bluuebunny/crossref_metadata_2025 huggingface dataset:
TILING DIRECTED GRAPHS WITH TOURNAMENTS
Authors: CZYGRINOW ANDRZEJ , DEBIASIO LOUIS , MOLLA THEODORE , TREGLOWN ANDREW
Published: February 2018

The Hajnal–Szemerédi theorem states that for any positive integer $r$ and any multiple $n$ of $r$, if $G$ is a graph on $n$ vertices and $\unicode[STIX]{x1D6FF}(G)\geqslant (1-1/r)n$, then $G$ can be partitioned into $n/r$ vertex-disjoint copies of the complete graph on $r$ vertices. We prove a very general analogue of this result for directed graphs: for any positive integer $r$ with $r\neq 3$ and any sufficiently large multiple $n$ of $r$, if $G$ is a directed graph on $n$ vertices and every vertex is incident to at least $2(1-1/r)n-1$ directed edges, then $G$ can be partitioned into $n/r$ vertex-disjoint subgraphs of size $r$ each of which contain every tournament on $r$ vertices (the case $r=3$ is different and was handled previously). In fact, this result is a consequence of a tiling result for standard multigraphs (that is multigraphs where there are at most two edges between any pair of vertices). A related Turán-type result is also proven.
Negotiating the Aims of African American Adult Education: Race and Liberalism in the Harlem Experiment, 1931–1935
Authors: Nocera Amato
Published: February 2018

This paper examines an “experimental” program in African American adult education that took place at the Harlem branch of the New York Public Library in the early 1930s. The program, called the Harlem Experiment, brought together a group of white funders (the Carnegie Corporation and the American Association for Adult Education)—who believed in the value of liberal adult education for democratic citizenship—and several prominent black reformers who led the program. I argue that the program represented a negotiation between these two groups over whether the black culture, politics, and protest that had developed in 1920s Harlem could be deradicalized and incorporated within the funder's “elite liberalism”—an approach to philanthropy that emphasized ideological neutrality, scholarly professionalism, and political gradualism. In his role as the official evaluator, African American philosopher Alain Locke insisted that it could, arguing that the program, and its occasionally Afrocentric curriculum, aligned with elite liberal ideals and demonstrated the capacity for a broader definition of (historically white) liberal citizenship. While the program was ultimately abandoned in the mid-1930s, the efforts of Locke and other black reformers helped pave the way for a future instantiation of racial incorporation: the intercultural education movement of the mid-twentieth century.
Educating Women for Self-Reliance and Economic Opportunity: The Strategic Entrepreneurialism of the Katharine Gibbs Schools, 1911–1968
Authors: Mullaney Marie Marmo , Hilbert Rosemary C.
Published: February 2018

Established in 1911 as a simple owner-operated commercial school in Providence, Rhode Island, the Katharine Gibbs School expanded over the decades to acquire an international reputation for excellence in secretarial training. This essay examines the origin, development, and ultimate demise of the chain, placing it within the context of the expansion of office work and the growth of clerical education. In presenting a secretarial career as an attractive option for women, the school developed a gender-specific message that was very much in keeping with the vocationalism that became a major component of women's education in both public high schools and proprietary institutions. Promoting the career secretary as a desirable career path for women, Gibbs used class and gender-based marketing to separate itself from competitors. Thriving at a time when educated women had few opportunities, the school declined when the feminist upheavals of the 1960s sparked a new ethos of workplace egalitarianism and widening cultural definitions of self-fulfillment for women.
On natural modes in moonpools and gaps in finite depth
Authors: Molin B. , Zhang X. , Huang H. , Remy F.
Published: February 2018

In this paper an extension of the theoretical model of Molin (J. Fluid Mech., vol. 430, 2001, pp. 27–50) is proposed, where the assumptions of infinite depth and infinite horizontal extent of the support are released. The fluid domain is decomposed into two subdomains: the moonpool (or the gap) and a lower subdomain bounded by the seafloor and by an outer cylinder where the linearized velocity potential is assumed to be nil. Eigenfunction expansions are used to describe the velocity potential in both subdomains. Garrett’s method is then applied to match the velocity potentials at the common boundary and an eigenvalue problem is formulated and solved, yielding the natural frequencies and associated modal shapes of the free surface. Applications are made, first in the case of a circular moonpool, then in the rectangular gap and moonpool cases. Based on so-called single-mode approximations, simple formulas are proposed that give the resonant frequencies.
Dynamics of capsules enclosing viscoelastic fluid in simple shear flow
Authors: Luo Zheng Yuan , Bai Bo Feng
Published: February 2018

Previous studies on capsule dynamics in shear flow have dealt with Newtonian fluids, while the effect of fluid viscoelasticity remains an unresolved fundamental question. In this paper, we report a numerical investigation of the dynamics of capsules enclosing a viscoelastic fluid and which are freely suspended in a Newtonian fluid under simple shear. Systematic simulations are performed at small but non-zero Reynolds numbers (i.e. $Re=0.1$) using a three-dimensional front-tracking finite-difference model, in which the fluid viscoelasticity is introduced via the Oldroyd-B constitutive equation. We demonstrate that the internal fluid viscoelasticity presents significant effects on the deformation behaviour of initially spherical capsules, including transient evolution and equilibrium values of their deformation and orientation. Particularly, the capsule deformation decreases slightly with the Deborah number De increasing from 0 to $O(1)$. In contrast, with De increasing within high levels, i.e. $O(1{-}100)$, the capsule deformation increases continuously and eventually approaches the Newtonian limit having a viscosity the same as the Newtonian part of the viscoelastic capsule. By analysing the viscous stress, pressure and viscoelastic stress acting on the capsule membrane, we reveal that the mechanism underlying the effects of the internal fluid viscoelasticity on the capsule deformation is the alterations in the distribution of the viscoelastic stress at low De and its magnitude at high De, respectively. Furthermore, we find some new features in the dynamics of initially non-spherical capsules induced by the internal fluid viscoelasticity. Particularly, the transition from tumbling to swinging of oblate capsules can be triggered at very high viscosity ratios by increasing De alone. Besides, the critical viscosity ratio for the tumbling-to-swinging transition is remarkably enlarged with De increasing at relatively high levels, i.e. $O(1{-}100)$, while it shows little change at low De, i.e. below $O(1)$.
Fiscal Policy, Consumption Risk, and Stock Returns: Evidence from U.S. States
Authors: Da Zhi , Warachka Mitch , Yun Hayong
Published: February 2018

We find that consumption risk is lower in states that implement countercyclical fiscal policies. Moreover, firms with an investor base that is concentrated in countercyclical states have lower stock returns, along with firms that relocate their headquarters to a countercyclical state. Therefore, countercyclical fiscal policies lower the consumption risk of investors and, consequently, their required equity return premium. This conclusion is confirmed by smaller declines in market participation during recessions in countercyclical states. Overall, the location of a firm’s investor base enables state-level fiscal policy to influence stock returns.
Pitfalls in the Use of Systemic Risk Measures
Authors: Löffler Gunter , Raupach Peter
Published: February 2018

We examine pitfalls in the use of return-based measures of systemic risk contributions (SRCs). For both linear and nonlinear return frameworks, assuming normal and heavy-tailed distributions, we identify nonexotic cases in which a change in a bank’s systematic risk, idiosyncratic risk, size, or contagiousness increases the risk of the system but lowers the measured SRC of the bank. Assessments based on estimated SRCs could thus produce false interpretations and incentives. We also identify potentially adverse side effects: A change in a bank’s risk structure can make the measured SRC of its competitors increase more strongly than its own.
Moving In and Out of In-work Poverty in the UK: An Analysis of Transitions, Trajectories and Trigger Events
Authors: HICK ROD , LANAU ALBA
Published: February 2018

There is growing concern about the problem of in-work poverty in the UK. Despite this, the literature on in-work poverty remains small in comparison with that on low pay and, in particular, we know relatively little about how people move in and out of in-work poverty. This paper presents an analysis of in-work poverty transitions in the UK, and extends the literature in this field in a number of identified ways. The paper finds that in-work poverty is more transitory than poverty amongst working-age adults more generally, and that the number of workers in the household is a particularly strong predictor of in-work poverty transitions. For most, in-work poverty is a temporary phenomenon, and most exits are by exiting poverty while remaining in work. However, our study finds that respondents who experience in-work poverty are three times more likely than non-poor workers to become workless, while one-quarter of respondents in workless, poor families who gained work entered in-work poverty. These findings demonstrate the limits to which work provides a route out of poverty, and points to the importance of trying to support positive transitions while minimising negative shocks faced by working poor families.
The crystal structure of MoO2(O2)H2O
Authors: Reid Joel W. , Kaduk James A. , Matei Lidia
Published: February 2018

The crystal structure of MoO2(O2)H2O has been solved by analogy with the WO2(O2)H2O structure and refined with synchrotron powder diffraction data obtained from beamline 08B1-1 at the Canadian Light Source. Rietveld refinement, performed with the software package GSAS, yielded monoclinic lattice parameters of a = 12.0417(4) Å, b = 3.87003(14) Å, c = 7.38390(24) Å, and β = 78.0843(11)° (Z = 4, space group P21/n). The structure is composed of double zigzag molybdate chains running parallel to the b-axis. The Rietveld refined structure was compared with density functional theory (DFT) calculations performed with CRYSTAL14, and show strong agreement with the DFT optimized structure.
NONLOCAL SOLUTIONS TO DYNAMIC EQUILIBRIUM MODELS: THE APPROXIMATE STABLE MANIFOLDS APPROACH
Authors: Ajevskis Viktors
Published: February 2018

This study presents a method for constructing a sequence of approximate solutions of increasing accuracy to general equilibrium models on nonlocal domains. The method is based on a technique originated from dynamical systems theory. The approximate solutions are constructed employing the Contraction Mapping Theorem and the fact that the solutions to general equilibrium models converge to a steady state. Under certain nonlocal conditions, the convergence of the approximate solutions to the true solution is proved. We also show that the proposed approach can be treated as a rigorous proof of convergence for the extended path algorithm in a class of nonlinear rational expectation models.
Readable flowers: global circulation and translation of collected saints’ lives
Authors: Greenwood Jonathan E.
Published: February 2018

This article argues that Flowers (flores sanctorum), collections of saints’ lives arranged by the liturgical calendar, were the first genre of devotional literature to have a global reach during the sixteenth and seventeenth centuries. This article begins with the medieval origins of Flowers before analysing their dispersion in the sixteenth and early seventeenth centuries by the Franciscans and Jesuits. By taking a temporal long view and a transoceanic perspective, the article contributes to the scholarship on early modern evangelization, translation, global networks, and the historiographies of the Franciscans and Jesuits.
The world’s fairs as spaces of global knowledge: Latin American archaeology and anthropology in the age of exhibitions
Authors: Schuster Sven
Published: February 2018

At the end of the nineteenth century, Brazil, Mexico, and Peru were among the countries participating in the most important world’s fairs in Europe and North America. These mass gatherings focused on national self-images as well as technological development and commodities, but the Latin American exhibition organizers also understood them to be transnational spaces that contributed to the mobility of persons, objects, and knowledge. In this context, the scientific display of pre-Columbian ‘antiquities’ was regarded as being as important as the participation in archaeological and anthropological congresses. By understanding the world’s fairs as ‘spaces of global knowledge’, this article highlights the agency of Latin American scientists, intellectuals, and collectors in the transnational endeavour to create a ‘Latin American antiquity’ at the fairgrounds. Although most fair attendees sought to study and display the pre-Columbian past in an objective manner, the older dream of (re-)constructing the splendour of America’s ancient civilizations never completely vanished.
Rehabilitation: Das ABC für den Zuweiser
Authors: Bachmann Stefan
Published: February 2018

Zusammenfassung. Die ärztlich durchgeführten oder angeordneten Massnahmen der medizinischen Rehabilitation sind nach KVG eine Pflichtleistung der sozialen Krankenversicherung. Nach der Diagnosestellung nach ICD-10 sollten die funktionellen Defizite nach ICF abgeleitet werden. Sind diese Defizite voraussichtlich länger bestehend und sollten sie sich durch Rehabilitationsmassnahmen beheben lassen, so ist die Indikation zu einer Rehabilitation gegeben. Der Patient sollte dann bevorzugt in eine Rehabilitationseinrichtung überwiesen werden, die zur Behandlung seiner primär vorherrschenden Funktionseinschränkungen geeignet ist, bzw. den entsprechenden Leistungsauftrag aufweist. Die Kostenübernahme ist dabei gemäss KLV nur auf vorgängige besondere Befürwortung des Krankenversicherers garantiert. Das Kostengutsprachegesuch muss daher zumindest Angaben zur Diagnose, zum funktionellen Defizit, zum Rehabilitationsziel und zur Rehabilitationsprognose beinhalten, damit der Vertrauensarzt der Krankenversicherung das Gesuch beurteilen kann.
Besonderheiten moderner Rehabilitation beim betagten Menschen
Authors: Engelter Stefan T. , Kressig Reto W.
Published: February 2018

Zusammenfassung. Aufgrund der demografischen Entwicklung gewinnt die Rehabilitation Betagter an Bedeutung. Im Vergleich zum jüngeren Patienten sind beim betagten Patienten die Autonomie und die Handlungsfähigkeit in Alltagssituationen meist rascher bedroht, die soziale Partizipation fragiler, und somit die Gefahr der Vereinsamung prinzipiell grösser. Die Kommunikation mit dem Umfeld spielt eine grössere Rolle. Das Risiko für Komplikationen ist hoch; andererseits äussern betagte Patienten in der Regel weniger Angst vor dem Tod als vor einem völligen Verlust der Selbständigkeit und davor, ihren Angehörigen «zur Last zu fallen». Auch betagte Patienten profitieren von organspezifischen Rehabilitationsmassnahmen auf dem Niveau der Alltagsfunktionalität und sozialen Partizipation, wie dies exemplarisch für die Neurorehabilitation nach Schlagfanfall gezeigt wurde. Die geriatrische Rehabilitation fokussiert spezifisch auf die Bedürfnisse Betagter, die durch Multimorbidität, Vulnerabilität oder Gebrechlichkeit (Frailty) charakterisiert sind. Sie ist als interprofessioneller Prozess aufgebaut, der polymodal körperliche, psychische und soziale Aspekte systematisch erfasst und mit dem Patienten und seinem Umfeld ein individuell adaptiertes Ziel erarbeitet. Zentral sind die Aspekte Mobilität, Selbsthilfefähigkeit, Ernährung, Kognition, Stimmung, Kontinenz und soziale Situation. Ein Tragpfeiler ist dabei eine altersadaptierte, proteinreiche Ernährung. Ärztlicherseits wird es – gerade bei der Rehabilitation Betagter – hilfreich sein, die Kompetenzen aus verschiedenen Fachrichtungen synergistisch zu nutzen. Unter der Vorstellung einer optimalen Betreuung und Beratung gerade in den Kompetenzfeldern Mobilität, Kognition und Ernährung kann eine Co-Betreuung ein zukunftsfähiges Modell sein. Im Hinblick auf die rehabilitative Prognose dürfte «Alter» im Sinne der Anzahl bisheriger Lebensjahre eine überschätzte Prognosevariable sein. «Höheres Alter» kann hingegen als Surrogatmarker für Komorbiditäten gelten, die mit zunehmendem Lebensalter an Häufigkeit zunehmen. Unter diesen Gesichtspunkten ist es unbedingt zu vermeiden, dass betagte Patienten rein auf Grund ihrer bereits verbrachten Lebensjahre weniger häufig als Jüngere die Chance einer rehabilitativen Behandlung erhalten.
Forschung in der Rehabilitationsmedizin
Authors: Luder Gere , Verra Martin L. , Trippolini Maurizio
Published: February 2018

Zusammenfassung. Reha-Forschung ist die Methode, um die Wirkung der diversen Interventionen, die in der Rehabilitation angewendet werden, zu testen. Um dieses anspruchsvolle Ziel zu erreichen, ist die muskuloskelettale Rehabilitation auf Grundlagenforschung, klinische Forschung und Versorgungsforschung angewiesen. Die Rehabilitationsforschung in der Schweiz sieht sich jedoch mit grossen Herausforderungen und mehreren Barrieren konfrontiert. Insgesamt lässt sich feststellen, dass es keine kohärenten und schweizweit akzeptierten Standards für die systematische Integration aktueller Forschungsergebnisse in die konkrete Reha-Praxis gibt. Als anwendungsbezogenen Handlungsbedarf in der Reha-Forschung in der Schweiz schlagen die Autoren u.a. die Entwicklung einer nationalen Agenda für Reha-Forschung und die Bildung von nationalen Forschungsnetzwerken unter Einbezug der Grundversorger, der Hochschulen, der Rehakliniken und Patientenorganisationen vor.
Specialized plant biochemistry drives gene clustering in fungi
Authors: Gluck-Thaler Emile , Slot Jason C
Published: February 2018

The fitness and evolution of prokaryotes and eukaryotes are affected by the organization of their genomes. In particular, the physical clustering of genes can coordinate gene expression and can prevent the breakup of co-adapted alleles. Although clustering may thus result from selection for phenotype optimization and persistence, the impact of environmental selection pressures on eukaryotic genome organization has rarely been systematically explored. Here, we investigated the organization of fungal genes involved in the degradation of phenylpropanoids, a class of plant-produced secondary metabolites that mediate many ecological interactions between plants and fungi. Using a novel gene cluster detection method, we identified 1110 gene clusters and many conserved combinations of clusters in a diverse set of fungi. We demonstrate that congruence in genome organization over small spatial scales is often associated with similarities in ecological lifestyle. Additionally, we find that while clusters are often structured as independent modules with little overlap in content, certain gene families merge multiple modules into a common network, suggesting they are important components of phenylpropanoid degradation strategies. Together, our results suggest that phenylpropanoids have repeatedly selected for gene clustering in fungi, and highlight the interplay between genome organization and ecological evolution in this ancient eukaryotic lineage.
STK17B promotes carcinogenesis and metastasis via AKT/GSK-3β/Snail signaling in hepatocellular carcinoma
Authors: Lan Yaliang , Han Jihua , Wang Yan , Wang Jiabei , Yang Guangchao , Li Keyu , Song Ruipeng , Zheng Tongsen , Liang Yingjian , Pan Shangha , Liu Xirui , Zhu Mingxi , Liu Yao , Meng Fanzheng , Mohsin Manzoor , Cui Yifeng , Zhang Bo , Subash Sharma , Liu Lianxin
Published: February 2018

Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide with frequent intrahepatic and distant metastasis. Elucidating the underlying molecular mechanism that modulates HCC progression is critical for exploring novel therapeutic strategies. Serine/Threonine Kinase 17B (STK17B) is upregulated in HCC tissues, but its role in HCC progression remains elusive. In the present studies, we reported that STK17B had a critical role in HCC progression. STK17B was significantly upregulated in HCC cell lines and specimens, and patients with ectopic STK17B expression characterized with poor clinicopathological features. In vitro and in vivo assay demonstrated that inhibition of STK17B markedly inhibits HCC tumorigenesis and metastasis, while STK17B overexpression promoted these processes. Furthermore, we found that STK17B promoted EMT process via activating AKT/GSK-3β/Snail signal pathway, and miR-455-3p was identified as the upstream regulator of STK17B. Combination of high level of STK17B and low level of miR-455-3p predicted poor prognosis with higher accuracy for HCC patients. In conclusion, our research demonstrated that STK17B promotes HCC progression, induces EMT process via activating AKT/GSK-3β/Snail signal and predicts poor prognosis in HCC.
Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect
Authors: Secker Philipp F. , Beneke Sascha , Schlichenmaier Nadja , Delp Johannes , Gutbier Simon , Leist Marcel , Dietrich Daniel R.
Published: February 2018

Recent FDA Drug Safety Communications report an increased risk for acute kidney injury in patients treated with the gliflozin class of sodium/glucose co-transport inhibitors indicated for treatment of type 2 diabetes mellitus. To identify a potential rationale for the latter, we used an in vitro human renal proximal tubule epithelial cell model system (RPTEC/TERT1), physiologically representing human renal proximal tubule function. A targeted metabolomics approach, contrasting gliflozins to inhibitors of central carbon metabolism and mitochondrial function, revealed a double mode of action for canagliflozin, but not for its analogs dapagliflozin and empagliflozin. Canagliflozin inhibited the glutamate dehydrogenase (GDH) and mitochondrial electron transport chain (ETC) complex I at clinically relevant concentrations. This dual inhibition specifically prevented replenishment of tricarboxylic acid cycle metabolites by glutamine (anaplerosis) and thus altered amino acid pools by increasing compensatory transamination reactions. Consequently, canagliflozin caused a characteristic intracellular accumulation of glutamine, glutamate and alanine in confluent, quiescent RPTEC/TERT1. Canagliflozin, but none of the classical ETC inhibitors, induced cytotoxicity at particularly low concentrations in proliferating RPTEC/TERT1, serving as model for proximal tubule regeneration in situ. This finding is testimony of the strong dependence of proliferating cells on glutamine anaplerosis via GDH. Our discovery of canagliflozin-mediated simultaneous inhibition of GDH and ETC complex I in renal cells at clinically relevant concentrations, and their particular susceptibility to necrotic cell death during proliferation, provides a mechanistic rationale for the adverse effects observed especially in patients with preexisting chronic kidney disease or previous kidney injury characterized by sustained regenerative tubular epithelial cell proliferation.
The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1
Authors: Su Feng , He Wang , Chen Changhao , Liu Mo , Liu Hongwei , Xue Feiyuan , Bi Junming , Xu Dawei , Zhao Yue , Huang Jian , Lin Tianxin , Jiang Chun
Published: February 2018

Long non-coding RNAs (lncRNAs) have been identified as significant regulators in cancer progression. Positive feedback loops between lncRNAs and transcription factors have attracted increasing attention. Akt pathway plays a crucial role in bladder cancer growth and recurrence. In the present study, we demonstrate a novel regulatory pattern involving FOXD2-AS1, Akt, and E2F1. FOXD2-AS1 is highly expressed in bladder cancer and is associated with tumor stage, recurrence, and poor prognosis. Further experiments showed that FOXD2-AS1 promotes bladder cancer cell proliferation, migration, and invasion in vitro and in vivo. Microarray analysis demonstrated that FOXD2-AS1 negatively regulates the expression of Tribbles pseudokinase 3 (TRIB3), a negative regulator of Akt. Mechanistically, FOXD2-AS1 forms an RNA-DNA complex with the promoter of TRIB3, the transcriptional activity of which is subsequently repressed, and leads to the activation of Akt, which further increases the expression of E2F1, a vital transcription factor involved in the G/S transition. Interestingly, E2F1 could bind to the FOXD2-AS1 promoter region and subsequently enhance its transcriptional activity, indicating that FOXD2-AS1/Akt/E2F1 forms a feedback loop. In summary, this regulatory pattern of positive feedback may be a novel target for the treatment of bladder cancer and FOXD2-AS1 has the potential to be a new recurrence predictor.
Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis
Authors: Rossi Chiara , Cusimano Melania , Zambito Martina , Finardi Annamaria , Capotondo Alessia , Garcia-Manteiga Jose Manuel , Comi Giancarlo , Furlan Roberto , Martino Gianvito , Muzio Luca
Published: February 2018

Microglia activation is a commonly pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a devastating disorder characterized by a selective motor neurons degeneration. Whether such activation might represent a causal event rather than a secondary epiphenomenon remains elusive. Here, we show that CNS-delivery of IL-4—via a lentiviral-mediated gene therapy strategy—skews microglia to proliferate, inducing these cells to adopt the phenotype of slowly proliferating cells. Transcriptome analysis revealed that IL-4-treated microglia express a broad number of genes normally encoded by embryonic microglia. Since embryonic microglia sustain CNS development, we then hypothesized that turning adult microglia to acquire such phenotype via IL-4 might be an efficient in vivo strategy to sustain motor neuron survival in ALS. IL-4 gene therapy in SOD1G93A mice resulted in a general amelioration of clinical outcomes during the early slowly progressive phase of the disease. However, such approach did not revert neurodegenerative processes occurring in the late and fast progressing phase of the disease.
Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip
Authors: Jalili-Firoozinezhad Sasan , Prantil-Baun Rachelle , Jiang Amanda , Potla Ratnakar , Mammoto Tadanori , Weaver James C. , Ferrante Thomas C. , Kim Hyun Jung , Cabral Joaquim M. S. , Levy Oren , Ingber Donald E.
Published: February 2018

Studies on human intestinal injury induced by acute exposure to γ-radiation commonly rely on use of animal models because culture systems do not faithfully mimic human intestinal physiology. Here we used a human Gut-on-a-Chip (Gut Chip) microfluidic device lined by human intestinal epithelial cells and vascular endothelial cells to model radiation injury and assess the efficacy of radiation countermeasure drugs in vitro. Exposure of the Gut Chip to γ-radiation resulted in increased generation of reactive oxygen species, cytotoxicity, apoptosis, and DNA fragmentation, as well as villus blunting, disruption of tight junctions, and compromise of intestinal barrier integrity. In contrast, pre-treatment with a potential prophylactic radiation countermeasure drug, dimethyloxaloylglycine (DMOG), significantly suppressed all of these injury responses. Thus, the human Gut Chip may serve as an in vitro platform for studying radiation-induced cell death and associate gastrointestinal acute syndrome, in addition to screening of novel radio-protective medical countermeasure drugs.
Genetic modification to induce CXCR2 overexpression in mesenchymal stem cells enhances treatment benefits in radiation-induced oral mucositis
Authors: Shen Zongshan , Wang Jiancheng , Huang Qiting , Shi Yue , Wei Zhewei , Zhang Xiaoran , Qiu Yuan , Zhang Min , Wang Yi , Qin Wei , Huang Shuheng , Huang Yinong , Liu Xin , Xia Kai , Zhang Xinchun , Lin Zhengmei
Published: February 2018

Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR2-overexpressing MSCs (MSCsCXCR2) for mucositis treatment. Indeed, MSCsCXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSCCXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.
Rage induces hepatocellular carcinoma proliferation and sorafenib resistance by modulating autophagy
Authors: Li Jun , Wu Peng-Wen , Zhou Yuan , Dai Bo , Zhang Peng-Fei , Zhang Yu-Hen , Liu Yang , Shi Xiao-Lei
Published: February 2018

The receptor for advanced glycation end products (Rage) is involved in the development of various tumors and acts as an oncogenic protein. Rage is overexpressed in tumors including hepatocellular carcinoma (HCC). However, the molecular mechanism of Rage in HCC progression and sorafenib resistance remains unclear. In this study, enhanced Rage expression is highly associated proliferation and contributes to sorafenib resistance. Rage deficiency contributed to autophagy induction through activating AMPK/mTOR signaling pathway, which is important for sorafenib response. Moreover, the interactions between Rage and Rage ligands such as high mobility group box 1 (HMGB1) and s100a4 positively increased Rage expression. Our data indicate that Rage may be a potential target for therapeutic intervention in HCC and biomarker for sorafenib resistance.
NR4A2 protects cardiomyocytes against myocardial infarction injury by promoting autophagy
Authors: Liu Honghong , Liu Pingping , Shi Xingxing , Yin Deling , Zhao Jing
Published: February 2018

Myocardial infarction (MI), characterized by ischemia-induced cardiomyocyte apoptosis, is the leading cause of mortality worldwide. NR4A2, a member of the NR4A orphan nucleus receptor family, is upregulated in mouse hearts with MI injury. Furthermore, NR4A2 knockdown aggravates heart injury as evidenced by enlarged hearts and increased apoptosis. To elucidate the underlying mechanisms of NR4A2-regulated apoptosis, we used H9c2 cardiomyocytes deprived of serum and neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia to mimic ischemic conditions in vivo. As NR4A2 knockdown aggravates cardiomyocyte apoptosis, while NR4A2 overexpression ameliorates it, NR4A2 upregulation was considered an adaptive response to ischemia-induced cardiomyocyte apoptosis. By detecting changes in LC3 and using autophagy detection tools including Bafilomycin A1, 3MA and rapamycin, we found that NR4A2 knockdown promoted apoptosis through blocking autophagic flux. This apoptotic response was phenocopied by downregulation of NR4A2 after autophagic flux was impaired by Bafilomycin A1. Further study showed that NR4A2 binds to p53 directly and decreases its levels when it inhibits apoptosis; thus, p53/Bax is the downstream effector of NR4A2-mediated apoptosis, as previously reported. Changes in p53/Bax that were regulated by NR4A2 were also detected in injured hearts with NR4A2 knockdown. In addition, miR-212-3p is the upstream regulator of NR4A2, and it could downregulate the expression of NR4A2, as well as p53/Bax. The mechanism underlying the role of NR4A2 in apoptosis and autophagy was elucidated, and NR4A2 may be a therapeutic drug target for heart failure.
#2714, a novel active inhibitor with potent G2/M phase arrest and antitumor efficacy in preclinical models
Authors: Lu Wen-Jie , Peng Wen , Sun Qian-Qian , Li Yong-Huai , Chen Bo , Yu Luo-Ting , Xu You-Zhi , Wang Si-Ying , Zhao Ying-Lan
Published: February 2018

Arresting cell cycle has been one of the most common approaches worldwide in cancer therapy. Specifically, arresting cells in the G2/M phase is a promising therapeutic approach in the battle against lung cancer. In the present study, we demonstrated the anticancer activities and possible mechanism of compound #2714, which can prompt G2/M phase arrest followed by cell apoptosis induction in Lewis lung carcinoma LL/2 cells. In vitro, #2714 significantly inhibited LL/2 cell viability in a concentration- and time-dependent manner while exhibiting few toxicities on non-cancer cells. The mechanism study showed that cell proliferation inhibition due to the treatment with #2714 correlated with G2/M phase arrest and was followed by LL/2 cell apoptosis. The characterized changes were associated with the downregulation of phosphorylated cell division cycle 25C (Cdc25C) and upregulation of p53. Apoptosis-associated activation of cleaved caspase-3 was also detected. Moreover, #2714 strongly attenuated LL/2 cell proliferation by disrupting the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). In vivo, intraperitoneal administration of #2714 (25–100 mg/kg/day) to mice bearing established tumors in xenograft models significantly prevented LL/2 tumor growth (58.1%) without detectable toxicity. Compound #2714 significantly increased apoptosis in LL/2 lung cancer cells in mice models, as observed via terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and the data from an immunohistochemical analysis showed that #2714 remarkably inhibited the proliferation and angiogenesis of lung cancer in vivo. Taken together, our data suggest that #2714 has a high potential anti-lung cancer efficacy with a pathway-specific mechanism of G2/M phase arrest and subsequent apoptosis induction both in vitro and in vivo; its potential to be an anticancer candidate warrants further investigation.
Oxidation-stable amine-containing adsorbents for carbon dioxide capture
Authors: Min Kyungmin , Choi Woosung , Kim Chaehoon , Choi Minkee
Published: February 2018

Amine-containing solids have been investigated as promising adsorbents for CO2 capture, but the low oxidative stability of amines has been the biggest hurdle for their practical applications. Here, we developed an extra-stable adsorbent by combining two strategies. First, poly(ethyleneimine) (PEI) was functionalized with 1,2-epoxybutane, which generates tethered 2-hydroxybutyl groups. Second, chelators were pre-supported onto a silica support to poison p.p.m.-level metal impurities (Fe and Cu) that catalyse amine oxidation. The combination of these strategies led to remarkable synergy, and the resultant adsorbent showed a minor loss of CO2 working capacity (8.5%) even after 30 days aging in O2-containing flue gas at 110 °C. This corresponds to a ~50 times slower deactivation rate than a conventional PEI/silica, which shows a complete loss of CO2 uptake capacity after the same treatment. The unprecedentedly high oxidative stability may represent an important breakthrough for the commercial implementation of these adsorbents.
Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease
Authors: Idowu Jessica , Home Trisha , Patel Nisha , Magenheimer Brenda , Tran Pamela V. , Maser Robin L. , Ward Christopher J. , Calvet James P. , Wallace Darren P. , Sharma Madhulika
Published: February 2018

Polycystic kidney disease (PKD) is a genetic disorder characterized by fluid-filled cysts in the kidney and liver that ultimately leads to end-stage renal disease. Currently there is no globally approved therapy for PKD. The Notch signaling pathway regulates cellular processes such as proliferation and de-differentiation, which are cellular hallmarks of PKD. Thus we hypothesized that the Notch pathway plays a critical role in PKD. Evaluation of protein expression of Notch signaling components in kidneys of Autosomal Recessive PKD (ARPKD) and Autosomal Dominant PKD (ADPKD) mouse models and of ADPKD patients revealed that Notch pathway members, particularly Notch3, were consistently upregulated or activated in cyst-lining epithelial cells. Notch3 expression correlated with rapidly growing cysts and co-localized with the proliferation marker, PCNA. Importantly, Notch inhibition significantly decreased forskolin-induced Notch3 activation and proliferation of primary human ADPKD cells, and significantly reduced cyst formation and growth of human ADPKD cells cultured in collagen gels. Thus our data indicate that Notch3 is aberrantly activated and facilitates epithelial cell proliferation in PKD, and that inhibition of Notch signaling may prevent cyst formation and growth.
The optimal movement patterns for mating encounters with sexually asymmetric detection ranges
Authors: Mizumoto Nobuaki , Dobata Shigeto
Published: February 2018

Animals have evolved various sex-specific characteristics to improve the efficiency of mating encounters. One is the sex-specific attracting signal. Signal receivers perform a combination of random search and navigation before and after signal detections. On the other hand, signal senders can also modify their movement patterns to optimize their encounter rates, which invokes a reverse side of random search problems that asks for the most efficient movement patterns of signal senders to be found by signal receivers. In this study, we focused on visual and auditory signals in particular, and quantified the efficiency of mating encounters of individual animals performing a Lévy walk, a special class of random walk, with a variety of speeds before signal detection. We found that signal senders should move more slowly and/or less diffusively than receivers to improve mating encounters. The optimal movement patterns of senders ranged from relatively slow to stationary ones depending on the density of individuals, the effective range of signals, and the ability of receivers to locate senders. By focusing on the optimal movement patterns of individuals that are often assumed to be given targets, the present study provides insights into strategies of effective attraction beyond the case of mate search.
Optogenetic Tractography for anatomo-functional characterization of cortico-subcortical neural circuits in non-human primates
Authors: Senova S. , Poupon C. , Dauguet J. , Stewart H. J. , Dugué G. P. , Jan C. , Hosomi K. , Ralph G. S. , Barnes L. , Drouot X. , Pouzat C. , Mangin J. F. , Pain F. , Doignon I. , Aron-Badin R. , Brouillet E. , Boyden E. S. , Mitrophanous K. A. , Hantraye P. , Palfi S.
Published: February 2018

Dissecting neural circuitry in non-human primates (NHP) is crucial to identify potential neuromodulation anatomical targets for the treatment of pharmacoresistant neuropsychiatric diseases by electrical neuromodulation. How targets of deep brain stimulation (DBS) and cortical targets of transcranial magnetic stimulation (TMS) compare and might complement one another is an important question. Combining optogenetics and tractography may enable anatomo-functional characterization of large brain cortico-subcortical neural pathways. For the proof-of-concept this approach was used in the NHP brain to characterize the motor cortico-subthalamic pathway (m_CSP) which might be involved in DBS action mechanism in Parkinson’s disease (PD). Rabies-G-pseudotyped and Rabies-G-VSVg-pseudotyped EIAV lentiviral vectors encoding the opsin ChR2 gene were stereotaxically injected into the subthalamic nucleus (STN) and were retrogradely transported to the layer of the motor cortex projecting to STN. A precise anatomical mapping of this pathway was then performed using histology-guided high angular resolution MRI tractography guiding accurately cortical photostimulation of m_CSP origins. Photoexcitation of m_CSP axon terminals or m_CSP cortical origins modified the spikes distribution for photosensitive STN neurons firing rate in non-equivalent ways. Optogenetic tractography might help design preclinical neuromodulation studies in NHP models of neuropsychiatric disease choosing the most appropriate target for the tested hypothesis.
Passively mode-locked interband cascade optical frequency combs
Authors: Bagheri Mahmood , Frez Clifford , Sterczewski Lukasz A. , Gruidin Ivan , Fradet Mathieu , Vurgaftman Igor , Canedy Chadwick L. , Bewley William W. , Merritt Charles D. , Kim Chul Soo , Kim Mijin , Meyer Jerry R.
Published: February 2018

Since their inception, optical frequency combs have transformed a broad range of technical and scientific disciplines, spanning time keeping to navigation. Recently, dual comb spectroscopy has emerged as an attractive alternative to traditional Fourier transform spectroscopy, since it offers higher measurement sensitivity in a fraction of the time. Midwave infrared (mid-IR) frequency combs are especially promising as an effective means for probing the strong fundamental absorption lines of numerous chemical and biological agents. Mid-IR combs have been realized via frequency down-conversion of a near-IR comb, by optical pumping of a micro-resonator, and beyond 7 μm by four-wave mixing in a quantum cascade laser. In this work, we demonstrate an electrically-driven frequency comb source that spans more than 1 THz of bandwidth centered near 3.6 μm. This is achieved by passively mode-locking an interband cascade laser (ICL) with gain and saturable absorber sections monolithically integrated on the same chip. The new source will significantly enhance the capabilities of mid-IR multi-heterodyne frequency comb spectroscopy systems.
Consequences of VHL Loss on Global DNA Methylome
Authors: Robinson Claire M. , Lefebvre Francois , Poon Betty P. , Bousard Aurelie , Fan Xiaojun , Lathrop Mark , Tost Jorg , Kim William Y. , Riazalhosseini Yasser , Ohh Michael
Published: February 2018

In clear-cell renal cell carcinoma (ccRCC), loss of von Hippel-Lindau (VHL) tumour suppressor gene and reduced oxygen tension promote stabilisation of hypoxia-inducible factor (HIF) family of transcription factors, which promote changes in the expression of genes that contribute to oncogenesis. Multiple studies have demonstrated significant perturbations in DNA methylation in ccRCC via largely unclear mechanisms that modify the transcriptional output of tumour cells. Here, we show that the methylation status of the CpG dinucleotide within the consensus hypoxia-responsive element (HRE) markedly influences the binding of HIF and that the loss of VHL results in significant alterations in the DNA methylome. Surprisingly, hypoxia, which likewise promotes HIF stabilisation and activation, has relatively few effects on global DNA methylation. Gene expression analysis of ccRCC patient samples highlighted expression of a group of genes whose transcription correlated with methylation changes, including hypoxic responsive genes such as VEGF and TGF. These results suggest that the loss of VHL alters DNA methylation profile across the genome, commonly associated with and contributing to ccRCC progression.
Compensatory increases in tear volume and mucin levels associated with meibomian gland dysfunction caused by stearoyl-CoA desaturase-1 deficiency
Authors: Inaba Takaaki , Tanaka Yasuhisa , Tamaki Shusaku , Ito Tomotaka , Ntambi James M. , Tsubota Kazuo
Published: February 2018

The stearoyl-CoA desaturase (SCD) family of enzymes catalyzes monounsaturated fatty acid synthesis by inserting a cis double bond at the Δ9 position of saturated fatty acids. Disruption of these enzymes has been reported to induce a severe dry skin phenotype. Since lipid abnormalities in the meibomian glands have been associated with dry eye, we analyzed selected eye tissues contributing to tear volume and composition in genetically SCD-1-deficient mice (SCD-1 KO), including the lacrimal glands and conjunctiva. Previous histopathological analysis had revealed atrophy and loss of meibomian glands; taken together with the increased goblet cell and MUC5AC expression in the conjunctiva reported here, these findings suggest that the tear volume and mucin levels secreted are enhanced in the absence of lipid secretion as a compensatory mechanism. The expression of lipid metabolism genes in lacrimal glands was decreased in SCD1 KO mice. Thus, these results provide new pathophysiological mechanisms to pursue with regard to meibomian gland dysfunction. In addition, lack of SCD-1 causes a compensatory increase in the tear volume and mucin levels associated with changes in expression of lipid metabolism genes. These results may be useful as a new concept for dry eye treatment strategies.
Opportunistic random searcher versus intentional search image user
Authors: Garay József , Varga Zoltán , Móri Tamás F. , López Inmaculada , Gámez Manuel , Gallego Juan R. , Cabello Tomás
Published: February 2018

We consider two types of optimal foragers: a random searcher and a search image user. A search image user can find its desired prey with higher and undesired prey with lower probability than a random searcher. Our model considers the density-dependent travelling time and the time duration of reproduction (oviposition). In the framework of optimal foraging theory for one predator–two prey systems, we find that there are ranges of prey densities in which the search image user has a higher net energy intake, and there are other ranges of prey densities in which the random searcher has higher net energy intake. The damsel bug Nabis pseudoferus Remane (Hemiptera: Nabidae) is a generalist predator rather than an omnivore. This species has a wide range of arthropod prey (predominantly insects and mites). Several aspects of the biology of this species have been studied, especially its cannibalistic behaviour, which is a quite important feature because N. pseudoferus is often used as a biological control agent against lepidopteran pests in greenhouse crops. Experimentally, we found that Nabis is a search image user in the above sense.