bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief Reports: Lysosomal Cross-Correction by Hematopoietic Stem Cell-Derived Macrophages Via Tunneling Nanotubes
Authors: Naphade Swati , Sharma Jay , Gaide Chevronnay Héloïse P. , Shook Michael A. , Yeagy Brian A. , Rocca Celine J. , Ur Sarah N. , Lau Athena J. , Courtoy Pierre J. , Cherqui Stephanie
Published: September 2014

Despite controversies on the potential of hematopoietic stem cells (HSCs) to promote tissue repair, we previously showed that HSC transplantation could correct cystinosis, a multisystemic lysosomal storage disease, caused by a defective lysosomal membrane cystine transporter, cystinosin (CTNS gene). Addressing the cellular mechanisms, we here report vesicular cross-correction after HSC differentiation into macrophages. Upon coculture with cystinotic fibroblasts, macrophages produced tunneling nanotubes (TNTs) allowing transfer of cystinosin-bearing lysosomes into Ctns-deficient cells, which exploited the same route to retrogradely transfer cystine-loaded lysosomes to macrophages, providing a bidirectional correction mechanism. TNT formation was enhanced by contact with diseased cells. In vivo, HSCs grafted to cystinotic kidneys also generated nanotubular extensions resembling invadopodia that crossed the dense basement membranes and delivered cystinosin into diseased proximal tubular cells. This is the first report of correction of a genetic lysosomal defect by bidirectional vesicular exchange via TNTs and suggests broader potential for HSC transplantation for other disorders due to defective vesicular proteins. Stem Cells  2015;33:301–309
Sheep CD34+ Amniotic Fluid Cells Have Hematopoietic Potential and Engraft After Autologous In Utero Transplantation
Authors: Shaw S. W. Steven , Blundell Michael P. , Pipino Caterina , Shangaris Panicos , Maghsoudlou Panagiotis , Ramachandra Durrgah L. , Georgiades Fanos , Boyd Michael , Thrasher Adrian J. , Porada Christopher D. , Almeida-Porada Graça , Cheng Po-Jen , David Anna L. , de Coppi Paolo
Published: September 2014

Unmatched allogeneic in utero stem cell transplantation (IUSCT) produces poor engraftment unless the fetus has congenital immunodeficiency, probably because of maternal and fetal immune responses to injected cells. We studied the functional hematopoietic potential of transduced green fluorescent protein (GFP+) sheep amniotic fluid (AF) stem cells, before and after autologous IUSCT. CD34+ cells were selected from first trimester sheep AF, transduced overnight, and injected intravenously into NOD-SCID-gamma (NSG) mice. At 3 months, primary recipient bone marrow (BM) was injected into secondary NSG recipients. GFP+ cells were detected in the hematopoietic organs and peripheral blood of primary and secondary recipients at 3 months. Autologous IUSCT (transduced GFP+CD34+AF) was performed in fetal sheep. Six months postnatally, lamb BM was injected into secondary NSG recipients. GFP+ cells were detected in the peripheral blood of primary and secondary recipients. This confirms the hematopoietic potential of AF stem cells supporting the concept of autologous IUSCT to treat congenital hematopoietic disease. Stem Cells  2015;33:122–132
Dual Reporter MESP1mCherry/w-NKX2-5eGFP/w hESCs Enable Studying Early Human Cardiac Differentiation
Authors: Den Hartogh Sabine C. , Schreurs Chantal , Monshouwer-Kloots Jantine J. , Davis Richard P. , Elliott David A. , Mummery Christine L. , Passier Robert
Published: September 2014

Understanding early differentiation events leading to cardiogenesis is crucial for controlling fate of human pluripotent stem cells and developing protocols that yield sufficient cell numbers for use in regenerative medicine and drug screening. Here, we develop a new tool to visualize patterning of early cardiac mesoderm and cardiomyocyte development in vitro by generating a dual MESP1mCherry/w-NKX2-5eGFP/w reporter line in human embryonic stem cells (hESCs) and using it to examine signals that lead to formation of cardiac progenitors and subsequent differentiation. MESP1 is a pivotal transcription factor for precardiac mesoderm in the embryo, from which the majority of cardiovascular cells arise. Transcription factor NKX2-5 is expressed upon cardiac crescent formation. Induction of cardiac differentiation in this reporter line resulted in transient expression of MESP1-mCherry, followed by continuous expression of NKX2-5-eGFP. MESP1-mCherry cells showed increased expression of mesodermal and epithelial-mesenchymal-transition markers confirming their mesodermal identity. Whole-genome microarray profiling and fluorescence-activated cell sorting analysis of MESP1-mCherry cells showed enrichment for mesodermal progenitor cell surface markers PDGFR-α, CD13, and ROR-2. No enrichment was found for the previously described KDR+PDGFR-α+ progenitors. MESP1-mCherry derivatives contained an enriched percentage of NKX2-5-eGFP and Troponin T expressing cells, indicating preferential cardiac differentiation; this was enhanced by inhibition of the Wnt-pathway. Furthermore, MESP1-mCherry derivatives harbored smooth muscle cells and endothelial cells, demonstrating their cardiac and vascular differentiation potential under appropriate conditions. The MESP1-NKX2-5 hESC reporter line allows us to identify molecular cues crucial for specification and expansion of human cardiac mesoderm and early progenitors and their differentiation to specific cardiovascular derivatives. Stem Cells  2015;33:56–67
Adiponectin Regulates Bone Marrow Mesenchymal Stem Cell Niche Through a Unique Signal Transduction Pathway: An Approach for Treating Bone Disease in Diabetes
Authors: Yu Liming , Tu Qisheng , Han Qianqian , Zhang Lan , Sui Lei , Zheng Leilei , Meng Shu , Tang Yin , Xuan Dongying , Zhang Jin , Murray Dana , Shen Qingping , Cheng Jessica , Kim Sung-Hoon , Dong Lily Q. , Valverde Paloma , Cao Xinming , Chen Jake
Published: September 2014

Adiponectin (APN) is an adipocyte-secreted adipokine that exerts well-characterized antidiabetic properties. Patients with type 2 diabetes (T2D) are characterized by reduced APN levels in circulation and impaired stem cell and progenitor cell mobilization from the bone marrow for tissue repair and remodeling. In this study, we found that APN regulates the mobilization and recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to participate in tissue repair and regeneration. APN facilitated BMSCs migrating from the bone marrow into the circulation to regenerate bone by regulating stromal cell-derived factor (SDF)−1 in a mouse bone defect model. More importantly, we found that systemic APN infusion ameliorated diabetic mobilopathy of BMSCs, lowered glucose concentration, and promoted bone regeneration in diet-induced obesity mice. In vitro studies allowed us to identify Smad1/5/8 as a novel signaling mediator of APN receptor (AdipoR)−1 in BMSCs and osteoblasts. APN stimulation of MC3T3-E1 osteoblastic cells led to Smad1/5/8 phosphorylation and nuclear localization and increased SDF-1 mRNA expression. Although APN-mediated phosphorylation of Smad1/5/8 occurred independently from adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1, it correlated with the disassembly of protein kinase casein kinase 2 and AdipoR1 in immunoprecipitation experiments. Taken together, this study identified APN as a regulator of BMSCs migration in response to bone injury. Therefore, our findings suggest APN signaling could be a potential therapeutic target to improve bone regeneration and homeostasis, especially in obese and T2D patients. Stem Cells  2015;33:240–252
“Blood, Guts, and Gore Galore:” Bodies, Moral Pollution, and Combat Trauma
Authors: Snyder Justin
Published: September 2014

This article is based on interviews with U.S. veterans diagnosed with combat‐related posttraumatic stress disorder (PTSD). In remembering war, the veterans consistently described grotesque death and injury. These stories of “blood, guts, and gore” were often closely associated with negative moral evaluations of war, which included outright moral claims, moralistic allusions, and expressions of moral emotions. I argue that memories of grotesque death and injury “code” combat as moral pollution, and as these veterans present it, combat pollutes every soldier who passes through it. Furthermore, this classification represents a modern moral culture in which the body is sacred, subject to sustained ritual cleanliness and to strict prohibitions against encroachment by others. A mutilated body is severely disordered and filthy, and when a product of human design, it represents an extremely cruel trespass. Consequently, mutilated bodies are doubly polluted and can code combat as negative in the extreme. This article illustrates that personal traumatic memories are sociologically and historically organized, that the traditional religious ideas of purity and pollution still order moral life, and that autobiographical memory can be approached as a classificatory structure.
Is it believable when it's scientific? How scientific discourse style influences laypeople's resolution of conflicts
Authors: Bromme Rainer , Scharrer Lisa , Stadtler Marc , Hömberg Johanna , Torspecken Ronja
Published: September 2014

Scientific texts are a genre in which adherence to specific discourse conventions allows for conclusions on the scientific integrity of the information and thus on its validity. This study examines whether genre‐typical features of scientific discourse influence how laypeople handle conflicting science‐based knowledge claims. In two experiments with a total of N = 120 participants we investigated to what extent laypeople take into account such features when judging the “scientificness” and credibility of conflicting knowledge claims about medical issues and issues related to climate change and when determining their personal agreement with conflicting claims. Results showed that laypeople use genre‐typical discourse features to evaluate the scientificness and credibility of conflicting science‐based information. However, depending on the scientific topic, they appear to distinguish between what they judge to be credible and what they personally believe to be true. Educational implications of the findings are discussed. © 2014 Wiley Periodicals, Inc. J Res Sci Teach 52: 36–57, 2015
Barriers to effective climate change mitigation: the case of senior government and business decision makers
Authors: Rickards Lauren , Wiseman John , Kashima Yoshi
Published: September 2014

While the case for rapid reductions in greenhouse gas emissions is compelling, actions being taken by most senior decision makers (SDMs) in government and business compound the problem. Given the systemic reach of much senior decision making, including decisions that constrain their own actions, there is an urgent need to open up the SDM black box. Focused on Western governments and multinational corporations, this article examines a cross‐disciplinary range of literature to ask: What are the key factors affecting the preparedness of SDMs—particularly those who accept the climate science—to take the decisive actions needed to drive rapid and significant emission reductions? The review brings together multiple perspectives on the many compounding factors operating across three interconnected scales: micro (individual and interpersonal factors including disciplinary background, worldview, gender, and risk perceptions); meso (network, organizational and institutional factors including management paradigms, organizational culture, and institutional complexity); and macro (environmental, social, cultural, political, and economic factors including climatic extremes, vested interests, and public opinion). It concludes that SDMs are strongly focused on their ‘local’ professional context and near‐term pressures, including reputation among peers, relationships with competitors, and real‐time financial status. As a group they exist within a largely closed circuit and perceive the world from a particular narrow perspective. Combined with the complexity and embedded character of existing systems, this occludes more systemic or reflexive thinking or action. This deep propensity for inaction suggests that a coordinated multi‐frontal approach is essential for a new more effective mitigation approach. WIREs Clim Change 2014, 5:753–773. doi: 10.1002/wcc.305

This article is categorized under:

Perceptions, Behavior, and Communication of Climate Change > Behavior Change and Responses
Cytonemes and the dispersion of morphogens
Authors: Kornberg Thomas B.
Published: September 2014

Filopodia are cellular protrusions that have been implicated in many types of mechanosensory activities. Morphogens are signaling proteins that regulate the patterned development of embryos and tissues. Both have long histories that date to the beginnings of cell and developmental biology in the early 20th century, but recent findings tie specialized filopodia called cytonemes to morphogen movement and morphogen signaling. This review explores the conceptual and experimental background for a model of paracrine signaling in which the exchange of morphogens between cells is directed to sites where cytonemes directly link cells that produce morphogens to cells that receive and respond to them.WIREs Dev Biol2014, 3:445–463. doi: 10.1002/wdev.151

This article is categorized under:

Establishment of Spatial and Temporal Patterns > Gradients

Invertebrate Organogenesis > Flies
College Students and Alcohol Abuse: A Test of Social Learning, Strain, and Acculturation Theories
Authors: DeSoto William , Tajalli Hassan , Smith Chad L. , Pino Nathan W.
Published: September 2014

This article uses an original data set to explore the utility of three classic sociological theories to test patterns of college student alcohol consumption: social learning, strain, and acculturation. The survey data indicate that the first two theories are supported. Acculturation, however, does not appear to explain variations in drinking habits of Latino students in our sample.
Can Policy Overcome Tradition? Assessing Russia's Ongoing Anti‐Alcohol Campaign
Authors: Schrad Mark Lawrence
Published: September 2014

Even following the years of economic and demographic crisis of the 1990s, the Russian Federation still ranks among the hardest drinking countries on earth, with alarming consequences for public health. In 2009, then‐president Dmitry Medvedev initiated the most ambitious campaign against drunkenness since the collapse of the Soviet Union. Based on preliminary evidence from official and unofficial sources, this article attempts an early consideration of the effectiveness of Russia's new alcohol‐control policies. Alcohol‐related mortality statistics show continued improvement since the beginning of the campaign, while alcohol consumption statistics are more ambiguous, casting doubt as to the effectiveness of the policies begun in 2009.
Policy Effectiveness in Historical Context: Pre‐Prohibition Liquor‐Control Studies Revisited
Authors: Schrad Mark Lawrence
Published: September 2014

The touchstone event in the history of alcohol control policy—both in the United States and globally—has unquestionably been the American experiment with alcohol prohibition. Yet in our haste to dismiss this failed policy as the product of misguided temperance zealotry, we risk overlooking a vast historical literature of objective liquor‐control studies that are surprisingly similar to more modern studies of policy effectiveness. This article explores this largely undiscovered liquor‐control literature, and places it into the context of the long history of alcohol‐control studies. The article concludes that not only is this early liquor‐control literature an important part of the heritage of the policy‐studies discipline, but also a potentially valuable resource for future historical and longitudinal studies into alcohol and alcohol‐control issues.
Suckling behavior in Eurasian lynx (Lynx lynx L.) cubs: Characteristics and correlation with competitive interactions
Authors: Glukhova Alla , Naidenko Sergey
Published: September 2014

There is substantial evidence in the literature that the offspring of many mammal species prefer a particular pair of nipples. There is also a definite “nipple order” in individual litters in which each young predominantly uses one or two particular nipples. In combination with early competitive interactions, such “constancy” can play an important role in the social development of the young. In this study, we reveal an unequal use of different pairs of mothers' nipples by 42 Eurasian lynx cubs in 16 litters and investigate the relationship of this phenomenon with the early competitive interactions of the cubs and their physical development. For the lynx cubs, the most often used pair of nipples is the middle pair. There is also definite “nipple order” in each litter. We found a negative correlation between nipples use by the offspring and their competitive activity. No influence of “nipple order” on the cubs' growth rate was detected. Zoo Biol. 33:388–393, 2014. © 2014 Wiley Periodicals Inc.
Creating Musculoskeletal Programs for Culturally Diverse, Underserved Communities: A Community-Based Participatory Research Survey
Authors: Goldsmith Sandra , Friedman Dana , Horton Roberta , Seehaus Mavis , Robbins Laura
Published: September 2014

Background

Arthritis and other musculoskeletal diseases are the most prevalent health conditions in the USA, causing enormous financial and social burdens, especially in underserved communities. Targeted care and prevention programs are urgently needed.

Questions/Purposes

Within an overall goal of revealing health disparities, the questionnaire explored (1) the use of and access to healthcare, (2) the factors affecting quality of life, and (3) the levels of provider–patient communication.

Methods

A New York City musculoskeletal hospital conducted a community health needs survey among its diverse ethnic/racial communities. A 39-item questionnaire was administered online, by mail, and in person (in English, Spanish, and Chinese). Answers were analyzed in terms of sociodemographics, to define health disparities within a total sample and two subsamples.

Results

In the total sample, respondents were 60% White, 16% Black, 14% Hispanic/Latino, and 11% Asian, mostly female, and aged 50 to 79. More than 17% of the total sample indicated they could not access a healthcare provider when needed. Poor nutrition and lack of physical activity were large areas of concern, as were falls and poor self-reported health status. Nearly all respondents said they took steps to communicate with their healthcare providers. Dramatic health disparities were found between Whites and non-Whites (e.g., non-Whites were most likely to rate their health poorly, consider their diet fair or poor, lack health insurance, and be unable to access a healthcare provider).

Conclusion

The findings are being used to further refine, develop, and expand the hospital's community programs, especially for culturally diverse and underserved communities.
Building a science of spending: Lessons from the past and directions for the future
Authors: Dunn Elizabeth W. , Weidman Aaron C.
Published: September 2014

A decade of research suggests that people derive more happiness from buying experiences (e.g., vacations, concert tickets) than from buying material things (e. g., shoes, televisions; see Gilovich, Kumar, & Jampol, 2014, this issue). This highly impactful program of research provides a valuable model to apply in building a broader “science of spending.” By examining both the strengths and limitations of research comparing experiential and material consumption, we extract two lessons for researchers interested in studying how consumers can buy the most happiness with their money, and suggest two methodological improvements that could yield new insights into the happiness benefits of experiential and material purchases. In addition, moving beyond past research on the material/experiential distinction, we offer two fertile areas for future research in the science of spending.
Impact dynamics for a floating elastic membrane
Authors: Duchemin L. , Vandenberghe N.
Published: September 2014

We study impacts of a rigid body on a thin elastic sheet floating on a liquid. When struck by a solid object of small size, the elastic sheet deforms and waves propagate in and on the membrane. The impact triggers a longitudinal elastic wave effectively stretching the membrane. The hydroelastic transverse wave that propagates in the stretched domain is similar to capillary waves on a free surface with an equivalent ‘surface tension’ that results from the stretching of the elastic membrane. Two limiting cases, for which a self-similar solution can be computed, corresponding to short and long times are identified. Surprisingly, our study reveals that the fluid–body system behaves as a regular liquid–gas interface, but with an effective surface tension coefficient that scales linearly with the impact velocity.
Networks' characteristics are important for systems biology
Authors: RIDER ANDREW K. , MILENKOVIĆ TIJANA , SIWO GEOFFREY H. , PINAPATI RICHARD S. , EMRICH SCOTT J. , FERDIG MICHAEL T. , CHAWLA NITESH V.
Published: September 2014

A fundamental goal of systems biology is to create models that describe relationships between biological components. Networks are an increasingly popular approach to this problem. However, a scientist interested in modeling biological (e.g., gene expression) data as a network is quickly confounded by the fundamental problem: how to construct the network? It is fairly easy to construct a network, but is itthenetwork for the problem being considered? This is an important problem with three fundamental issues: How to weight edges in the network in order to capture actual biological interactions? What is the effect of the type of biological experiment used to collect the data from which the network is constructed? How to prune the weighted edges (or what cut-off to apply)? Differences in the construction of networks could lead to different biological interpretations.

Indeed, we find that there are statistically significant dissimilarities in the functional content and topology between gene co-expression networks constructed using different edge weighting methods, data types, and edge cut-offs. We show that different types of known interactions, such as those found through Affinity Capture-Luminescence or Synthetic Lethality experiments, appear in significantly varying amounts in networks constructed in different ways. Hence, we demonstrate that different biological questions may be answered by the different networks. Consequently, we posit that the approach taken to build a network can be matched to biological questions to get targeted answers. More study is required to understand the implications of different network inference approaches and to draw reliable conclusions from networks used in the field of systems biology.
Stellar Populations and the Star Formation Histories of LSB Galaxies: III. Stellar Population Models
Authors: Schombert James , McGaugh Stacy
Published: September 2014

A series of population models are designed to explore the star formation history of gas-rich, low surface brightness (LSB) galaxies. LSB galaxies are unique in having properties of very blue colors, low Hα emission and high gas fractions that indicated a history of constant star formation (versus the declining star formation models used for most spirals and irregulars). The model simulations use an evolving multi-metallicity composite population that follows a chemical enrichment scheme based on Milky Way observations. Color and time sensitive stellar evolution components (i.e., BHB, TP-AGB and blue straggler stars) are included, and model colors are extended into theSpitzerwavelength regions for comparison to new observations. In general, LSB galaxies are well matched to the constant star formation scenario with the variation in color explained by a fourfold increase/decrease in star formation over the last 0.5 Gyrs (i.e., weak bursts). Early-type spirals, from the S4G sample, are better fit by a declining star formation model where star formation has decreased by 40% in the last 12 Gyrs.
INTERNATIONAL RESPONSIBILITY FOR DOMESTIC ADJUDICATION: DENIAL OF JUSTICE DECONSTRUCTED
Authors: Douglas Zachary
Published: September 2014

This article revisits the core difficulties with the international delict known as a denial of justice and, drawing insights from philosophical writing on adjudication, offers novel solutions to three principal issues: (a) the scope of the acts and omissions that can form the predicate conduct for a denial of justice; (b) the proper threshold for liability in respect of those acts or omissions; (c) the relationship between denial of justice and other international norms impacting upon domestic adjudication. The article concludes with a restatement of the law of denial of justice.
Long-term follow up of sudden sensorineural hearing loss patients treated with intratympanic steroids: audiological and quality of life evaluation
Authors: Dallan I , Fortunato S , Casani A P , Bernardini E , Sellari-Franceschini S , Berrettini S , Nacci A
Published: September 2014

Objective:

To evaluate the long-term stability of intratympanic steroids and investigate the ‘real’ impact of sudden sensorineural hearing loss on patients.

Method:

A total of 14 patients treated with intratympanic steroids were evaluated by audiometric and vestibular examinations. The modified Glasgow Benefit Inventory was used to evaluate quality of life changes after intratympanic steroid treatment.

Results:

There was no significant difference between pure tone average post-intratympanic steroids and at follow up. The general Glasgow Benefit Inventory score was not significantly associated with the presence of tinnitus or dizziness, or with patient age. The change in pure tone average after intratympanic steroid treatment did not correlate with social or physical scores, but correlated strongly with the general Glasgow Benefit Inventory score (p = 0.0023). Intratympanic steroid administration led to a stable improvement in hearing. Quality of life assessment showed that patients can feel satisfaction regardless of the hearing outcome. Patients who regained a social hearing level expressed greater satisfaction than patients without serviceable hearing. Overall, quality of life improvement was not related to hearing improvement.

Conclusion:

Sudden sensorineural hearing loss is devastating. Considering the audiological effects alone ignores the ‘human’ perspective. Audiological success can correlate with poor quality of life outcome.
Exaptive translations between biology and architecture
Authors: Smith Chris L. , Kaji-O'Grady Sandra
Published: September 2014

‘Translation’ is dealt with in this paper as a descriptor of the transformation that occurs as a concept, structure, image or notion is appropriated from one discipline to another. This understanding of translation as process or movement, rather than a field of overlap between disciplines, is facilitated by the work of the philosopher Michel Foucault. Foucault considers disciplinarity as the structural demarcation of knowledge and information (discourse) and the demarcations that are disciplined by knowledge. This understanding may be expressed as: disciplines as a disciplining. Foucault rejects the idea of disciplines as bounded self-similar content, arguing instead that disciplinarity lies in the framing of logics applied to content. The disciplines in question are considered in their contingency and temporality yet are not entirely bound by them. Thus, a coherent and organised discipline such as biology dates from the beginning of the nineteenth century. Before then its subject matters either were comprehended within other disciplinary frameworks (natural history) or were considered outside science itself (natural theology). In The Order of Things (1966), Foucault groups several naturalists, including Buffon (French eighteenth century) and Darwin (British nineteenth century), as belonging to the same ‘discourse’ or discursive family. Separating disciplinarity from the origin of ideas and time of writing fosters the productive translation of concepts, images and artefacts between disciplines.
Performance and style in the work of Olgyay and Olgyay
Authors: Leatherbarrow David , Wesley Richard
Published: September 2014

The sun control device has to be on the outside of the building, an element of the facade, an element of architecture. And because this device is so important a part of our open architecture, it may develop into as characteristic a form as the Doric column.

Victor Olgyay (1910–1970), a Hungarian architect who came to the United States in 1947 with his twin brother and collaborator, Aladár (1910–1963), is best known today as the author of Design with Climate: Bioclimatic Approach to Architectural Regionalism (1963), an important book often referenced in the environmental building design field [1]. As leaders in research in bioclimatic architecture from the early 1950s to the late 1960s, the Olgyay brothers could be considered the ‘fathers’ of contemporary environmental building design. Their research and publications laid the foundation for much of the building simulation software in use today. Other than the difference between working on graph paper and using computer-generated graphics, there is little difference between Autodesk's Ecotect Analysis (simulation and building energy analysis software) and the Olgyays' techniques for the analysis of environmental factors and graphical representation of climate. The manner in which the Olgyays established connections between building design and the science of climate laid the foundation for the development of environmental simulation, one of contemporary architecture's leading methods of form generation. Victor Olgyay's teaching, however, represents another kind of thinking, a broader concern for architecture, beyond energy performance. ‘The primary task of architecture,’ Olgyay announced to his students, ‘is to act in man's favour; to interpose itself between man and his natural surroundings in order to remove the environmental load from his shoulders.
Kinetic Modeling of 11C-LY2795050, A Novel Antagonist Radiotracer for PET Imaging of the Kappa Opioid Receptor in Humans
Authors: Naganawa Mika , Zheng Ming-Qiang , Nabulsi Nabeel , Tomasi Giampaolo , Henry Shannan , Lin Shu-Fei , Ropchan Jim , Labaree David , Tauscher Johannes , Neumeister Alexander , Carson Richard E , Huang Yiyun
Published: September 2014

11C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of 11C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the best models to provide reliable measures of binding parameters. The rank order of 11C-LY2795050 distribution volume ( VT) matched the known regional KOR densities in the human brain. Blocking scans with naltrexone indicated no ideal reference region for 11C-LY2795050. Three methods for calculation of the nondisplaceable distribution volume ( VND) were assessed: (1) individual VND estimated from naltrexone occupancy plots, (2) mean VND across subjects, and (3) a fixed fraction of cerebellum VT. Approach (3) produced the lowest intersubject variability in the calculation of binding potentials ( BPND, BPF, and BPP). Therefore, binding potentials of 11C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions. In conclusion, results from the present study show the suitability of 11C-LY2795050 to image and quantify KOR in humans.
Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy
Authors: Burton Bronwen R. , Britton Graham J. , Fang Hai , Verhagen Johan , Smithers Ben , Sabatos-Peyton Catherine A. , Carney Laura J. , Gough Julian , Strobel Stephan , Wraith David C.
Published: September 2014

Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4+ T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4+ T cells. Analysis of the CD4+ T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4+ T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy.
A Mechanistic, Multiscale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 1—Theoretical Model
Authors: Chen X , Hickling TP , Vicini P
Published: September 2014

A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins was formulated by recapitulating key biological mechanisms, including antigen presentation, activation, proliferation, and differentiation of immune cells, secretion of antidrug antibodies (ADA), as well as in vivo disposition of ADA and therapeutic proteins. This system‐level model contains three scales: a subcellular level representing antigen presentation processes by dendritic cells; a cellular level accounting for cell kinetics during humoral immune response; and a whole‐body level accounting for therapeutic protein in vivo disposition. The model simulations for in vivo responses against antigenic protein challenge are consistent with many known immunological observations. By simulating immune responses under various initial parameter conditions, the model suggests hypotheses for future experimental investigation and contributes to the mechanistic understanding of immunogenicity. With future experimental validation, this model may potentially provide a platform to generate and test hypotheses about immunogenicity risk assessment and ultimately aid in immunogenicity prediction.

CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e133; doi:10.1038/psp.2014.30; published online 03 September 2014
A Mechanistic, Multiscale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 2—Model Applications
Authors: Chen X , Hickling TP , Vicini P
Published: September 2014

A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins was built by recapitulating key underlying known biological processes for immunogenicity. The model is able to simulate immune responses based on protein‐specific antigenic properties (e.g., number of T‐epitopes and their major histocompatibility complex (MHC)‐II binding affinities) and host‐specific immunological/physiological characteristics (e.g., MHC‐II allele genotype, drug clearance rate). Preliminary validation was performed using mouse studies with antigens such as ovalbumin (OVA) or OVA‐derived peptide. Further, using adalimumab as an example therapeutic protein, the model is able to simulate immune responses against adalimumab in individual subjects and in a population, and also provides estimations of immunogenicity incidence and drug exposure reduction that can be validated experimentally. This is a first attempt at modeling immunogenicity of biologics, so the model simulations should be used to help understand the immunogenicity mechanisms and impacting factors, rather than making direct predictions. This prototype model needs to be subjected to extensive experimental validation and refinement before fulfilling its ultimate mission of predicting immunogenicity. Nevertheless, the current model could potentially set up the starting framework to integrate various in silico, in vitro, in vivo, and clinical immunogenicity assessment results to help meet the challenge of immunogenicity prediction.

CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e134; doi:10.1038/psp.2014.31; published online 03 September 2014
Transcriptomic profiling of rat liver samples in a comprehensive study design by RNA-Seq
Authors: Gong Binsheng , Wang Charles , Su Zhenqiang , Hong Huixiao , Thierry-Mieg Jean , Thierry-Mieg Danielle , Shi Leming , Auerbach Scott S. , Tong Weida , Xu Joshua
Published: September 2014

RNA-Seq provides the capability to characterize the entire transcriptome in multiple levels including gene expression, allele specific expression, alternative splicing, fusion gene detection, and etc. The US FDA-led SEQC (i.e., MAQC-III) project conducted a comprehensive study focused on the transcriptome profiling of rat liver samples treated with 27 chemicals to evaluate the utility of RNA-Seq in safety assessment and toxicity mechanism elucidation. The chemicals represented multiple chemogenomic modes of action (MOA) and exhibited varying degrees of transcriptional response. The paired-end 100 bp sequencing data were generated using Illumina HiScanSQ and/or HiSeq 2000. In addition to the core study, six animals (i.e., three aflatoxin B1 treated rats and three vehicle control rats) were sequenced three times, with two separate library preparations on two sequencing machines. This large toxicogenomics dataset can serve as a resource to characterize various aspects of transcriptomic changes (e.g., alternative splicing) that are byproduct of chemical perturbation.
Enhanced heat transfer is dependent on thickness of graphene films: the heat dissipation during boiling
Authors: Ahn Ho Seon , Kim Jin Man , Kim TaeJoo , Park Su Cheong , Kim Ji Min , Park Youngjae , Yu Dong In , Hwang Kyoung Won , Jo HangJin , Park Hyun Sun , Kim Hyungdae , Kim Moo Hwan
Published: September 2014

Boiling heat transfer (BHT) is a particularly efficient heat transport method because of the latent heat associated with the process. However, the efficiency of BHT decreases significantly with increasing wall temperature when the critical heat flux (CHF) is reached. Graphene has received much recent research attention for applications in thermal engineering due to its large thermal conductivity. In this study, graphene films of various thicknesses were deposited on a heated surface and enhancements of BHT and CHF were investigated via pool-boiling experiments. In contrast to the well-known surface effects, including improved wettability and liquid spreading due to micron- and nanometer-scale structures, nanometer-scale folded edges of graphene films provided a clue of BHT improvement and only the thermal conductivity of the graphene layer could explain the dependence of the CHF on the thickness. The large thermal conductivity of the graphene films inhibited the formation of hot spots, thereby increasing the CHF. Finally, the provided empirical model could be suitable for prediction of CHF.
Ion Channel Drug Discovery: a Historical Perspective
Authors: Cox Brian
Published: September 2014

Widely regarded as attractive drug targets for many therapeutic applications, worldwide sales of modulators of ion channel function are estimated at US$12 billion. With over 400 genes encoding for more than 300 members of the ion channel family, often referred to genomically as the “chanome” or “channelome”, it is perhaps surprising that less than twenty percent of ion channels are currently commercially exploited. Historically, drug discovery efforts on ion channel targets have progressed without the benefit of molecular and structural information, but with recent advances in the area of target validation, screening technologies and optimization paradigms, increasingly utilizing structural-based design, natural products and antibody approaches, this offers the exciting prospect of a more productive era of ion channel drug discovery.
Automated Electrophysiology in Ion Channel Drug Discovery
Authors: Dunlop John
Published: September 2014

Ion channels - integral membrane proteins controlling ion flux across biological membranes - play fundamental roles in diverse physiological functions and many have been implicated in pathophysiological processes contributing to disease. Consequently they have become the focus of intense drug discovery efforts in the pharma and biotech industries. Despite some success in ion channel targeted drug discovery, it has generally been accepted in the field that a significant impediment to the discovery of novel agents targeting ion channels has been the lack of high throughput methods for studying compound effects on the electrophysiological properties of ion channels. In the last 10–15 years we have seen a dramatic evolution and broad implementation of a number of innovative technology platforms now capable of achieving the near same high quality recordings of ion channel function achieved using the gold standard, but extremely low throughput, technique of manual patch clamp electrophysiology. The use of these platforms in an integrated manner to support ion channel targeted drug discovery efforts is discussed here with a posit that this revolutionized modern day approach offers much promise for the future development of ion channel targeted therapeutics.
AMPA Receptor Positive Allosteric Modulators – a Case History
Authors: Ward Simon E
Published: September 2014

Significant advances have been made over recent years in our understanding of the tremendous complexity underlying the function of the human brain, in particular gaining insight into the mechanisms of synaptic plasticity which are key to developmental, adaptive and learning processes. Glutamate, the major excitatory neurotransmitter in the central nervous system (CNS), is of critical importance to these processes, acting at chemical synapses on two major classes of receptors – the metabotropic family of G-protein coupled receptors (mGluRs 1-8), and ionotropic family of ion channel forming receptors (iGluRs). The latter comprises the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainate receptors. Despite similarities shared within this ion channel family, there exist clear structural and pharmacological differences which underlie their individual modes of action. This chapter provides a case history of ion channel lead optimisation, discusses challenges in lead optimisation and selection of clinical discovery candidates, and thoughts on the future of drug discovery programmes.
Sensing with nanopores – the influence of asymmetric blocking on electrochemical redox cycling current
Authors: Krause Kay J. , Kätelhön Enno , Lemay Serge G. , Compton Richard G. , Wolfrum Bernhard
Published: September 2014

Simulation of electrochemical nanoporous redox cycling devices: the influence of pore blocking on current fluctuations.
Sub-micron proximal probe thermal desorption and laser mass spectrometry on painting cross-sections
Authors: Owens Shawn C. , Berenbeim Jacob A. , Patterson Catherine Schmidt , Dillon Eoghan P. , de Vries M. S.
Published: September 2014

Cross-sections containing organic dyes are used to demonstrate sub-micron atomic force microscopy thermal desorption (AFM-TD), followed by laser mass spectrometry.
One-pot synthesized DNA-templated Ag/Pt bimetallic nanoclusters as peroxidase mimics for colorimetric detection of thrombin
Authors: Zheng Cheng , Zheng Ai-Xian , Liu Bo , Zhang Xiao-Long , He Yu , Li Juan , Yang Huang-Hao , Chen Guonan
Published: September 2014

One-pot synthesized DNA-templated Ag/Pt bimetallic nanoclusters possess highly-efficient peroxidase-like catalytic activity and are applied to design a colorimetric aptasensor for the protein detection with high sensitivity and selectivity.
Dinuclear osmium(ii) probes for high-resolution visualisation of cellular DNA structure using electron microscopy
Authors: Wragg Ashley , Gill Martin R. , Hill Christopher J. , Su Xiaodi , Meijer Anthony J. H. M. , Smythe Carl , Thomas Jim A.
Published: September 2014

Dinuclear osmium(ii) complexes are excellent easy-to-handle probes for transmission electron microscopy, facilitating high-resolution intracellular imaging of sub-nuclear structures.
Ligands effects on the magnetic anisotropy of tetrahedral cobalt complexes
Authors: Saber Mohamed R. , Dunbar Kim R.
Published: September 2014

A trend of increasingly more negative zero-field splitting parameters D was observed for a series of pseudo-tetrahedral mononuclear cobalt complexes, Co(L)2I2 (1–3) (L = quinolone, PPh3 or AsPh3) in going down the group from N to P and As (1 = +9.2 cm−1, 2 = −36.9 cm−1 and 3 = −74.7 cm−1) with 2 and 3 exhibiting slow relaxation of the magnetization under an applied DC field.
Ionophore-based ion-exchange emulsions as novel class of complexometric titration reagents
Authors: Zhai Jingying , Xie Xiaojiang , Bakker Eric
Published: September 2014

Complexometric titrations rely on a drastic change of the pM value at the equivalence point with a water soluble chelator forming typically 1 : 1 complexes of high stability.
Electrocatalytic CO2 reduction with a membrane supported manganese catalyst in aqueous solution
Authors: Walsh James J. , Neri Gaia , Smith Charlotte L. , Cowan Alexander J.
Published: September 2014

[Mn(bpy)(CO)3Br]/MWCNT/Nafion membranes are active heterogeneous electrocatalysts for CO2 reduction to CO in aqueous electrolyte at relatively low overpotentials.
A continuum solvent model of ion–ion interactions in water
Authors: Duignan Timothy T. , Parsons Drew F. , Ninham Barry W.
Published: September 2014

We present a continuum solvent model of ion–ion interactions in water that reproduces activities with only two fitted parameters.
Characterization of C60 fullerene complexation with antibiotic doxorubicin
Authors: Prylutskyy Yu. I. , Evstigneev M. P. , Pashkova I. S. , Wyrzykowski D. , Woziwodzka A. , Gołuński G. , Piosik J. , Cherepanov V. V. , Ritter U.
Published: September 2014

Unusual thermodynamic properties of C60 fullerene complexation with antibiotic doxorubicin were observed and explained.
Surface core-level binding energy shifts for MgO(100)
Authors: Nelin Connie J. , Uhl Felix , Staemmler Volker , Bagus Paul S. , Fujimori Yuichi , Sterrer Martin , Kuhlenbeck Helmut , Freund Hans-Joachim
Published: September 2014

Theoretical and experimental results for the surface core-level binding energy, BE, shifts, SCLS, for MgO(100) are presented and the anomalous O(1s) SCLS is interpreted in terms of the surface electronic structure.
Explicitly correlated PNO-MP2 and PNO-CCSD and their application to the S66 set and large molecular systems
Authors: Schmitz Gunnar , Hättig Christof , Tew David P.
Published: September 2014

Combining the highly compact local PNO representation with F12 theory is an excellent route towards accurate low-scaling correlated wavefunctions for large systems and high quality reference data.
Thermo-molecular orientation effects in fluids of dipolar dumbbells
Authors: Daub Christopher D. , Åstrand Per-Olof , Bresme Fernando
Published: September 2014

Plots of first-order (left) and novel second-order (right) thermomolecular orientation effects in fluids of dipolar dumbbells.
Anionic N-heterocyclic carbenes (NHCs): a versatile route to saturated NHCs bearing pendant weakly coordinating anions
Authors: Phillips Nicholas , Tirfoin Rémi , Aldridge Simon
Published: September 2014

A versatile methodology is reported for the synthesis of anionic NHCs featuring a 5-, 6-, or 7-membered saturated heterocyclic core.
Electron transfer mediation by aqueous C60aggregates in H2O2/UV advanced oxidation of indigo carmine
Authors: Ge Ling , Moor Kyle , Zhang Bo , He Yiliang , Kim Jae-Hong
Published: September 2014

C60fullerene has long been known to exhibit favorable electron accepting and shuttling properties, but little is known about the possibility of electron transfer mediation by fullerene aggregates (nC60) in water.