constructs, the resulting PCR amplicons were electrophoresed using 15% polyacrylamide gels. Two types of heteroduplexes exhibited retarded electrophoretic migration compared with individual homoduplexes. Therefore, we applied this HMA to detect transcription activator‐like effector nucleases (TALEN)‐induced insertion and/or deletion (indel) mutations at an endogenous locus. We found that TALEN in vivo activity was easily estimated by the degree of multiple HMA profiles derived from TALEN‐injected F0 embryos. Furthermore, TALEN‐injected F0 founder fish produced several unique HMA profiles in F1 embryos. Sequence analysis confirmed that the different HMA profiles contained distinct indel mutations. Thus, HMA is a rapid and sensitive analytical method for the detection of the TALEN‐mediated genome modifications.
System to quantify the import of peroxisomal matrix proteins by fluorescence intensity
Authors: Noguchi Masafumi , Okumoto Kanji , Fujiki Yukio
Published: April 2013

Fourteen distinct peroxins are essential for peroxisome biogenesis in mammals, of which ten are involved in the import of matrix proteins into peroxisomes. Peroxisomal matrix protein import is regulated by various cellular factors; however, the mechanisms underlying this regulation are poorly understood. This is primarily because no quantitative detection method with high resolution is available to study the import of peroxisomal matrix proteins. Here, we developed a monitoring system that uses a fluorescent reporter that is stabilized in peroxisomes but is degraded in the cytosol. An FK506 binding protein 12 variant, termed destabilization domain (DD), is rapidly and constitutively degraded by proteasomes when expressed in mammalian cells. DD is reversibly protected by the addition of a specific synthetic ligand. In the absence of the ligand, a reporter molecule, enhanced GFP (EGFP) fused with DD and peroxisomal targeting signal 1 (DD‐EGFP‐PTS1), is largely degraded in the cytosol. By contrast, in the presence of the ligand, the reporter is stabilized and translocates into peroxisomes. Upon withdrawal of the ligand, the reporter in peroxisomes remains intact, whereas that in the cytosol is rapidly degraded. Thus, peroxisomal protein import can be readily quantified by measuring the fluorescence intensity of whole cells.
Lateral Conduction Switching in Sputtered Ni‐rich NiO Thin Films for Write‐Once‐Read‐Many‐Times Memory Applications
Authors: Liu Zhen , Zhang Hai Yan , Chen Tu Pei , Liu Pan , Zhang Sam , Zhang Wa Li
Published: April 2013

Magnetron sputtering has been used to deposit Ni‐rich nickel oxide thin films. Based on the switching of lateral current conduction in the nickel oxide thin film between two in‐plane electrodes, a planar write‐once‐read‐many‐times memory device has been demonstrated. The switching from a low‐conductance state (i.e., the OFF state) to a high‐conductance state (i.e., the ON state) is induced by a writing voltage, and it is irreversible due to the formation of tilted conductive filaments that are hard to be dissolved by the Joule heating effect. For 80 devices under test, the writing voltage is in a narrow range of 2.0−3.5 V and the ON/OFF resistance ratio is larger than 105 at the reading voltage of 0.3 V. An excellent reading endurance (106 readings) for both ON and OFF states is demonstrated. The device is promising in low‐power applications as it can operate at ultra‐low voltages (e.g., the reading voltage can be below 100 mV).
Neuraminidase inhibitor susceptibility surveillance of influenza viruses circulating worldwide during the 2011 Southern Hemisphere season
Authors: Okomo‐Adhiambo Margaret , Sleeman Katrina , Lysén Colleen , Nguyen Ha T. , Xu Xiyan , Li Yan , Klimov Alexander I. , Gubareva Larisa V.
Published: April 2013

Background

Neuraminidase (NA) inhibitors (NAIs) are currently the only antivirals effective against influenza infections due to widespread resistance to M2 inhibitors.

Methods

Influenza A and B viruses (n = 1079) collected worldwide between April 01, 2011, and September 30, 2011, were assessed for susceptibility to FDA‐approved NAIs, oseltamivir and zanamivir, and investigational peramivir, using the fluorescent‐based NA‐Fluor™ Influenza Neuraminidase Assay Kit. A subset of viruses (n = 98) were tested for susceptibility to the investigational NAI, laninamivir.

Results

Influenza A(H1N1)pdm09 viruses (n = 326) were sensitive to all NAIs, except for two (0·6%) with H275Y (N1 numbering; H274Y in N2 numbering) substitution, which exhibited elevated IC50s for oseltamivir and peramivir, and a third with previously unreported N325K substitution, exhibiting reduced susceptibility to oseltamivir. Influenza A(H3N2) viruses (n = 407) were sensitive to all NAIs. Influenza B viruses (n = 346) were sensitive to all NAIs, except two (0·6%) with H273Y (N1 numbering; H274Y in N2 numbering) substitution, exhibiting reduced susceptibility to oseltamivir and peramivir, and one with previously unreported G140R and N144K substitutions, exhibiting reduced susceptibility to oseltamivir, zanamivir, and peramivir. All influenza A and B viruses were sensitive to laninamivir. It is unknown whether substitutions N325K, G140R, and N144K were present in the virus prior to culturing because clinical specimens were unavailable for testing.

Conclusions

This study summarizes NAI susceptibility of influenza viruses circulating worldwide during the 2011 Southern Hemisphere (SH) season, assessed using the NA‐Fluor™ Kit. Despite low resistance to NAIs among tested influenza viruses, constant surveillance of influenza virus susceptibility to NAIs should be emphasized.
Alula size signals male condition and predicts reproductive performance in an Arctic‐breeding passerine
Authors: Guindre‐Parker Sarah , Gilchrist H. Grant , Baldo Sarah , Love Oliver P.
Published: April 2013

While studies of achromatic plumage signaling are scarce relative to chromatic ornaments, achromatic ornaments have the potential to act as an efficient form of visual communication due to the highly conspicuous contrast between black and white body regions. Recently, achromatic plumage reflectance has been shown to indicate condition, yet the condition‐dependence of achromatic patch size remains unstudied. Here we show the first evidence that alula size, an achromatic plumage patch, has the potential to signal a male’s condition and predict reproductive performance. In Arctic‐breeding snow buntings Plectrophenax nivalis, the size of the alula simultaneously predicted pre‐breeding physiological health and the number of offspring produced, through an intermediate variable (lay date). Snow buntings appear to pair assortatively; males and females arriving earlier pair together, and changes in body condition over the breeding season are positively related within pairs. We suggest that simple achromatic plumage patches, like alula size, have the potential to act as condition‐dependent signals. Consequently, females may benefit from assessing these signals to reliably evaluate a male’s condition and reproductive potential as a means of maximizing their reproductive success.
Chronic stress in infancy fails to affect body size and immune response of adult female blue‐footed boobies or their offspring
Authors: Carmona‐Isunza María Cristina , Núñez‐de la Mora Alejandra , Drummond Hugh
Published: April 2013

Experiments on birds, fish and mammals have shown that adverse conditions during infancy can produce diverse long‐term and delayed deficits during adulthood, prejudicing both the individual and its offspring. Natural selection should prepare animals to cope with adversity of the type, magnitude and timing that commonly occur in their natural habitat, but very little is known about such evolved developmental buffering against natural ‘poor starts’ in life. In two‐chick broods of the blue‐footed boobySula nebouxii, the junior (younger) chick usually experiences aggressive subordination, reduced nutrition and growth and elevated circulating corticosterone. To test whether this poor start produces long‐term, delayed or intergenerational deficits in body size, body condition or cell‐mediated immune response, we measured 3–8 yr old female breeders banded as chicks, and their infant offspring. Results failed to support our predictions. Compared to former seniors and former singletons (solitary nestlings), former juniors showed no deficit in cell‐mediated immune response at any age. They showed an 8.04% deficit in body condition at age 4–6 yr but this deficit disappeared completely by age 7–8 yr. Furthermore, their offspring showed no deficits in body size, body condition or immune response. Junior chicks are affected by their poor start, but their developmental resilience, also confirmed by studies of post‐fledging survivorship, recruitment, natal dispersal, aggressive nest defense and reproduction, is evidence of evolved developmental buffering against predictable adversity during infancy.
Chick growth and survival in northern lapwings Vanellus vanellus indicate that secondary females do the best of a bad job
Authors: Grønstøl Gaute , Hafsmo Jo Esten , Byrkjedal Ingvar , Lislevand Terje
Published: April 2013

The polygyny threshold model predicts that monogamous and secondary females on average settle at the same time and have similar reproductive success. This is not generally found. Incorporating varying female competitive strength into the model, changes the predictions to state that secondary females should breed later and show a reduced success compared to that of monogamous and primary females. We examined if this was the case by investigating growth and survival in chicks of northern lapwings Vanellus vanellus from mothers of monogamous, primary and secondary mating status. Chicks where monitored from hatching to the age of 15–18 d. Growth and survival in secondary chicks was lower than in monogamous and primary chicks. Primary chicks survived significantly better than secondary chicks. Survival of monogamous chicks was comparable to primary chicks and close to significantly higher than in secondary chicks (p = 0.086). Among surviving chicks, daily weight gain in monogamous chicks was significantly higher than in secondary chicks. Growth rates of primary chicks were comparable to monogamous chicks and tended to be higher than in secondary chicks (p = 0.11). Monogamous and primary females both bred significantly earlier than secondary females, and chick survival and body‐mass growth decreased significantly with hatching date. Given the premium on early breeding in lapwings, secondary females appeared to do the best of a bad job, and their later onset of breeding could have been caused by poorer condition and/or lower breeding experience. Additional costs might also have accrued from sharing breeding resources with primary females that presumably were stronger competitors.
Periodontitis: a host‐mediated disruption of microbial homeostasis. Unlearning learned concepts
Authors: Bartold P. Mark , Van Dyke Thomas E.
Published: April 2013

New concepts evolve when existing ones fail to address known factors adequately or are invalidated by new evidence. For decades periodontitis has been considered to be caused by specific bacteria or groups of bacteria and, accordingly, treatment protocols have largely been based on anti‐infective therapies. However, close inspection of current data leads one to question whether these bacteria are the cause or the result of periodontitis. Good evidence is emerging to suggest that it is indeed the host response to oral bacteria that leads to the tissue changes noted in gingivitis. These changes lead to an altered subgingival environment that favors the emergence of ‘periodontal pathogens’ and the subsequent development of periodontitis if the genetic and external environmental conditions are favorable for disease development. Thus, it seems that it is indeed the initial early host‐inflammatory and immune responses occurring during the development of gingivitis, and not specific bacteria or their so‐called virulence factors, which determine whether periodontitis develops and progresses. In this review we consider these concepts and their potential to change the way in which we view and manage the inflammatory periodontal diseases.
Risk factors for periodontal disease
Authors: Genco Robert J. , Borgnakke Wenche S.
Published: April 2013

Risk factors play an important role in an individual’s response to periodontal infection. Identification of these risk factors helps to target patients for prevention and treatment, with modification of risk factors critical to the control of periodontal disease. Shifts in our understanding of periodontal disease prevalence, and advances in scientific methodology and statistical analysis in the last few decades, have allowed identification of several major systemic risk factors for periodontal disease. The first change in our thinking was the understanding that periodontal disease is not universal, but that severe forms are found only in a portion of the adult population who show abnormal susceptibility. Analysis of risk factors and the ability to statistically adjust and stratify populations to eliminate the effects of confounding factors have allowed identification of independent risk factors. These independent but modifiable, risk factors for periodontal disease include lifestyle factors, such as smoking and alcohol consumption. They also include diseases and unhealthy conditions such as diabetes mellitus, obesity, metabolic syndrome, osteoporosis, and low dietary calcium and vitamin D. These risk factors are modifiable and their management is a major component of the contemporary care of many periodontal patients. Genetic factors also play a role in periodontal disease and allow one to target individuals for prevention and early detection. The role of genetic factors in aggressive periodontitis is clear. However, although genetic factors (i.e., specific genes) are strongly suspected to have an association with chronic adult periodontitis, there is as yet no clear evidence for this in the general population. It is important to pursue efforts to identify genetic factors associated with chronic periodontitis because such factors have potential in identifying patients who have a high susceptibility for development of this disease. Many of the systemic risk factors for periodontal disease, such as smoking, diabetes and obesity, and osteoporosis in postmenopausal women, are relatively common and can be expected to affect most patients with periodontal disease seen in clinics and dental practices. Hence, risk factor identification and management has become a key component of care for periodontal patients.
Catheterization During Adrenal Vein Sampling for Primary Aldosteronism: Failure to Use (1–24) ACTH May Increase Apparent Failure Rate
Authors: Kline Gregory A. , So Benny , Dias Valerian C. , Harvey Adrian , Pasieka Janice L.
Published: April 2013

“Successful” adrenal vein catheterization in primary aldosteronism (PA) is often defined by a ratio of >3:1 of cortisol in the adrenal vein vs the inferior vena cava. Non‐use of corticotropin (ACTH) during sampling may increase the apparent failure rate of adrenal vein catheterization due to lower cortisol levels. A retrospective study was performed on all patients with confirmed unilateral PA between June 2005 and August 2011. Adrenal vein sampling (AVS) included simultaneous bilateral baseline samples with repeat sampling 15 minutes after intravenous infusion of 250 μg of Cortrosyn (ACTH‐S). Successful catheter placement was judged as adrenal cortisol:IVC cortisol of >3:1, applied to both baseline and ACTH‐S samples and lateralization of aldosteronism was judged as normalized aldosterone/cortisol (A/C) ratio >3 times the contralateral A/C ratio. In ACTH‐S samples, 94% of right‐sided catheterizations were biochemically successful with 100% success on the left. Among baseline samples, only 47% of right‐ and 44% of left‐sided samples met the 3:1 cortisol criteria. However, 95% of apparent “failed” baseline cortisol sets still showed lateralization of A/C ratios that matched the ultimate pathology. Non–ACTH‐stimulated samples may be incorrectly judged as failed catheter placement when a 3:1 ratio is used. ACTH‐stimulated sampling is the preferred means to confirm catheterization during AVS.
Association of B2 Receptor Polymorphisms and ACE Activity With ACE Inhibitor–Induced Angioedema in Black and Mixed‐Race South Africans
Authors: Moholisa Retsilisitsoe R. , Rayner Brian R. , Patricia Owen E. , Schwager Sylva L. U. , Stark Joalice S. , Badri Motassim , Cupido Clint L. , Sturrock Edward D.
Published: April 2013

Angiotensin‐converting enzyme (ACE) inhibitors are first‐line therapy for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. ACE inhibitors are associated with adverse side effects such as persistent dry cough (ACE‐cough) and, rarely, life‐threatening angioedema (ACE‐AE). The authors investigated the influence of ACE I/D polymorphism in combination with serum ACE activity, B2 receptor −9/+9 polymorphism, and B2 receptor C‐58T single nucleotide polymorphism (SNP) on the development of ACE‐AE and ACE‐cough. The frequencies of ACE I/D as well as B2 receptor +9/−9 and C‐58T polymorphisms were compared in patients with ACE‐AE, ACE‐cough, and ACE inhibitor–exposed controls, and serum ACE activity was measured. There were 52 cases of ACE‐AE, 36 cases of ACE‐cough, and 77 controls. The genotyping revealed a significant association between the B2 −9 allele and ACE inhibitor–induced AE (62% vs 38%, P=.008), and ACE inhibitor–induced cough (61% vs 38%, P=.02) when compared with controls. There was no significant association between ACE I/D polymorphism as well as the B2 C‐58T SNP with both ACE‐induced AE and cough. ACE activity was significantly higher in controls compared with patients with ACE‐AE (34.5±1.14 mU/mL vs 17.8±0.86 mU/mL, P=.0001) and ACE‐cough (34.5±1.14 mU/mL vs 23.3±1.88 mU/mL, P=.0001). Thus, our data suggest that the B2 −9 allele and reduced ACE activity are associated with both ACE‐AE and ACE‐cough.
Kir6.2 E23K polymorphism is related to secondary failure of sulfonylureas in non‐obese patients with type 2 diabetes
Authors: Shimajiri Yoshinori , Yamana Akiko , Morita Shuhei , Furuta Hiroto , Furuta Machi , Sanke Tokio
Published: April 2013

Aims/Introduction

The Kir6.2 E23K polymorphism was studied with a special reference to secondary sulfonylurea (SU) failure in non‐obese patients with type 2 diabetes.

Materials and Methods

We recruited 278 non‐obese (body mass index ≤30.0 kg/m2) Japanese patients with type 2 diabetes who had a history of SU treatment (for 11.2 ± 6.3 years) and compared the frequency of the secondary SU failure among the genotypes of the polymorphism. Genotyping of the Kir6.2 E23K was carried out by polymerase chain reaction‐restriction fragment length polymorphism.

Results

The genotype frequencies of the polymorphism were similar to those previously reported in Japanese patients with type 2 diabetes. The frequency with which patients deteriorated into secondary SU failure was significantly higher in those with the KK genotype than those with EE or EK genotypes. Among 214 patients who eventually received insulin therapy because of secondary SU failure, the period of SU treatment in those with the KK genotype was significantly shorter than those with the EE or EK genotype, although the period from diagnosis to the start of SU treatment was not significantly different.

Conclusions

These data suggest that the Kir6.2 E23K polymorphism is related to the acceleration of secondary SU failure in non‐obese Japanese patients with type 2 diabetes.