bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug conjugates—an emerging approach to treat breast cancer
Authors: Hasan Mahmud , Leak Rehana K. , Stratford Robert E. , Zlotos Darius P. , Witt‐Enderby Paula A.
Published: July 2018

Breast cancer treatment using a single drug is associated with a high failure rate due, in part, to the heterogeneity of drug response within individuals, nonspecific target action, drug toxicity, and/or development of resistance. Use of dual‐drug therapies, including drug conjugates, may help overcome some of these roadblocks by more selective targeting of the cancer cell and by acting at multiple drug targets rather than one. Drug‐conjugate approaches include linking drugs to antibodies (antibody‐drug conjugates), radionuclides (radioimmunoconjugates), nanoparticles (nanoparticle‐drug conjugates), or to other drugs (drug‐drug conjugates). Although all of these conjugates might be designed as effective treatments against breast cancer, the focus of this review will be on drug‐drug conjugates because of the increase in versatility of these types of drugs with respect to mode of action at the level of the cancer cell either by creating a novel pharmacophore or by increasing the potency and/or efficacy of the drugs’ effects at their respective molecular targets. The development, synthesis, and pharmacological characteristics of drug‐drug conjugates will be discussed in the context of breast cancer with the hope of enhancing drug efficacy and reducing toxicities to improve patient quality of life.
Gradual Evolution From Quantum‐Well‐Like to Quantum‐Dot‐Like Characteristics in InGaAs/GaAs Nanostructures
Authors: Nadtochiy Alexey M. , Maximov Mikhail V. , Mintairov Sergey A. , Kalyuzhnyy Nikolay A. , Nevedomskiy Vladimir N. , Rouvimov Sergey S. , Zhukov Alexey E.
Published: July 2018

Dense arrays of carrier localizing indium‐rich regions (referred to as quantum well‐dots, QWDs) formed inside an indium‐depleted residual quantum well by metalorganic vapor phase epitaxial deposition of 4–16 monolayers (ML) of InxGa1−xAs (0.3 < x < 0.5) on 6° misoriented GaAs (100) substrates are studied. It is shown that in addition to QWDs the deposited layers may contain other objects with size and shape similar to conventional self‐organized quantum dots (QDs). Transmission electron microscopy and photoluminescence studies reveal that the density of QDs grows with the increase in indium composition and average amount of deposited InGaAs. The QWDs show efficient absorption in the optical region of 900–1100 nm, whereas QDs do not contribute to photocurrent spectra and result in a waste of carriers. Optimal indium composition x to form QWDs with high structural and optical quality is about 0.4. For x = 0.3 the QWDs are not yet well developed, while for x = 0.5 the density of QDs becomes too high.
Exact two‐sided statistical tolerance limits for sample variances
Authors: Sarmiento Martin G.C. , Chakraborti S. , Epprecht Eugenio K.
Published: July 2018

Statistical tolerance intervals are widely used in the industry and in various areas of sciences, especially in conformity assessment and acceptance of products or processes in terms of quality. When the interest is in precision, a tolerance interval for the variance is useful. In this paper, we consider two‐sided tolerance intervals for the population of sample variances for data that arise from a normal distribution. These intervals are useful in applications where one needs information about process deterioration as well as process improvement, to properly assess product quality. In this paper, the theory for these tolerance intervals is developed and tables for the tolerance factors, required to calculate the proposed tolerance limits, are provided for various settings. Construction and implementation of the proposed tolerance intervals are illustrated using a dataset from a real application. Summary and conclusions are offered.
Towards a benefits dependency network for DevOps based on a systematic literature review
Authors: Jabbari Ramtin , bin Ali Nauman , Petersen Kai , Tanveer Binish
Published: July 2018

DevOps as a new way of thinking for software development and operations has received much attention in the industry, while it has not been thoroughly investigated in academia yet. The objective of this study is to characterize DevOps by exploring its central components in terms of principles, practices and their relations to the principles, challenges of DevOps adoption, and benefits reported in the peer‐reviewed literature. As a key objective, we also aim to realize the relations between DevOps practices and benefits in a systematic manner. A systematic literature review was conducted. Also, we used the concept of benefits dependency network to synthesize the findings, in particular, to specify dependencies between DevOps practices and link the practices to benefits. We found that in many cases, DevOps characteristics, ie, principles, practices, benefits, and challenges, were not sufficiently defined in detail in the peer‐reviewed literature. In addition, only a few empirical studies are available, which can be attributed to the nascency of DevOps research. Also, an initial version of the DevOps benefits dependency network has been derived. The definition of DevOps principles and practices should be emphasized given the novelty of the concept. Further empirical studies are needed to improve the benefits dependency network presented in this study.
Effect of the Slag Composition and a Protective Atmosphere on Chemical Reactions and Non‐Metallic Inclusions during Electro‐Slag Remelting of a Hot‐Work Tool Steel
Authors: Schneider Reinhold S.E. , Molnar Manuel , Gelder Siegfried , Reiter Gerhard , Martinez Carlos
Published: July 2018

The remelting behavior of the hot‐work tool steel X37CrMoV5‐1 is investigated with several experimental melts on a lab‐scale ESR‐plant. The investigated parameters comprise a variation of the slag compositions and the use of a protective nitrogen atmosphere. Variations of the slag composition include slags with different contents of CaF2, CaO, and Al2O3 as well as a variation of the SiO2‐content in the slag. The remelted ingots are forged and analyzed regarding their chemical composition. The distribution and composition of the non‐metallic inclusions (NMI) is studied by an automated SEM‐EDX method. Additionally, the chemical composition of the slag after remelting is analyzed. The results show clearly an equilibrium reaction between Si and Al in the steel with SiO2 and Al2O3 in the slag as well as the effect of oxygen in open ESR operation. A protective atmosphere reduces the Si‐losses during remelting, but has no major effect on the number or composition of NMI compared to open remelting. The content of NMI, especially the larger ones, is reduced significantly in all remelting experiments. The majority of the NMI are MA‐spinel type except for the CaO‐free slag, where alumina inclusions prevail. In general, remelting leads to an almost complete removal of sulfides, a reduction of oxisulfides, and a slight increase of oxides.
A proposed structural design method considering fluid viscous damper degradations
Authors: Ataei Hossein , Kalbasi Anaraki Kamiar
Published: July 2018

The purpose of this study is to perform a seismic assessment of the moment resistant steel structures enhanced with viscous dampers where the dampers are degraded due to possible leak of viscous fluid. This paper proposes a design procedure based on corrected response spectrums as a result of seismic assessments based on nonlinear time series analyses on three‐, five‐, and seven‐story steel frame structures denoted as “generic structures.” The proposed design procedure is a seismic displacement‐based design methodology for buildings with viscous dampers as passive energy dissipation systems. Prior literature on these types of structures often overlook the viscous dampers degradation due to the fluid leak. In this paper, in order to study these effects, a target displacement is specified at first and the lateral forces and required stiffness are obtained. The effectiveness of the proposed procedure is verified with the collapse fragility curves of the generic structures according to the ASCE 7‐10 and displacement‐based design methodology. The results show that the structures designed based on proposed procedure demonstrate acceptable performance with degrading dampers.
On multi-field flows in gravity and holography
Authors: Nitti Francesco , Pimenta Leandro Silva , Steer Danièle A.
Published: July 2018

Abstract

We perform a systematic analysis of flow-like solutions in theories of Einstein gravity coupled to multiple scalar fields, which arise as holographic RG flows as well as in the context of cosmological solutions driven by scalars. We use the first order formalism and the superpotential formulation to classify solutions close to generic extrema of the scalar potential, and close to “bounces,” where the flow is inverted in some or all directions and the superpotential becomes multi-valued. Although the superpotential formulation contains a large redundancy, we show how this can be completely lift by suitable regularity conditions. We place the first order formalism in the context of Hamilton-Jacobi theory, where we discuss the possibility of non-gradient flows and their connection to non-separable solutions of the Hamilton-Jacobi equation. We argue that non-gradient flows may be useful in the presence of global symmetries in the scalar sector.
Existence of strong minimizers for the Griffith static fracture model in dimension two
Authors: Conti Sergio , Focardi Matteo , Iurlano Flaviana
Published: July 2018

We consider the Griffith fracture model in two spatial dimensions, and prove existence of strong minimizers, with closed jump set and continuously differentiable deformation fields. One key ingredient, which is the object of the present paper, is a generalization to the vectorial situation of the decay estimate by De Giorgi, Carriero, and Leaci. This is based on replacing the coarea formula by a method to approximate

SBD^{p}

functions with small jump set by Sobolev functions, and is restricted to two dimensions. The other two ingredients will appear in companion papers and consist respectively in regularity results for vectorial elliptic problems of the elasticity type and in a method to approximate in energy

GSBD^{p}

functions by

SBV^{p}

ones.
Cuckoo search algorithm for applied structural and design optimization: Float system for experimental setups
Authors: Jalal Mostafa , Goharzay Maral
Published: July 2018

In the present study, Cuckoo Search (CS) as a nature-inspired optimization algorithm was applied for structural and design optimization of a new float system for experimental setups. For this purpose, based on the setup configuration, it was tried to minimize the total length of the float, while maintaining the structural and performance-based constraints. Different geometries for the float structure were examined to come up with the feasible options. The problem was formulated into a constrained optimization in terms of four or five variables, depending on the geometry, along with two performance-based constraints and some structural constraints. CS was used to solve the constrained optimization problem and the convergence trends of the parameters to optimal solutions were examined in details. Generalized reduced gradient (GRG) method known as GRG nonlinear was also used for validation and comparison purpose. The results of the optimization and the performance of the float produced showed that CS can be used as a powerful tool for applied structural and design problems. It should be mentioned that the float problem can be used as a benchmark structural design problem for validation of new optimization algorithms. Besides, the optimal float can be produced for various experimental setups with different structures and constraints, depending on the application.

Highlights Cuckoo Search (CS) algorithm as a metaheuristic approach. Constrained optimization in structural design using CS algorithm. Designing a new float for experimental setups. Production of an optimal float for measurement system. Float design as a benchmark problem for optimization algorithms.
Westgate Oxford Pop Up Museum
Authors: Peacock Becky J.
Published: July 2018

Westgate Oxford is a commercial redevelopment of a large shopping complex in the center of Oxford, with clients Westgate Oxford Alliance and principal contractor Laing O'Rourke. The excavations, carried out by Oxford Archaeology, between 2014 and 2016, were required as part of UK Planning Guidelines and were the largest ever undertaken in the city and principally focused on a large medieval suburban friary. The project won Best Archaeological Project 2016 at the prestigious national British Archaeological Awards, and the outreach program, which included an evolving pop-up museum, was a significant contributing factor. This essay will demonstrate how to set up a pop-up museum in eight steps. The essay will look at how to work with different partners of a project. It will discuss choosing a story to tell and how to deal with a changing narrative on an archaeological site in “real time.” It will show how the Pop Up museum became the principal location for dissemination for the Westgate Oxford project. The essay will conclude with how to keep the story alive and plans for the future of the Westgate Oxford Pop Up Museum.
Extending working life and the management of change. Is the workplace ready for the ageing worker?
Authors: Wainwright David , Crawford Joanne , Loretto Wendy , Phillipson Christopher , Robinson Mark , Shepherd Sue , Vickerstaff Sarah , Weyman Andrew
Published: July 2018

Increasing longevity and the strain on state and occupational pensions have brought into question long-held assumptions about the age of retirement, and raised the prospect of a workplace populated by ageing workers. In the United Kingdom the default retirement age has gone, incremental increases in state pension age are being implemented and ageism has been added to workplace anti-discrimination laws. These changes are yet to bring about the anticipated transformation in workplace demographics, but it is coming, making it timely to ask if the workplace is ready for the ageing worker and how the extension of working life will be managed. We report findings from qualitative case studies of five large organisations located in the United Kingdom. Interviews and focus groups were conducted with employees, line managers, occupational health staff and human resources managers. Our findings reveal a high degree of uncertainty and ambivalence among workers and managers regarding the desirability and feasibility of extending working life; wide variations in how older workers are managed within workplaces; a gap between policies and practices; and evidence that while casualisation might be experienced negatively by younger workers, it may be viewed positively by financially secure older workers seeking flexibility. We conclude with a discussion of the challenges facing employers and policy makers in making the modern workplace fit for the ageing worker.
SES effects on the use of variation sets in child-directed speech
Authors: TAL Shira , ARNON Inbal
Published: July 2018

Socio-economic status (SES) impacts the amount and type of input children hear in ways that have developmental consequences. Here, we examine the effect of SES on the use of variation sets (successive utterances with partial self-repetitions) in child-directed speech (CDS). Variation sets have been found to facilitate language learning, but have been studied only in higher-SES groups. Here, we examine their use in naturalistic speech in two languages (Hebrew and English) for both low- and high-SES caregivers. We find that variation sets are more frequent in the input of high-SES caregivers in both languages, indicating that SES also impacts structural properties of CDS.
Mechanisms of the “Low-Flow” State during Resuscitation of the Totally Ischemic Brain
Authors: Tweed W. A. , Wade J. G. , Davidson W. J.
Published: July 2018

Resuscitation of the brain following total circulatory arrest may be impeded by difficulty in establishing cerebral tissue perfusion, a post-ischemic “low-flow” state. We have confirmed this hypothesis in a rat model of total cerebral ischemia and have demonstrated marked improvement in post-ischemic brain tissue perfusion following epinephrine injection. This is mainly due to the systemic vascular effects of epinephrine, resulting in improved central aortic pressure and cerebral perfusion pressure. Hyperkalemic induced vasoconstriction has also been postulated as a cause of the “low-flow”. We have, therefore, investigated the in vitro effects of increasing potassium ion concentration on cerebrovascular smooth muscle strips. Large arteries constrict, while small arteries dilate in response to hyperkalemia. The net effect on cerebral blood flow remains unsettled. Our research to date suggests that resuscitation of the totally ischemic brain, in animal models at least, is enhanced by epinephrine, mainly via its effects on central aortic pressure.
Regional Cerebral Blood Flow Statistical Patterns and Psychological Performance in Multi-Infarct Dementia and Alzheimer’s Disease
Authors: Perez Francisco I. , Mathew Ninan T. , Stump David A. , Mfyer John S.
Published: July 2018

Multivariate data analysis statistical procedures were applied to identify regional cerebral blood flow (rCBF) patterns in patients with multi-infarct dementia (M.I.D.) and Alzheimer’s disease (A.D.) when compared to a control group (C). A fronto-temporal-parietal pattern was identified for the A.D. group. The M.I.D. group demonstrated a predominant temporal-parietal pattern. A discriminant function analysis classified 96% of the A.D. and C. patients correctly. One hundred percent hit rate was obtained in discriminating between M.I.D. and C. Discrimination of A.D. and M.I.D. obtained 82% diagnostic accuracy. When the three groups were compared the hit rate was 93%. Mean rCBF and mean relative weight of the gray matter (Wg) differences were found when each dementia group was compared with C.M.I.D. and A.D. did not differ in mean rCBF but significant differences were found for Wg, with M.I.D. having greater reduction. The performance on standardized psychological tests of two independent samples of A.D. and M.I.D. were compared. The Memory Quotient from the Wechsler Memory Scale was consistently more impaired for the A.D. group. No correlation between degree of psychological impairment and rCBF or W g reduction was found.
Reproducible and Replicable: An Empirical Assessment of the Social Construction of Politically Relevant Target Groups
Authors: Kreitzer Rebecca J. , Smith Candis Watts
Published: July 2018

Schneider and Ingram introduced the pivotal theory of social construction of target populations in the American Political Science Review nearly 25 years ago. There, they developed four ideal type groups: advantaged, contenders, dependents, and deviants. They noted that there may be contention around the construction of the groups but implied an expectation of consensus. There has not been, however, a systematic categorization of politically salient target groups based on these categories, nor has there been an empirical assessment of whether or the extent to which consensus around the social constructions of salient target groups exists. We revisit this theory to offer a novel perspective and do so by leveraging advances in technology and methodological strategies. By crowdsourcing the task of evaluating the social construction of various target populations, we are able to assess underlying assumptions of theory as well as outline avenues for future research on policy design.
The Role of Complex Combination Therapy in the Treatment of Refractory Bipolar Illness
Authors: Post Robert M. , Frye Mark A. , Leverich Gabriele S. , Denicoff Kirk D.
Published: July 2018

In this article, we present rationales for using complex combination therapy in treatment-refractory bipolar patients and discuss the agents available for use in this therapeutic approach. We review a case example of successful remission that was achievable only with complex combination therapy, and examine its theoretical implications. Practical approaches to devising the optimal complex combination treatment for individual patients are explained, and we look to the development of new methodologies and a more systematic database for decision making in the future.
Rationalizing Systems Analysis for the Evaluation of Adaptation Strategies in Complex Human‐Water Systems
Authors: Essenfelder Arthur H. , Pérez‐Blanco C. Dionisio , Mayer Alex S.
Published: July 2018

Water resources management is a nontrivial process requiring a holistic understanding of the factors driving the dynamics of human‐water systems. Policy‐induced or autonomous behavioral changes in human systems may affect water and land management, which may affect water systems and feedback to human systems, further impacting water and land management. Currently, hydro‐economic models lack the ability to describe such dynamics either because they do not account for the multifactor/multioutput nature of these systems and/or are not designed to operate at a river basin scale. This paper presents a flexible and replicable methodological framework for integrating a microeconomic multifactor/multioutput Positive Multi‐Attribute Utility Programming (PMAUP) model with an eco‐hydrologic model, the Soil and Water Assessment Tool (SWAT). The connection between the models occurs in a sequential modular approach through a common spatial unit, the “hydrologic‐economic representative units” (HERUs), derived from the boundaries of decision‐making entities and hydrologic responsive units. The resulting SWAT‐PMAUP model aims to provide the means for exploring the dynamics between the behavior of socio‐economic agents and their connection with the water system through water and land management. The integrated model is illustrated by simulating the impacts of irrigation restriction policies on the Río Mundo subbasin in south‐eastern Spain. The results suggest that agents' adaptation strategies in response to the irrigation restrictions have broad economic impacts and subsequent consequences on surface and groundwater hydrology. We suggest that the integrated modeling framework can be a valuable tool to support decision‐making in water resources management across a wide range of scales.
Twelve Questions for the Participatory Modeling Community
Authors: Jordan Rebecca , Gray Steven , Zellner Moira , Glynn Pierre D. , Voinov Alexey , Hedelin Beatrice , Sterling Eleanor J. , Leong Kirsten , Olabisi Laura Schmitt , Hubacek Klaus , Bommel Pierre , BenDor Todd K. , Jetter Antonie J. , Laursen Bethany , Singer Alison , Giabbanelli Philippe J. , Kolagani Nagesh , Carrera Laura Basco , Jenni Karen , Prell Christina ,   National Socio‐Environmental Synthesis Center Participatory Modeling Pursuit Working Group
Published: July 2018

Participatory modeling engages the implicit and explicit knowledge of stakeholders to create formalized and shared representations of reality and has evolved into a field of study as well as a practice. Participatory modeling researchers and practitioners who focus specifically on environmental resources met at the National Socio‐Environmental Synthesis Center (SESYNC) in Annapolis, Maryland, over the course of 2 years to discuss the state of the field and future directions for participatory modeling. What follows is a description of 12 overarching groups of questions that could guide future inquiry.
Energetic Electron Diffusion by Modulated Heating of the Ionosphere
Authors: Chang Shanshan , Ni Binbin , Cao Xing , Zhang Xuemin , Zhu Zhengping , Luo Weihua
Published: July 2018

Aiming to assess the effect on the radiation belts due to modulated heating of the ionosphere, this study adopts the test particle simulation to investigate the resonant interaction between energetic electron and the heater‐induced monotonic ELF/VLF (extremely low frequency/very low frequency) waves, with wave distribution obtained by DEMETER observations and numerical computation. It is found that while energy diffusion is weak, pitch angle scattering on energetic electrons can be intense at low equatorial pitch angles near the loss cone for both field‐aligned monotonic waves generated by high‐latitude heater and highly oblique monotonic waves generated by low‐latitude heater. Our investigation supports the feasibility of modulated heating of both high‐latitude ionosphere and low‐latitude ionosphere for controlled precipitation of energetic electron but also suggests that electron diffusion of field‐aligned monotonic waves is more effective, as the diffusion rates can be larger for lower energy electron or at higher equatorial pitch angles and do not vary much with the modulated frequency. Finally, the results are compared with the quasi‐linear theory. Though the test particle diffusion coefficients are in good agreement with the quasi‐linear diffusion coefficients for field‐aligned monotonic waves, they are in very limited agreement for highly oblique monotonic waves, which bring into question the applicability of quasi‐linear theory to monotonic highly oblique wave.
Long‐Range Radiation and Interference Pattern of Multisource M2 Internal Tides in the Philippine Sea
Authors: Wang Yang , Xu Zhenhua , Yin Baoshu , Hou Yijun , Chang Hang
Published: July 2018

Long‐range radiation and interference of M2 internal tides from multiple sources in the Philippine Sea are examined by driving a high‐resolution numerical model. The M2 internal tides are effectively generated around the boundary area, which includes the Luzon Strait, Ryukyu Island chain, Bonin Ridge, Mariana Arc, and Izu Ridge, favoring the occurrence of complex interference patterns. The local sources (mainly Daito Islands and Palau Ridge) inside the basin contribute to a small portion (~5%) of total energy but enhance the geographical inhomogeneity of the baroclinic field. The mode‐1 and mode‐2 M2 tidal beams from boundary sources radiate a long distance into the basin but exhibit different interference‐modulated geography variations. A 2‐D line source model characterizing interference can reproduce the general baroclinic field. Two notable interference cases are investigated: (1) the superposition of internal tides from Luzon Strait and Miyako Strait bifurcates into several southeastward beams, consistent with previous numerical simulations and altimeter measurements, and (2) the interference between Tokara Strait and Bonin Ridge exhibits a multiscale spatial pattern, which is modulated by the local generated energy and bathymetry features. Energetic dissipation occurs both near the boundary sources and in the basin. A locally dissipated fraction q of ~0.4 is estimated at the Luzon Strait and Bonin Ridge with continuous bathymetry features, while q of ~0.6 is estimated at the Ryukyu Island chain and Mariana Arc with discrete topographic variability. A lower locally dissipated fraction indicates a stronger energy flux radiating into the basin, where enhanced dissipation coincides closely with the interference‐modulated flux field.
Estimator of Surface Ozone Using Formaldehyde and Carbon Monoxide Concentrations Over the Eastern United States in Summer
Authors: Cheng Ye , Wang Yuhang , Zhang Yuzhong , Crawford James H. , Diskin Glenn S. , Weinheimer Andrew J. , Fried Alan
Published: July 2018

Strong correlations of O3‐CH2O, O3‐CO and CO‐CH2O were observed during the Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER‐AQ) aircraft experiment in July 2011 over the Washington‐Baltimore area. The linear regression slopes of observed O3‐CH2O, O3‐CO, and CO‐CH2O do not vary significantly with time (11 a.m. to 4 p.m.) or altitude in the boundary layer. These observed relationships are simulated well by a regional chemical transport model. Using tagged‐tracer simulations, we find that biogenic isoprene oxidation makes the largest contribution to the regression slope of O3‐CH2O across much of the eastern United States, providing a good indicator for O3 enhanced by biogenic isoprene oxidation. In contrast, the regression slope of O3‐CO is controlled by both anthropogenic and biogenic emissions. Therefore, we use the CO‐CH2O relationship to separate biogenic from anthropogenic contributions to CO. By combining these regressions, we can track the contributions to surface O3 by anthropogenic and biogenic factors and build a fast‐response ozone estimator using near‐surface CH2O and CO concentrations as inputs. We examine the quality of O3 estimator by increasing or decreasing anthropogenic emissions by up to 50%. The estimated O3 distribution is in reasonably good agreement with the full‐model simulations (R2 > 0.77 in the range of −30% to +50% of anthropogenic emissions). The analysis provides the basis for using high‐quality geostationary satellites with UV, thermal infrared, or near‐infrared instruments for observing CH2O and CO to improve surface O3 distribution monitoring. The estimation model can also be applied to derive observation‐derived regional metrics to evaluate and improve full‐fledged 3‐D air quality models.
Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification
Authors: Melnik Svitlana , Dvornikov Dmytro , Müller-Decker Karin , Depner Sofia , Stannek Peter , Meister Michael , Warth Arne , Thomas Michael , Muley Tomas , Risch Angela , Plass Christoph , Klingmüller Ursula , Niehrs Christof , Glinka Andrey
Published: July 2018

Use of the diabetes type II drug Metformin is associated with a moderately lowered risk of cancer incidence in numerous tumor entities. Studying the molecular changes associated with the tumor-suppressive action of Metformin we found that the oncogene SOX4, which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/β-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. Unraveling the underlying specificity, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor DDIT3, known to block Wnt signaling. Moreover, our results suggest that intracellular acidification universally inhibits Wnt signaling. Based on these findings, we combined MCI inhibitors with H+ ionophores, to escalate cancer cells into intracellular hyper-acidification and ATP depletion. This treatment lowered intracellular pH both in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated SOX4, and strongly decreased stemness and viability of cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of β-catenin, encouraging applications in treatment of cancers caused by APC and β-catenin mutations.
Large-scale gene losses underlie the genome evolution of parasitic plant Cuscuta australis
Authors: Sun Guiling , Xu Yuxing , Liu Hui , Sun Ting , Zhang Jingxiong , Hettenhausen Christian , Shen Guojing , Qi Jinfeng , Qin Yan , Li Jing , Wang Lei , Chang Wei , Guo Zhenhua , Baldwin Ian T. , Wu Jianqiang
Published: July 2018

Dodders (Cuscuta spp., Convolvulaceae) are root- and leafless parasitic plants. The physiology, ecology, and evolution of these obligate parasites are poorly understood. A high-quality reference genome of Cuscuta australis was assembled. Our analyses reveal that Cuscuta experienced accelerated molecular evolution, and Cuscuta and the convolvulaceous morning glory (Ipomoea) shared a common whole-genome triplication event before their divergence. C. australis genome harbors 19,671 protein-coding genes, and importantly, 11.7% of the conserved orthologs in autotrophic plants are lost in C. australis. Many of these gene loss events likely result from its parasitic lifestyle and the massive changes of its body plan. Moreover, comparison of the gene expression patterns in Cuscuta prehaustoria/haustoria and various tissues of closely related autotrophic plants suggests that Cuscuta haustorium formation requires mostly genes normally involved in root development. The C. australis genome provides important resources for studying the evolution of parasitism, regressive evolution, and evo-devo in plant parasites.
An intercross population study reveals genes associated with body size and plumage color in ducks
Authors: Zhou Zhengkui , Li Ming , Cheng Hong , Fan Wenlei , Yuan Zhengrong , Gao Qiang , Xu Yaxi , Guo Zhanbao , Zhang Yunsheng , Hu Jian , Liu Hehe , Liu Dapeng , Chen Weihuang , Zheng Zhuqing , Jiang Yong , Wen Zhiguo , Liu Yongming , Chen Hua , Xie Ming , Zhang Qi , Huang Wei , Wang Wen , Hou Shuisheng , Jiang Yu
Published: July 2018

Comparative population genomics offers an opportunity to discover the signatures of artificial selection during animal domestication, however, their function cannot be directly revealed. We discover the selection signatures using genome-wide comparisons among 40 mallards, 36 indigenous-breed ducks, and 30 Pekin ducks. Then, the phenotypes are fine-mapped based on resequencing of 1026 ducks from an F2 segregating population generated by wild × domestic crosses. Interestingly, the two key economic traits of Pekin duck are associated with two selective sweeps with fixed mutations. A novel intronic insertion most possibly leads to a splicing change in MITF accounted for white duck down feathers. And a putative long-distance regulatory mutation causes continuous expression of the IGF2BP1 gene after birth which increases body size by 15% and feed efficiency by 6%. This study provides new insights into genotype–phenotype associations in animal research and constitutes a promising resource on economically important genes in fowl.
Discovery of a drug candidate for GLIS3-associated diabetes
Authors: Amin Sadaf , Cook Brandoch , Zhou Ting , Ghazizadeh Zaniar , Lis Raphael , Zhang Tuo , Khalaj Mona , Crespo Miguel , Perera Manuradhi , Xiang Jenny Zhaoying , Zhu Zengrong , Tomishima Mark , Liu Chengyang , Naji Ali , Evans Todd , Huangfu Danwei , Chen Shuibing
Published: July 2018

GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3−/− β-like cells have been unsuccessful. Here, we develop a “minimal component” protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3−/− hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.
Collective molecular switching in hybrid superlattices for light-modulated two-dimensional electronics
Authors: Gobbi Marco , Bonacchi Sara , Lian Jian X. , Vercouter Alexandre , Bertolazzi Simone , Zyska Björn , Timpel Melanie , Tatti Roberta , Olivier Yoann , Hecht Stefan , Nardi Marco V. , Beljonne David , Orgiu Emanuele , Samorì Paolo
Published: July 2018

Molecular switches enable the fabrication of multifunctional devices in which an electrical output can be modulated by external stimuli. The working mechanism of these devices is often hard to prove, since the molecular switching events are only indirectly confirmed through electrical characterization, without real-space visualization. Here, we show how photochromic molecules self-assembled on graphene and MoS2generate atomically precise superlattices in which a light-induced structural reorganization enables precise control over local charge carrier density in high-performance devices. By combining different experimental and theoretical approaches, we achieve exquisite control over events taking place from the molecular level to the device scale. Unique device functionalities are demonstrated, including the use of spatially confined light irradiation to define reversible lateral heterojunctions between areas possessing different doping levels. Molecular assembly and light-induced doping are analogous for graphene and MoS2, demonstrating the generality of our approach to optically manipulate the electrical output of multi-responsive hybrid devices.
Systemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila
Authors: Cho Bumsik , Spratford Carrie M. , Yoon Sunggyu , Cha Nuri , Banerjee Utpal , Shim Jiwon
Published: July 2018

Drosophila hemocytes are akin to mammalian myeloid blood cells that function in stress and innate immune-related responses. A multi-potent progenitor population responds to local signals and to systemic stress by expanding the number of functional blood cells. Here we show mechanisms that demonstrate an integration of environmental carbon dioxide (CO2) and oxygen (O2) inputs that initiate a cascade of signaling events, involving multiple organs, as a stress response when the levels of these two important respiratory gases fall below a threshold. The CO2 and hypoxia-sensing neurons interact at the synaptic level in the brain sending a systemic signal via the fat body to modulate differentiation of a specific class of immune cells. Our findings establish a link between environmental gas sensation and myeloid cell development in Drosophila. A similar relationship exists in humans, but the underlying mechanisms remain to be established.
Tools for engineering coordinated system behaviour in synthetic microbial consortia
Authors: Kylilis Nicolas , Tuza Zoltan A. , Stan Guy-Bart , Polizzi Karen M.
Published: July 2018

Advancing synthetic biology to the multicellular level requires the development of multiple cell-to-cell communication channels that propagate information with minimal signal interference. The development of quorum-sensing devices, the cornerstone technology for building microbial communities with coordinated system behaviour, has largely focused on cognate acyl-homoserine lactone (AHL)/transcription factor pairs, while the use of non-cognate pairs as a design feature has received limited attention. Here, we demonstrate a large library of AHL-receiver devices, with all cognate and non-cognate chemical signal interactions quantified, and we develop a software tool that automatically selects orthogonal communication channels. We use this approach to identify up to four orthogonal channels in silico, and experimentally demonstrate the simultaneous use of three channels in co-culture. The development of multiple non-interfering cell-to-cell communication channels is an enabling step that facilitates the design of synthetic consortia for applications including distributed bio-computation, increased bioprocess efficiency, cell specialisation and spatial organisation.
An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease
Authors: Jin Ming , O’Nuallain Brian , Hong Wei , Boyd Justin , Lagomarsino Valentina N. , O’Malley Tiernan T. , Liu Wen , Vanderburg Charles R. , Frosch Matthew P. , Young-Pearse Tracy , Selkoe Dennis J. , Walsh Dominic M.
Published: July 2018

Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer’s disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the use of Aβ-rich aqueous extracts of brain samples from AD patients as a source of human Aβ and live-cell imaging of iPSC-derived human neurons to develop a bioassay capable of quantifying the relative protective effects of multiple anti-Aβ antibodies. We report the characterization of 1C22, an aggregate-preferring murine anti-Aβ antibody, which better protects against forms of Aβ oligomers that are toxic to neurites than do the murine precursors of the clinical immunotherapeutics, bapineuzumab and solanezumab. These results suggest further examination of 1C22 is warranted, and that this bioassay maybe useful as a primary screen to identify yet more potent anti-Aβ therapeutics.
The impact of stimulus size and orientation on individual face coding in monkey face-selective cortex
Authors: Taubert Jessica , Van Belle Goedele , Vogels Rufin , Rossion Bruno
Published: July 2018

Face-selective neurons in the monkey temporal cortex discharge at different rates in response to pictures of different individual faces. Here we tested whether this pattern of response across single neurons in the face-selective area ML (located in the middle Superior Temporal Sulcus) tolerates two affine transformations; picture-plane inversion, known to decrease the average response of face-selective neurons and the other, stimulus size. We recorded the response of 57 ML neurons in two awake and fixating monkeys. Face stimuli were presented at two sizes (10 and 5 degrees of visual angle) and two orientations (upright and inverted). Different faces elicited distinct patterns of activity across ML neurons that were reliable (i.e., predictable with a classifier) within a specific size and orientation condition. Despite observing a reduction in the average response magnitude of face-selective neurons to inverted faces, compared to upright faces, classifier performance was above chance for both upright and inverted faces. While decoding was largely preserved across changes in stimulus size, a classifier trained with one orientation condition and tested on the other did not lead to performance above chance level. We conclude that different individual faces can be decoded from patterns of responses in the monkey area ML regardless of orientation or size, but with qualitatively different patterns of responses for upright and inverted faces.
Evolutionary and expression analysis of CAMTA gene family in Nicotiana tabacum yielded insights into their origin, expansion and stress responses
Authors: Kakar Kaleem U. , Nawaz Zarqa , Cui Zhouqi , Cao Peijian , Jin Jingjing , Shu Qingyao , Ren Xueliang
Published: July 2018

Calmodulin-binding transcription activators (CAMTAs) represent the novel gene family of transcriptional regulators, which play important biological functions. Though, the first ever plant CAMTA gene was evidenced in Nicotiana tabacum in 2002. But, the systematic identification, origin and function of this gene family has not been performed due to the lack of reference genome information until now. Here, we identified 29 CAMTA genes in four Nicotiana species, including thirteen NtabCAMTAs, six NsylCAMTAs, and five NtomCAMTAs and NbenCAMTAs. These CAMTA families were classified into five phylogenetic groups (I-V), among which, the group-IV CAMTAs probably emerged the earliest. The NtabCAMTA family genes have diverse structures, and are randomly localized on five chromosomes and scaffolds. N. tabacum acquired 11 copies of homolog CAMATA genes from the parental genomes of N. tomentosiformis and N. sylvestris, followed by expansion through polyploidization and duplication. The NtabCAMTA genes were differentially expressed in different plant parts, and showed sensitivity towards different abiotic and biotic stresses. Co-expression network analysis revealed that some NtabCAMTA subunits interact with each other, and co-expressed. The current study is the first report presenting a comprehensive overview of Nicotiana CAMTA families, and opens a new avenue for the improvement of the cultivated tobacco.
A subduction and mantle plume origin for Samoan volcanism
Authors: Strak Vincent , Schellart Wouter P.
Published: July 2018

The origin of Samoan volcanism in the southwest Pacific remains enigmatic. Whether mantle melting is solely caused by a mantle plume is questionable because some volcanism, here referred to as non-hotspot volcanism, defies the plume model and its linear age-progression trend. Indeed, non-hotspot volcanism occurred as far as 740 km west of the predicted Samoan hotspot after 5 Ma. Here we use fully-dynamic laboratory subduction models and a tectonic reconstruction to show that the nearby Tonga-Kermadec-Hikurangi (TKH) subduction zone induces a broad mantle upwelling around the northern slab edge that coincides with the non-hotspot volcanic activity after 5 Ma. Using published potential mantle temperatures for the ambient mantle and Samoan mantle plume, we find that two geodynamic processes can explain mantle melting responsible for intraplate volcanism in the Samoan region. We propose that before 5 Ma, the volcanism is consistent with the plume model, whereas afterwards non-hotspot volcanism resulted from interaction between the Subduction-Induced Mantle Upwelling (SIMU) and Samoan mantle plume material that propagated west from the hotspot due to the toroidal component of slab rollback-induced mantle flow. In this geodynamic scenario, the SIMU drives decompression melting in the westward-swept plume material, thus producing the non-hotpot volcanism.
Voltage-Controlled Magnetic Anisotropy in Fe1−xCox/Pd/MgO system
Authors: Shukla Amit Kumar , Goto Minori , Xu Xiandong , Nawaoka Kohei , Suwardy Joko , Ohkubo Tadakatsu , Hono Kazuhiro , Miwa Shinji , Suzuki Yoshishige
Published: July 2018

Voltage-controlled magnetic anisotropy (VCMA) in an epitaxially grown Fe/Fe1−xCox/Pd/MgO system was investigated using spin-wave spectroscopy. The spin-wave resonant frequency linearly depended on the bias-voltage. The resonant-frequency shift increased with the Co fraction in Fe1−xCox/Pd. We achieved a VCMA of approximately 250 fJ/Vm at the Co/Pd/MgO region.
Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts
Authors: Edgar Suzanne , Hopley Blake , Genovese Licia , Sibilla Sara , Laight David , Shute Janis
Published: July 2018

Nutraceuticals containing collagen peptides, vitamins, minerals and antioxidants are innovative functional food supplements that have been clinically shown to have positive effects on skin hydration and elasticityin vivo. In this study, we investigated the interactions between collagen peptides (0.3–8 kDa) and other constituents present in liquid collagen-based nutraceuticals on normal primary dermal fibroblast function in a novel, physiologically relevant, cell culture model crowded with macromolecular dextran sulphate. Collagen peptides significantly increased fibroblast elastin synthesis, while significantly inhibiting release of MMP-1 and MMP-3 and elastin degradation. The positive effects of the collagen peptides on these responses and on fibroblast proliferation were enhanced in the presence of the antioxidant constituents of the products. These data provide a scientific, cell-based, rationale for the positive effects of these collagen-based nutraceutical supplements on skin properties, suggesting that enhanced formation of stable dermal fibroblast-derived extracellular matrices may follow their oral consumption.