bluuebunny/crossref_metadata_2025 huggingface dataset:
Fragment-based approaches to TB drugs
Authors: MARCHETTI CHIARA , CHAN DANIEL S. H. , COYNE ANTHONY G. , ABELL CHRIS
Published: November 2016

Tuberculosis is an infectious disease associated with significant mortality and morbidity worldwide, particularly in developing countries. The rise of antibiotic resistance in Mycobacterium tuberculosis (Mtb) urgently demands the development of new drug leads to tackle resistant strains. Fragment-based methods have recently emerged at the forefront of pharmaceutical development as a means to generate more effective lead structures, via the identification of fragment molecules that form weak but high quality interactions with the target biomolecule and subsequent fragment optimization. This review highlights a number of novel inhibitors of Mtb targets that have been developed through fragment-based approaches in recent years.
An Intellectual Entertainment: Thought and Thinking
Authors: Hacker P. M. S.
Published: November 2016

This dialogue is on the nature of thought and thinking. The five disputants are Socrates, an imaginary neuroscientist from California (whose opinions reflect those of contemporary cognitive neuroscientists), an Oxford don from the 1950s (who employs the linguistic analytic techniques of his times), a Scottish post-doctoral student, and John Locke (who speaks for himself). The discussion takes place in Elysium in the late afternoon. They examine the idea that thinking is an activity of the mind or the brain, whether the medium of thought consists of words or ideas, whether thoughtful speech is speech accompanied by thought, whether thinking, i.e. reasoning and inferring, is a process, and what is meant by the claim that ‘thinking is the last interpretation’. The dialogue ends when the protagonists go to dinner, but will be resumed after the meal.
An Intellectual Entertainment: Thought and Language
Authors: Hacker P. M. S.
Published: November 2016

This dialogue on thought and language is a sequel to my dialogue ‘Thought and Thinking’, but can be read independently of it. The five disputants are the same as in the previous dialogue, namely Socrates; an imaginary neuroscientist from California (whose opinions reflect those of contemporary cognitive neuroscientists); an Oxford don from the 1950s (who employs the linguistic analytic techniques of his times); a Scottish post-doctoral student; and John Locke (who speaks for himself). The discussion takes place in Elysium in the early evening after dinner. They discuss the relationship between what one thinks and what one says, examine the reasons for supposing that there must be a language of thought and show why there cannot be one, investigate the supposition that thought must have a medium – that one must think in something (words, ideas, pre-linguistic concepts) – and demonstrate that it cannot have one. They investigate whether there can be non-linguistic thinking and whether non language-using animals can be said to think, and determine the limits of thought and thinking.
Novel three-dimensional optimal path planning method for vehicles with constrained pitch and yaw
Authors: Wehbe B. , Bazzi S. , Shammas E.
Published: November 2016

This paper presents a novel method for generating three-dimensional optimal trajectories for a vehicle or body that moves forward at a constant speed and steers in both horizontal and vertical directions. The vehicle's dynamics limit the body-frame pitch and yaw rates; additionally, the climb and decent angles of the vehicle are also bounded. Given the above constraints, the path planning problem is solved geometrically by building upon the two-dimensional Dubins curves and then Pontryagin's Maximum Principle is used to validate that the proposed solution lies within the family of candidate time-optimal trajectories. Finally, given the severe boundedness constraints on the vertical motion of the system, the robustness of the proposed path planning method is validated by naturally extending it to remain applicable to high-altitude final configurations.
Community structure of fern-affiliated endophytes in three neotropical forests
Authors: Del Olmo-Ruiz Mariana , Arnold A. Elizabeth
Published: November 2016

From the saprotrophs that decay plant material to the pathogens and mutualists that shape plant demography at local and regional scales, fungi are major drivers of tropical forest dynamics. Although endophytic fungi are abundant and diverse in many biomes, they reach their greatest diversity in tropical forests, where they can influence plant physiology, performance and survival. The number of quantitative studies regarding endophytes has increased dramatically in the past two decades, but general rules have not yet emerged regarding the biogeography, host affiliations, local or regional distributions, or phylogenetic diversity of endophytes in most tropical settings. Here, endophytic fungal communities associated with 18 species of eupolypod fern were compared among forest reserves in Panama, Costa Rica and Mexico. Molecular sequence data for >2000 isolates were used to determine the relationships of host taxonomy, forest (site), and environmental dissimilarity to endophyte community composition. Communities in related ferns differed significantly among forests, reflecting the interplay of geographic distance and environmental dissimilarity. Although the same phyla and classes of fungi were prevalent at each site, they differed in relative abundance. All sites were dominated by the same order (Xylariales), but sites differed in the phylogenetic clusteringvs.evenness of their endophyte communities. By addressing the relationship of endophyte communities to host taxonomy, geographic distance and environmental factors, this study complements previous work on angiosperms and contributes to a growing perspective on the factors shaping communities of ecologically important fungi in tropical forests.
Getting to Peace: Roger Fisher's Scholarship in International Law and the Social Sciences
Authors: MAMO ANDREW
Published: November 2016

This article examines Roger Fisher's scholarship in international law in the decades prior to the publication ofGetting to Yes. Fisher engaged with the same major questions as other international law scholars during the Cold War, but his scholarship was distinguished by the degree to which he grappled with the cutting-edge social science of the mid-century. Even as Fisher collaborated with game theorists and nuclear strategists to understand the theory of conflict, he maintained a critical view of the basic assumptions of game theoretic analysis – defending certain normative elements of the methodology even as he denied its descriptive claims. Subsequent work sought to generate robust descriptions of the role of law in international decision-making during crises. Fisher's normative and descriptive studies of the role of law in such crises led directly toGetting to Yes, creating a body of ‘meta-game theory’ that situated formal studies of conflict within a lawyer's understanding of dispute resolution. Fisher's engagement with social scientists helps illuminate current methodological debates in international law by highlighting the stakes of these theoretical questions and the tensions between scholarship and practice in international law.
Archaeologies of risk and wonder
Authors: Alberti Benjamin
Published: November 2016

In this statement, I argue that one way for archaeology to realize the potential of its materials to tell us something different about the past is to confront the question of alterity, understood as the ontological difference that lies at the roots of much archaeological material. If we accept alterity as a starting point of analysis then we stand a chance of challenging the strictures of interpretive frameworks that foreclose the possibility of encountering something new. Methodologically and theoretically I argue for risk-taking, especially taking on conceptual resources from indigenous thinkers and adopting a stance of wonder in the face of our materials which can open up unsuspected archaeological realities.
Tangled between paradigms in the neo-baroque era
Authors: Criado-Boado Felipe
Published: November 2016

The underlying notion for this article is that archaeology requires an amalgamation of humanities and science, and of narrative and scientific knowledge. The need for this fusion has arisen in a context in which contemporary society is experiencing major changes in epistemics, aesthetics and fashion; an increase in virtual experiences; and an economic crisis. I refer to this situation as the neo-baroque, a condition that is elusive and partially ambiguous. This social context (perhaps the final crisis of modernity), and the breakdown of this integration in pragmatic terms, call for a repoliticization of science.
To hell with ethnoarchaeology!
Authors: Gosselain Olivier P.
Published: November 2016

This paper is a charge against ethnoarchaeology. Deliberately provocative, it aims at highlighting the flaws and ideological pitfalls of a sub-discipline whose actual contribution to archaeology remains hardly decipherable. Beside a methodological deficiency and the frequent narrow-mindedness of the research agenda, ethnoarchaeology suffers from two major problems. First, it carries implicitly an old evolutionary – and racist – ideology that divides the world between modern Western societies (inappropriate for ethnoarchaeological research) and premodern exotic societies (well fitted for ethnoarchaeological research). Second, the quest for universal models of interpretation leads ethnoarchaeologists to play down historical contingency and cultural specificities, which not only deprive them of a good understanding of the ethnographical contexts, but also contribute to restricting ethnoarchaeological applications to a mere quest for similarities (or dissimilarities) in the material record. The problems are too profound to justify an umpteenth salvage of the sub-discipline. Rather, the proposition is to get rid of ethnoarchaeology once and for all, and join forces with other, more serious, disciplines.
Applications in Stimulated Emission Depletion Microscopy: Localization of a Protein Toxin in the Endoplasmic Reticulum Following Retrograde Transport
Authors: Herrera Cristina , Mantis Nicholas J. , Cole Richard
Published: November 2016

Retrograde transport is a process in which proteins are trafficked from the plasma membrane and endosomes to biosynthetic and secretory organelles, namely the Golgi apparatus and endoplasmic reticulum (ER). A number of plant and bacterial toxins, including cholera toxin and ricin toxin, exploit retrograde transport to gain entry into host cells, although the specifics of this process have remained difficult to probe by laser scanning confocal microscopy (LSCM). Here we demonstrate the use of super-resolution and live-cell imaging [stimulated emission depletion (STED)] to visualize exogenously applied ricin toxin within the ER. The improved resolution obtained by STED, as compared with LSCM (0.09 versus 0.19μm), provides a more accurate determination of the amount of ricin that had trafficked to the ER.
Study of unflattened photon beams shaped by multileaf collimator using BEAMnrc code
Authors: kajaria Ankit , Sharma Neeraj , Sharma Shiru , Pradhan Satyajit , Mandal Abhijit , Aggarwal Lalit M.
Published: November 2016

Purpose

In our study basic dosimetric properties of a flattening filter free 6 MV photon beam shaped by multileaf collimators (MLC) is examined using the Monte Carlo (MC) method.

Methods and Materials

BEAMnrc code was used to make a MC simulation model for 6 MV photon beam based on Varian Clinic 600 unique performance linac, operated with and without a flattening filter in beam line. Dosimetric features including central axis depth dose, beam profiles, photon and electron spectra were calculated and compared for flattened and unflattened cases.

Results

Dosimetric field size and penumbra were found to be smaller for unflattened beam, and the decrease in field size was less for MLC shaped in comparison with jaw-shaped unflattened beam. Increase in dose rate of >2·4 times was observed for unflattened beam indicating a shorter beam delivery time for treatment. MLC leakage was found to decrease significantly when the flattening filter was removed from the beam line. The total scatter factor showed slower deviation with field sizes for unflattened beam indicating a reduced head scatter.

Conclusions

Our study demonstrated that improved accelerator characteristics can be achieved by removing flattening filter from beam line.
Support for using five attributes to describe spirituality among families with a parent in hospice
Authors: Stephenson Pam Shockey , Sheehan Denice , Shahrour Ghada
Published: November 2016

Objective:

The importance of spirituality in the dying process is well documented. However, what spirituality means in these situations is hard to discern because few people (patients, families, researchers, or caregivers) will view spirituality in the same way. The present research supports the use of a spiritual framework consisting of five common attributes (meaning, beliefs, connections, self-transcendence, and value) as a mechanism for viewing spirituality for people nearing the end of life. Using qualitative interviews from two related studies, our study aims to describe the prevalence of spirituality and its nature according to these five spiritual attributes.

Methods:

Data from two previous studies were analyzed. The first employed the methods of grounded theory to understand the strategies adolescents used to manage the impending death of a parent. Some 61 participants from 26 families were interviewed, including ill parents/patients, well parents/caregivers, and adolescents. The second study consisted of 15 interviews with the surviving parent and adolescents from 6 of these families after the death of the parent.

Results:

The original research from which these data were drawn did not seek to describe spirituality. However, spiritual themes were prevalent in the stories of many participants and included each of the five spiritual attributes.

Significance of Results:

Our findings demonstrate the prevalence of spirituality in the everyday lives of these families and supports the use of the spiritual framework according to the five common attributes to describe spirituality.
Stakeholder engagement in prioritizing sustainability assessment themes for smallholder coffee production in Uganda
Authors: Ssebunya Brian Robert , Schmid Erwin , van Asten Piet , Schader Christian , Altenbuchner Christine , Stolze Matthias
Published: November 2016

Many sustainability assessment frameworks have been developed in recent years, but translating them into practical tools to guide decision making remains challenging. By engaging coffee stakeholders in Uganda, we demonstrate a process of translating the widely-accepted framework for Sustainability Assessments of Food and Agriculture Systems (SAFA), developed by the Food and Agriculture Organisation of the United Nations (FAO), to smallholder production systems. Stakeholders prioritized the sustainability themes in terms of relevance and feasibility, and subsequently identified relevant sub-themes. We find that the structure and scope of some generally accepted themes need appropriate modifications in order to address the social and structural heterogeneity of smallholder production systems. Although importance and feasibility rankings significantly vary within and between stakeholder groups, governance and economic themes are commonly perceived as very important though equally the least feasible for smallholders. Thus, the inclusion of the ‘farmer-group’ structure as part of the sustainability assessment criteria is perceived as necessary especially toward achieving governance-related goals. These findings emphasize the need of engaging stakeholders in defining locally adapted sustainability assessment criteria.
Tipps und Tricks zur Behandlung des pankreatopriven Diabetes mellitus
Authors: Kempf Patrick , Laimer Markus , Stettler Christoph
Published: November 2016

Zusammenfassung. Verschiedenste Erkrankungen des exokrinen Pankreas können auch Störungen des endokrinen Pankreasanteils verursachen. Der resultierende Diabetes mellitus wird als pankreatopriver (Typ-3c-Diabetes) bezeichnet. Mangel an funktionierendem Pankreasgewebe heisst nicht nur Insulinmangel sondern insbesondere auch Mangel an Glukagon, womit die Zuckereinstellung erschwert wird und die Gefahr schwerer Hypoglykämien unter Insulintherapie steigt. Obwohl es sich beim Typ 3c Diabetes um eine relativ seltenere Diabetesform handelt, ist er in der Häufigkeit dennoch nicht zu unterschätzen. Bedingt durch seine metabolische Komplexizität mit hoher Glukosevariabilität stellt er eine schwierig einzustellende Diabetesform dar. Eine frühzeitige und gute Therapie ist bei den oftmals schwer kranken Patienten mit pankreatoprivem Diabetes dafür umso wichtiger, um ein gutes kurz-, mittel- und langfristiges Outcome zu erreichen.
Zystische Pankreasläsion – Wie weiter?
Authors: Tinguely Pascale , Candinas Daniel , Gloor Beat
Published: November 2016

Zusammenfassung. Zystische Läsionen im Pankreas werden häufig gefunden, oft primär auf einer CT oder MR Untersuchung des Oberbauches. Primär erlaubt die Anamnese die Unterscheidung zwischen entzündlichen Flüssigkeitsansammlungen oder Pseudozysten nach einer akuten Pankreatitis und neoplastischen zystischen Läsionen, die oft zufällig bei asymptomatischen Patienten diagnostiziert werden. Es gilt dann die Veränderung genauer zu charakterisieren und einer klinischen Entität zuzuordnen, wobei primär zwischen serösen und muzinösen Zysten unterschieden werden muss. Letztere haben ein unterschiedlich hohes Malignitätspotenzial. Eine Endosonographie mit Punktion erlaubt in der Regel die zystische Läsion genauer zu charakterisieren, im Vergleich zur reinen Bildgebung mittels MRT oder CT. Gelingt es eine Läsion genügend zu charakterisieren, empfiehlt sich heute ein Vorgehen entsprechend der 2012 publizierten Konsensus Richtlinien. Insbesondere bei Seitenast IPMN sind die Bücher noch nicht geschlossen, da die Angaben bezüglich Häufigkeit der malignen Veränderungen extrem schwanken und somit der Nutzen einer prophylaktischen Pankreasteilresektion unter Umständen kleiner ist als das Risiko des Eingriffs.
Behr Receives 2016 Jason Morgan Early Career Award
Authors:   AGU
Published: November 2016

Whitney Behr will receive the 2016 Jason Morgan Early Career Award at the 2016 American Geophysical Union Fall Meeting, to be held 12–16 December in San Francisco, Calif. The award is for significant early-career contributions in Tectonophysics.
Erupted frothy xenoliths may explain lack of country-rock fragments in plutons
Authors: Burchardt Steffi , Troll Valentin R. , Schmeling Harro , Koyi Hemin , Blythe Lara
Published: November 2016

Magmatic stoping is discussed to be a main mechanism of magma emplacement. As a consequence of stoping, abundant country-rock fragments should occur within and at the bottom of, magma reservoirs as “xenolith graveyards”, or become assimilated. However, the common absence of sufficient amounts of both xenoliths and crustal contamination have led to intense controversy about the efficiency of stoping. Here, we present new evidence that may explain the absence of abundant country-rock fragments in plutons. We report on vesiculated crustal xenoliths in volcanic rocks that experienced devolatilisation during heating and partial melting when entrained in magma. We hypothesise that the consequential inflation and density decrease of the xenoliths allowed them to rise and become erupted instead of being preserved in the plutonic record. Our thermomechanical simulations of this process demonstrate that early-stage xenolith sinking can be followed by the rise of a heated, partially-molten xenolith towards the top of the reservoir. There, remnants may disintegrate and mix with resident magma or erupt. Shallow-crustal plutons emplaced into hydrous country rocks may therefore not necessarily contain evidence of the true amount of magmatic stoping during their emplacement. Further studies are needed to quantify the importance of frothy xenolith in removing stoped material.
Erratum: High-energy side-peak emission of exciton-polariton condensates in high density regime
Authors: Horikiri Tomoyuki , Yamaguchi Makoto , Kamide Kenji , Matsuo Yasuhiro , Byrnes Tim , Ishida Natsuko , Löffler Andreas , Höfling Sven , Shikano Yutaka , Ogawa Tetsuo , Forchel Alfred , Yamamoto Yoshihisa
Published: November 2016

Scientific Reports 6: Article number: 25655; published online: 19 May 2016; updated: 02 November 2016
An open-hardware platform for optogenetics and photobiology
Authors: Gerhardt Karl P. , Olson Evan J. , Castillo-Hair Sebastian M. , Hartsough Lucas A. , Landry Brian P. , Ekness Felix , Yokoo Rayka , Gomez Eric J. , Ramakrishnan Prabha , Suh Junghae , Savage David F. , Tabor Jeffrey J.
Published: November 2016

In optogenetics, researchers use light and genetically encoded photoreceptors to control biological processes with unmatched precision. However, outside of neuroscience, the impact of optogenetics has been limited by a lack of user-friendly, flexible, accessible hardware. Here, we engineer the Light Plate Apparatus (LPA), a device that can deliver two independent 310 to 1550 nm light signals to each well of a 24-well plate with intensity control over three orders of magnitude and millisecond resolution. Signals are programmed using an intuitive web tool named Iris. All components can be purchased for under $400 and the device can be assembled and calibrated by a non-expert in one day. We use the LPA to precisely control gene expression from blue, green, and red light responsive optogenetic tools in bacteria, yeast, and mammalian cells and simplify the entrainment of cyanobacterial circadian rhythm. The LPA dramatically reduces the entry barrier to optogenetics and photobiology experiments.
Laminin-guided highly efficient endothelial commitment from human pluripotent stem cells
Authors: Ohta Ryo , Niwa Akira , Taniguchi Yukimasa , Suzuki Naoya M. , Toga Junko , Yagi Emiko , Saiki Norikazu , Nishinaka-Arai Yoko , Okada Chihiro , Watanabe Akira , Nakahata Tatsutoshi , Sekiguchi Kiyotoshi , Saito Megumu K.
Published: November 2016

Obtaining highly purified differentiated cells via directed differentiation from human pluripotent stem cells (hPSCs) is an essential step for their clinical application. Among the various conditions that should be optimized, the precise role and contribution of the extracellular matrix (ECM) during differentiation are relatively unclear. Here, using a short fragment of laminin 411 (LM411-E8), an ECM predominantly expressed in the vascular endothelial basement membrane, we demonstrate that the directed switching of defined ECMs robustly yields highly-purified (>95%) endothelial progenitor cells (PSC-EPCs) without cell sorting from hPSCs in an integrin-laminin axis-dependent manner. Single-cell RNA-seq analysis revealed that LM411-E8 resolved intercellular transcriptional heterogeneity and escorted the progenitor cells to the appropriate differentiation pathway. The PSC-EPCs gave rise to functional endothelial cells both in vivo and in vitro. We therefore propose that sequential switching of defined matrices is an important concept for guiding cells towards desired fate.
Neoadjuvant chemotherapy for Patients with advanced epithelial ovarian cancer: A Meta-Analysis
Authors: Zeng Long-Jia , Xiang Chun-Lin , Gong Yi-Zhen , Kuang Yan , Lu Fang-Fang , Yi Su-Yi , Zhang Yue , Liao Meng
Published: November 2016

The value of neoadjuvant chemotherapy (NAC) has not yet been fully defined. We aimed to systematically evaluate the influence of neoadjuvant chemotherapy (NAC) on survival and complete cytoreduction after debulking surgery in advanced epithelial ovarian cancer (AEOC) patients. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for the randomized controlled trials (RCTs) comparing NAC and primary debulking surgery (PDS) in AEOC patients. The last search date is February 25, 2016. Cochrane systematic evaluation was used to evaluate bias risk of included studies. RevMan 5.3 software was used for statistical analysis. A total of 4 RCTs involving 1922 patients were included. Compared with PDS, NAC may contribute to the completeness of debulking removal [no residual disease (RR: 2.37; 95%CI: 1.94–2.91; P<0.00001), residual disease ≤1 cm (RR: 1.28; 95%CI: 1.04–1.57; P = 0.02), optimal cytoreduction rate (RR: 1.76; 95%CI: 1.57–1.98; P<0.00001)], but there were no significant differences in both groups with regard to overall survival (HR: 0.94; 95%Cl: 0.81–1.08; P = 0.38) and progression-free survival (HR: 0.89; 95%Cl: 0.77–1.03; P = 0.12). This meta-analysis indicates that the higher rate of optimal debulking made NAC more favorable as a treatment option for AEOC patients with non-inferior survival compared with PDS.
General hyperconcentration of photonic polarization-time-bin hyperentanglement assisted by nitrogen-vacancy centers coupled to resonators
Authors: Du Fang-Fang , Deng Fu-Guo , Long Gui-Lu
Published: November 2016

Entanglement concentration protocol (ECP) is used to extract the maximally entangled states from less entangled pure states. Here we present a general hyperconcentration protocol for two-photon systems in partially hyperentangled Bell states that decay with the interrelation between the time-bin and the polarization degrees of freedom (DOFs), resorting to an input-output process with respect to diamond nitrogen-vacancy centers coupled to resonators. We show that the resource can be utilized sufficiently and the success probability is largely improved by iteration of the hyper-ECP process. Besides, our hyper-ECP can be directly extended to concentrate nonlocal partially hyperentangled N-photon Greenberger-Horne-Zeilinger states, and the success probability remains unchanged with the growth of the number of photons. Moreover, the time-bin entanglement is a useful DOF and it only requires one path for transmission, which means it not only economizes on a large amount of quantum resources but also relaxes from the path-length dispersion in long-distance quantum communication.
Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments
Authors: Badura Aleksandra , Clopath Claudia , Schonewille Martijn , De Zeeuw Chris I.
Published: November 2016

Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity.
A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis
Authors: Li Yating , Zhang Tao , Zhou Yuncai , Sun Yi , Cao Yue , Chang Xiaoai , Zhu Yunxia , Han Xiao
Published: November 2016

The presenilin-mediated Notch1 cleavage pathway plays a critical role in controlling pancreatic beta cell fate and survival. The aim of the present study was to investigate the role of Notch1 activation in glucotoxicity-induced beta cell impairment and the contributions of miR-375, miR-30a, and miR-34a to this pathway. We found that the protein levels of presenilins (PSEN1 and PSEN2), and NOTCH1 were decreased in INS-1 cells after treatment with increased concentrations of glucose, whereas no significant alteration of mRNA level of Notch1 was observed. Targeting of miR-375, miR-30a, and miR-34a to the 3′utr of Psen1, Psen2, and Notch1, respectively, reduced the amounts of relevant proteins, thereby reducing NICD1 amounts and causing beta cell apoptosis. Overexpression of NICD1 blocked the effects of glucotoxicity as well as miRNA overabundance. Downregulating the expression of miR-375, miR-30a, and miR-34a restored PSEN1, PSEN2, and NICD1 production and prevented glucotoxicity-induced impairment of the beta cells. These patterns of miRNA regulation of the Notch1 cleavage pathway were reproduced in GK rats as well as in aged rats. Our findings demonstrated that miRNA-mediated suppression of NICD1 links the presenilin/Notch1 pathway to glucotoxicity in mature pancreatic beta cells.
Keap1 hypomorphism protects against ischemic and obstructive kidney disease
Authors: Tan Roderick J. , Chartoumpekis Dionysios V. , Rush Brittney M. , Zhou Dong , Fu Haiyan , Kensler Thomas W. , Liu Youhua
Published: November 2016

The Keap1/Nrf2 pathway is a master regulator of antioxidant, anti-inflammatory, and other cytoprotective mechanisms important in protection from kidney disease. For the first time in kidney disease, we describe the use of Keap1 hypomorphic mice, which possess Nrf2 hyperactivation. We exposed these mice and wild type controls to ischemia/reperfusion injury (IRI). The initial tubular injury at 24 hours post-IRI appeared to be unaffected, with the only observed difference being a decrease in inflammatory cytokine expression in the hypomorphs. However, we noted significant improvement in serum creatinine in the hypomorphs at 3 and 10 days after injury, and renal fibrosis was dramatically attenuated at the late timepoint. Assessment of Nrf2-regulated targets (GSTM1, GSTP1, NQO1) revealed higher expression in the hypomorphs at baseline. While injury tended to suppress these genes in wild-type mice, the suppression was attenuated or reversed in Keap1 hypomorphs, suggesting that protection in these mice was mediated by increased Nrf2 transcriptional activity. To assess the generalizability of our findings, we subjected the hypomorphs to unilateral ureteral obstruction (UUO) and again found significant protection and increased expression of Nrf2 targets. Overall, these results support the conclusion that the Nrf2 pathway is protective in a variety of kidney diseases.
Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release
Authors: Xin Guang , Wei Zeliang , Ji Chengjie , Zheng Huajie , Gu Jun , Ma Limei , Huang Wenfang , Morris-Natschke Susan L. , Yeh Jwu-Lai , Zhang Rui , Qin Chaoyi , Wen Li , Xing Zhihua , Cao Yu , Xia Qing , Lu Yanrong , Li Ke , Niu Hai , Lee Kuo-Hsiung , Huang Wen
Published: November 2016

Thrombosis and its complications are the leading cause of death in patients with diabetes. Metformin, a first-line therapy for type 2 diabetes, is the only drug demonstrated to reduce cardiovascular complications in diabetic patients. However, whether metformin can effectively prevent thrombosis and its potential mechanism of action is unknown. Here we show, metformin prevents both venous and arterial thrombosis with no significant prolonged bleeding time by inhibiting platelet activation and extracellular mitochondrial DNA (mtDNA) release. Specifically, metformin inhibits mitochondrial complex I and thereby protects mitochondrial function, reduces activated platelet-induced mitochondrial hyperpolarization, reactive oxygen species overload and associated membrane damage. In mitochondrial function assays designed to detect amounts of extracellular mtDNA, we found that metformin prevents mtDNA release. This study also demonstrated that mtDNA induces platelet activation through a DC-SIGN dependent pathway. Metformin exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing the release of free mtDNA, which induces platelet activation in a DC-SIGN-dependent manner. This study has established a novel therapeutic strategy and molecular target for thrombotic diseases, especially for thrombotic complications of diabetes mellitus.
Understanding the immune system architecture and transcriptome responses to southern rice black-streaked dwarf virus in Sogatella furcifera
Authors: Wang Lin , Tang Nan , Gao Xinlei , Guo Dongyang , Chang Zhaoxia , Fu Yating , Akinyemi Ibukun A. , Wu Qingfa
Published: November 2016

Sogatella furcifera, the white-backed planthopper (WBPH), has become one of the most destructive pests in rice production owing to its plant sap-sucking behavior and efficient transmission of Southern rice black-streaked dwarf virus (SRBSDV) in a circulative, propagative and persistent manner. The dynamic and complex SRBSDV-WBPH-rice plant interaction is still poorly understood. In this study, based on a homology-based genome-wide analysis, 348 immune-related genes belonging to 28 families were identified in WBPH. A transcriptome analysis of non-viruliferous (NVF) and viruliferous groups with high viral titers (HVT) and median viral titers (MVT) revealed that feeding on SRBSDV-infected rice plants has a significant impact on gene expression, regardless of viral titers in insects. We identified 278 up-regulated and 406 down-regulated genes shared among the NVF, MVT, and HVT groups and detected significant down-regulation of primary metabolism-related genes and oxidoreductase. In viruliferous WBPH with viral titer-specific transcriptome changes, 1,906 and 1,467 genes exhibited strict monotonically increasing and decreasing expression, respectively. The RNAi pathway was the major antiviral response to increasing viral titers among diverse immune responses. These results clarify the responses of immune genes and the transcriptome of WBPH to SRBSDV and improve our knowledge of the functional relationship between pathogen, vector, and host.
Tumour microenvironment-responsive lipoic acid nanoparticles for targeted delivery of docetaxel to lung cancer
Authors: Gu Fenfen , Hu Chuling , Tai Zhongguang , Yao Chong , Tian Jing , Zhang Lijuan , Xia Qingming , Gong Chunai , Gao Yuan , Gao Shen
Published: November 2016

In the present study, we developed a novel type of reduction-sensitive nanoparticles (NPs) for docetaxel (DTX) delivery based on cross-linked lipoic acid NPs (LANPs). The physicochemical properties, cellular uptake and in vitro cytotoxicity of DTX loaded LANPs (DTX-LANPs) on A549 cells were investigated. Furthermore, the in vivo distribution and in vivo efficacy of DTX-LANPs was evaluated. The results showed that DTX-LANPs had a particle size of 110 nm and a negative zeta potential of −35 mv with excellent colloidal stability. LANPs efficiently encapsulated DTX with a high drug loading of 4.51% ± 0.49% and showed remarkable reduction-sensitive drug release in vitro. Cellular uptake experiments demonstrated that LANPs significantly increased intracellular DTX uptake by about 10 fold as compared with free DTX. The cytotoxicity of DTX-LANPs showed significantly higher potency in inhibiting A549 cell growth than free DTX, while blank LANPs had a good biocompatibility. In addition, in vivo experiments demonstrated that DTX-LANPs could enhance tumour targeting and anti-tumour efficacy with low systemic toxicity. In conclusion, LANPs may prove to be a potential tumour microenvironment-responsive delivery system for cancer treatment, with the potential for commercialization due to the simple component, controllable synthesis, stability and economy.
Isolation and mass spectrometry analysis of urinary extraexosomal proteins
Authors: Hildonen Siri , Skarpen Ellen , Halvorsen Trine Grønhaug , Reubsaet Léon
Published: November 2016

The aim of the present study was to develop a LC-MS/MS-based proteomic analysis method of urinary exosomal proteins that has the potential to discover disease biomarkers. In short, urinary exosomes from healthy subjects were isolated by immunocapture on magnetic beads, detected by immunofluorescence and TEM, trypsin digested directly on the beads for an accelerated time with no addition of detergents before performing an LC-MS analysis of the trypsinate. To our knowledge, this is the first proteomic analysis of proteins displayed on the outer surface of exosomes. The outer exosome proteome may contain proteins that are of higher biomarker value compared to soluble cargo protein as the proteins projecting into the extracellular milieu might be more directly involved in physiological functions of exosomes. The proteomic analysis identified 49 proteins that were considered significant; the majority is involved in carbohydrate and lipid metabolism or in immune responses. Thirty of the proteins are linked to diseases. The developed proteomic method exploiting urinary exosomes might be of great value in search for diagnostic or prognostic biomarkers of especially metabolic and immune-related diseases.
Genome-wide analyses reveal a highly conserved Dengue virus envelope peptide which is critical for virus viability and antigenic in humans
Authors: Fleith Renata C. , Lobo Francisco P. , dos Santos Paula F. , Rocha Mariana M. , Bordignon Juliano , Strottmann Daisy M. , Patricio Daniel O. , Pavanelli Wander R. , Lo Sarzi Maria , Santos Claudia N. D. , Ferguson Brian J. , Mansur Daniel S.
Published: November 2016

Targeting regions of proteins that show a high degree of structural conservation has been proposed as a method of developing immunotherapies and vaccines that may bypass the wide genetic variability of RNA viruses. Despite several attempts, a vaccine that protects evenly against the four circulating Dengue virus (DV) serotypes remains elusive. To find critical conserved amino acids in dengue viruses, 120 complete genomes of each serotype were selected at random and used to calculate conservation scores for nucleotide and amino acid sequences. The identified peptide sequences were analysed for their structural conservation and localisation using crystallographic data. The longest, surface exposed, highly conserved peptide of Envelope protein was found to correspond to amino acid residues 250 to 270. Mutation of this peptide in DV1 was lethal, since no replication of the mutant virus was detected in human cells. Antibodies against this peptide were detected in DV naturally infected patients indicating its potential antigenicity. Hence, this study has identified a highly conserved, critical peptide in DV that is a target of antibodies in infected humans.
Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine
Authors: Nyendak Melissa , Swarbrick Gwendolyn M. , Duncan Amanda , Cansler Meghan , Huff Ervina Winata , Hokey David , Evans Tom , Barker Lewellys , Blatner Gretta , Sadoff Jerald , Douoguih Macaya , Pau Maria Grazia , Lewinsohn Deborah A. , Lewinsohn David M.
Published: November 2016

The development of a vaccine for Mycobacterium tuberculosis (Mtb) has been impeded by the absence of correlates of protective immunity. One correlate would be the ability of cells induced by vaccination to recognize the Mtb-infected cell. AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA expressing a fusion protein of Mtb antigens 85A, 85B and TB10.4. We undertook a phase I double-blind, randomized placebo controlled trial of vaccination with AERAS-402 following BCG. Analysis of the vaccine-induced immune response revealed strong antigen-specific polyfunctional CD4+ and CD8+ T cell responses. However, analysis of the vaccine-induced CD8+ T cells revealed that in many instances these cells did not recognize the Mtb-infected cell. Our findings highlight the measurement of vaccine-induced, polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying the Mtb-infected cell and correspondingly, the value of detailed experimental medicine studies early in vaccine development.
Contribution of Atmospheric Diffusion Conditions to the Recent Improvement in Air Quality in China
Authors: Wang Xiaoyan , Wang Kaicun , Su Liangyuan
Published: November 2016

This study analyzed hourly mass concentration observations of PM2.5 (particulate matters with diameter less than 2.5 μm) at 512 stations in China from December 2013 to May 2015. We found that the mean concentrations of PM2.5 during the winter and spring of 2015 Dec. 2014 to Feb. 2015 and Mar. 2015 to May 2015) decreased by 20% and 14% compared to the previous year, respectively. Hazardous air-quality days decreased by 11% in 2015 winter, with more frequent good to unhealthy days; and the good and moderate air-quality days in 2015 spring increased by 9% corresponding to the less occurrence of unhealthy conditions. We compared the atmospheric diffusion conditions during these two years and quantified its contribution to the improvement of air quality during the first half of 2015 over China. Our results show that during the 2015 winter and spring, 70% and 57% of the 512 stations experienced more favorable atmospheric diffusion conditions compared to those of previous year. Over central and northern China, approximately 40% of the total decrease in PM2.5 during the 2015 winter can be attributed to the favorable atmospheric diffusion conditions. The atmospheric diffusion conditions during the spring of 2015 were not as favorable as in winter; and the average contributions of the atmospheric conditions were slight.
A flexible triboelectric-piezoelectric hybrid nanogenerator based on P(VDF-TrFE) nanofibers and PDMS/MWCNT for wearable devices
Authors: Wang Xingzhao , Yang Bin , Liu Jingquan , Zhu Yanbo , Yang Chunsheng , He Qing
Published: November 2016

This paper studied and realized a flexible nanogenerator based on P(VDF-TrFE) nanofibers and PDMS/MWCNT thin composite membrane, which worked under triboelectric and piezoelectric hybrid mechanisms. The P(VDF-TrFE) nanofibers as a piezoelectric functional layer and a triboelectric friction layer are formed by electrospinning process. In order to improve the performance of triboelectric nanogenerator, the multiwall carbon nanotubes (MWCNT) is doped into PDMS patterned films as the other flexible friction layer to increase the initial capacitance. The flexible nanogenerator is fabricated by low cost MEMS processes. Its output performance is characterized in detail and structural optimization is performed. The device’s output peak-peak voltage, power and power density under triboelectric mechanism are 25 V, 98.56 μW and 1.98 mW/cm3 under the pressure force of 5 N, respectively. The output peak-peak voltage, power and power density under piezoelectric working principle are 2.5 V, 9.74 μW, and 0.689 mW/cm3 under the same condition, respectively. We believe that the proposed flexible, biocompatible, lightweight, low cost nanogenerator will supply effective power energy sustainably for wearable devices in practical applications.
Comprehensive DNA methylation analysis of the Aedes aegypti genome
Authors: Falckenhayn Cassandra , Carneiro Vitor Coutinho , de Mendonça Amarante Anderson , Schmid Katharina , Hanna Katharina , Kang Seokyoung , Helm Mark , Dimopoulos George , Fantappié Marcelo Rosado , Lyko Frank
Published: November 2016

Aedes aegypti mosquitoes are important vectors of viral diseases. Mosquito host factors play key roles in virus control and it has been suggested that dengue virus replication is regulated by Dnmt2-mediated DNA methylation. However, recent studies have shown that Dnmt2 is a tRNA methyltransferase and that Dnmt2-dependent methylomes lack defined DNA methylation patterns, thus necessitating a systematic re-evaluation of the mosquito genome methylation status. We have now searched the Ae. aegypti genome for candidate DNA modification enzymes. This failed to reveal any known (cytosine-5) DNA methyltransferases, but identified homologues for the Dnmt2 tRNA methyltransferase, the Mettl4 (adenine-6) DNA methyltransferase, and the Tet DNA demethylase. All genes were expressed at variable levels throughout mosquito development. Mass spectrometry demonstrated that DNA methylation levels were several orders of magnitude below the levels that are usually detected in organisms with DNA methylation-dependent epigenetic regulation. Furthermore, whole-genome bisulfite sequencing failed to reveal any evidence of defined DNA methylation patterns. These results suggest that the Ae. aegypti genome is unmethylated. Interestingly, additional RNA bisulfite sequencing provided first evidence for Dnmt2-mediated tRNA methylation in mosquitoes. These findings have important implications for understanding the mechanism of Dnmt2-dependent virus regulation.
Legionella pneumophila prevents proliferation of its natural host Acanthamoeba castellanii
Authors: Mengue Luce , Régnacq Matthieu , Aucher Willy , Portier Emilie , Héchard Yann , Samba-Louaka Ascel
Published: November 2016

Legionella pneumophila is a ubiquitous, pathogenic, Gram-negative bacterium responsible for legionellosis. Like many other amoeba-resistant microorganisms, L. pneumophila resists host clearance and multiplies inside the cell. Through its Dot/Icm type IV secretion system, the bacterium injects more than three hundred effectors that modulate host cell physiology in order to promote its own intracellular replication. Here we report that L. pneumophila prevents proliferation of its natural host Acanthamoeba castellanii. Infected amoebae could not undergo DNA replication and no cell division was observed. The Dot/Icm secretion system was necessary for L. pneumophila to prevent the eukaryotic proliferation. The absence of proliferation was associated with altered amoebal morphology and with a decrease of mRNA transcript levels of CDC2b, a putative regulator of the A. castellanii cell cycle. Complementation of CDC28-deficient Saccharomyces cerevisiae by the CDC2b cDNA was sufficient to restore proliferation of CDC28-deficient S. cerevisiae and suggests for the first time that CDC2b from A. castellanii could be functional and a bona fide cyclin-dependent kinase. Hence, our results reveal that L. pneumophila impairs proliferation of A. castellanii and this effect could involve the cell cycle protein CDC2b.
The peacock train does not handicap cursorial locomotor performance
Authors: Thavarajah Nathan K. , Tickle Peter G. , Nudds Robert L. , Codd Jonathan R.
Published: November 2016

Exaggerated traits, like the peacock train, are recognized as classic examples of sexual selection. The evolution of sexual traits is often considered paradoxical as, although they enhance reproductive success, they are widely presumed to hinder movement and survival. Many exaggerated traits represent an additional mechanical load that must be carried by the animal and therefore may influence the metabolic cost of locomotion and constrain locomotor performance. Here we conducted respirometry experiments on peacocks and demonstrate that the exaggerated sexually selected train does not compromise locomotor performance in terms of the metabolic cost of locomotion and its kinematics. Indeed, peacocks with trains had a lower absolute and mass specific metabolic cost of locomotion. Our findings suggest that adaptations that mitigate any costs associated with exaggerated morphology are central in the evolution of sexually selected traits.
Efficient pattern unmixing of multiplex proteins based on variable weighting of texture descriptors
Authors: Yang Qin , Tang Lijuan , Yu Ruqin
Published: November 2016

A novel computational system TexVW-MPUnmixing is proposed for multiplex protein pattern unmixing utilizing micropattern spatial structure-based texture descriptors and variable weighting strategies.
Old tricks, new dogs: organocatalytic dienamine activation of α,β-unsaturated aldehydes
Authors: Marcos Vanesa , Alemán José
Published: November 2016

Here we outline and discuss the state-of-the-art in organocatalytic dienamine activation of enals, classifying examples according to different reactive activation pathways.