bluuebunny/crossref_metadata_2025 huggingface dataset:
Global output‐feedback stabilization for nonlinear systems with unknown relative degree
Authors: Wang Meiqiao , Liu Yungang , Man Yongchao
Published: October 2017

This paper is devoted to the global stabilization via output feedback for a class of nonlinear systems with unknown relative degree, dynamics uncertainties, unknown control direction, and nonparametric uncertain nonlinearities. In particular, the unknown relative degree is without known upper bound, which renders us to research for a filter with varying dimension rather than the ones with over dimensions in the existing literature. In comparison with more popular but a bit stronger input‐to‐state stable or input‐to‐state practically stable requirement, only bounded‐input bounded‐state stable requirement is imposed on the dynamics uncertainties, which affect the systems in a persistent intensity rather than in a decaying one. In this paper, to compensate multiple serious system uncertainties and realize global output‐feedback stabilization, a design scheme via switching logic together with varying dimensional filter is developed. In this scheme, 2 switching sequences, which separately generate the gains of the controller and act as the varying dimensions of the filter, are designed to overcome unknown control direction, dynamics uncertainties and nonparametric uncertain nonlinearities, and unknown relative degree, respectively. A 2‐mass lumped‐parameter structure is provided to show the effectiveness of the proposed method in this paper.
Body size, experience, and sex do matter: Multiyear study shows improved passage rates for alewife (Alosa pseudoharengus) through small‐scale Denil and pool‐and‐weir fishways
Authors: Nau G. S. , Spares A. D. , Andrews S. N. , Mallory M. L. , McLellan N. R. , Stokesbury M. J. W.
Published: October 2017

Alewife (Alosa pseudoharengus) passage through 3 fishways was assessed during the 2013–2016 spawning runs in 3 rivers of the Isthmus of Chignecto, Canada. From April 24 to June 10, 5,423 alewife with a mean ± SD fork length of 227 ± 18 mm were tagged with passive integrated transponders. During their tagging year, approximately half of individuals (40% to 64%) went undetected whereas those detected used fishways from April 16 to July 8. Detected alewife were significantly longer than those undetected. Attraction rates to fishway entrances in 2015 and 2016 ranged from 85% to 98%. Annual fishway passage rates for pooled fish tagged that year and returnees, varied from 64% to 97% for 2 Denil style fishways. A pool‐and‐weir fishway that was dysfunctional (2013), repaired (2014), and replaced (2015–2016) yielded 0.5%, 25%, 60%, and 73% annual pooled passage rates, respectively. Larger individuals, previously tagged returnees, and males compared to females of a similar size had higher passage success suggesting some fishways may apply population‐level selective pressures. Alewife passage rates related to fishway style, design, and proper function, with greater passage for the 2 Denils than the pool‐and‐weir fishway in our study. Regular structural maintenance and fish passage reviews are essential management considerations to ensure fishway functioning and river connectivity. Replacement of a fishway with poor fish passage may be the best option to improve passage rates. Future research should address the effects of multiple anthropogenic instream obstructions, environmental variables, negative sublethal post‐tagging effects, and the importance of returnees on fish passage rates in fishways.
Accuracy of swallow roost locations assigned using weather surveillance radar
Authors: Kelly Jeffrey F. , Pletschet Sandra M.
Published: October 2017

Weather surveillance radars (WSR) have been used to detect roosting aggregations of swallows since the 1950s. We provide the first quantitative assessment of the accuracy of roost locations derived from WSR images. We found 265 swallow roosts in WSR images from the Eastern US (east of 100oW) between June and September over 7 years (2010–2016). We quantified error in WSR‐based roost locations of 72 of these roosts by comparing them to ground‐truth locations. Purple Martins (Progne subis) formed 67 (93%) of ground‐truthed roosts. Tree Swallows (Tachycineta bicolor) and Bank Swallows (Riparia riparia) formed the other 5 roosts (7%); all of which were in the northeastern U.S. (north of 41oN and east of 80oW). Magnitude of roost‐location error was 2.94 kilometers (SD = 1.63 km, N = 72, range = 0–7.3). This error increased slightly, but significantly, with distance from the WSR (R2 = 0.13, P = 0.002). Location error was not influenced by wind speed. Directions of location errors (from confirmed to estimated location) were clumped in a southeasterly direction (x̅ = 128.9°, SD = 1.32, N = 72, P < 0.05). Similarly, prevailing wind direction (x̅ = 180.0°, SD = 1.28, N = 71, P < 0.01) tended to come from the south. Wind direction and direction to the nearest WSR were not correlated with direction of the location error. Magnitude and direction of error associated with using WSR images to assign geographic locations to swallow roosts is small. This error is largely unaffected by variation in distance and direction to WSR stations and prevailing wind conditions. These results enable future studies that seek automated approaches to roost identification and permit association with other environmental data at the appropriate level of spatial precision.
Functionalized Nanochannels from Self‐Assembled and Photomodified Poly(Styrene‐b‐Butadiene‐b‐Styrene)
Authors: Sutisna Burhannudin , Polymeropoulos George , Musteata Valentina , Sougrat Rachid , Smilgies Detlef‐M. , Peinemann Klaus‐Viktor , Hadjichristidis Nikolaos , Nunes Suzana P.
Published: October 2017

Membranes are prepared by self‐assembly and casting of 5 and 13 wt% poly(styrene‐b‐butadiene‐b‐styrene) (PS‐b‐PB‐b‐PS) copolymers solutions in different solvents, followed by immersion in water or ethanol. By controlling the solution‐casting gap, porous films of 50 and 1 µm thickness are obtained. A gradient of increasing pore size is generated as the distance from the surface increased. An ordered porous surface layer with continuous nanochannels can be observed. Its formation is investigated, by using time‐resolved grazing incident small angle X‐ray scattering, electron microscopy, and rheology, suggesting a strong effect of the air–solution interface on the morphology formation. The thin PS‐b‐PB‐b‐PS ordered films are modified, by promoting the photolytic addition of thioglycolic acid to the polybutadiene groups, adding chemical functionality and specific transport characteristics on the preformed nanochannels, without sacrificing the membrane morphology. Photomodification increases fivefold the water permeance to around 2 L m−2 h−1 bar−1, compared to that of the unmodified one. A rejection of 74% is measured for methyl orange in water. The membranes fabrication with tailored nanochannels and chemical functionalities can be demonstrated using relatively lower cost block copolymers. Casting on porous polyacrylonitrile supports makes the membranes even more scalable and competitive in large scale.
Interdependence of attachment styles and relationship quality in parent‐adolescent dyads
Authors: Chow Chong Man , Hart Ellen , Ellis Lillian , Tan Cin Cin
Published: September 2017

The current study examined how attachment styles of parents and adolescents may jointly influence the quality of their relationship. Parent‐adolescent (Ndyads = 77) pairs were recruited from a Midwestern town in the United States. The mean of adolescents' age was 16.25. Both members reported their attachment styles, relationship closeness, and relationship discord. The Actor‐Partner Interdependence Model (APIM) showed that both members' attachment avoidance was associated with self‐report lower levels of closeness. Parents' attachment anxiety was related to relationship discord. Parents with higher avoidant attachment reported lower closeness when adolescents were higher in avoidant attachment. Higher parents' anxious attachment was related to higher relationship closeness when adolescents were higher on anxious attachment. Such an association was negative when adolescents had lower anxious attachment. Higher parents’ anxious attachment was related to greater discord when adolescents were lower on anxiety attachment. This study reveals the complex dyadic dynamics of relationship quality in parent‐adolescent pairs.
Necrotizing fasciitis of the head and neck: Surgical follow up of 2 cases with the use of LRINEC score
Authors: AlBader Abdulmohsen , AlObaid Faisal , AlArouj Hamoud , Bhat Imtiyaz
Published: September 2017

Necrotizing fasciitis of the head and neck is a rare, rapidly progressive infection involving the skin, subcutaneous tissue and fascia. We report two cases that presented at the otolaryngology department at our institute in 2016. Both patients presented with a history of diabetes and according to the LRINEC score they both showed a moderate risk of having the disease. LRINEC is a valuable tool in both diagnosing the case and can be used to follow up the case, as the first case showed a decrease in score during her stay in the hospital, the second case showed an increase in score. We advocate the importance of early detection, eradicating the source of infection followed by frequent, meticulous wound dressing and strict blood sugar control to obtain better outcomes in managing necrotizing fasciitis of the head and neck.

Highlights
Alzheimer's disease in humans and other animals: A consequence of postreproductive life span and longevity rather than aging
Authors: Gunn‐Moore Danièlle , Kaidanovich‐Beilin Oksana , Iradi María Carolina Gallego , Gunn‐Moore Frank , Lovestone Simon
Published: September 2017

Introduction

Alzheimer's disease and diabetes mellitus are linked by epidemiology, genetics, and molecular pathogenesis. They may also be linked by the remarkable observation that insulin signaling sets the limits on longevity. In worms, flies, and mice, disrupting insulin signaling increases life span leading to speculation that caloric restriction might extend life span in man. It is our contention that man is already a long‐lived organism, specifically with a remarkably high postfertility life span, and that it is this that results in the prevalence of Alzheimer's disease and diabetes.

Methods

We review evidence for this hypothesis that carries specific predictions including that other animals with exceptionally long postreproductive life span will have increased risk of both diabetes and Alzheimer's disease.

Results and Conclusions

We present novel evidence that Dolphin, like man, an animal with exceptional longevity, might be one of the very few natural models of Alzheimer's disease.
Loss of cardiac resynchronization therapy in a patient with a biventricular implantable cardioverter‐defibrillator
Authors: Alasti Mohammad , Rangasamy Karthikeyan , Healy Stewart , Adam David , Kotschet Emily
Published: September 2017

Here, we discuss the case of a man with a history of ischemic cardiomyopathy and cardiac resynchronization therapy defibrillator implantation, who presented to emergency department with decompensated heart failure due to the loss of resynchronization therapy. The reason for the malfunction was left ventricle upper rate interval lock‐in due to inappropriate programming of the device.
Struggles over Land and Authority in Africa
Authors: Berry Sara
Published: October 2017

This article reviews major changes in policies and practices of land allocation and use in sub-Saharan Africa since ca 1990, using two comparative case studies to illustrate their implications for relations between local and national authority. One case contrasts Ghana, where intense local conflicts over land and authority did not translate into political conflict at the national level, with Côte d’Ivoire, where they did. The other compares political strategies and the influence of traditional chiefs in Ghana and South Africa.
PARTITIONS OF THE SET OF NONNEGATIVE INTEGERS WITH THE SAME REPRESENTATION FUNCTIONS
Authors: LI JIA-WEN , TANG MIN
Published: October 2017

Let$\mathbb{N}$be the set of all nonnegative integers. For a given set$S\subset \mathbb{N}$the representation function$R_{S}(n)$counts the number of solutions of the equation$n=s+s^{\prime }$with$s<s^{\prime }$and$s,s^{\prime }\in S$. We obtain some results on a problem of Chen and Lev [‘Integer sets with identical representation functions’,Integers16(2016), Article ID A36, 4 pages] about sets$A$and$B$such that$A\cup B=\mathbb{N}$,$A\cap B=r+m\mathbb{N}$and whose representation functions coincide.
Evaluating a transdiagnostic acceptance and commitment therapy psychoeducation intervention
Authors: Cartwright Jessica , Hooper Nic
Published: October 2017

Psychoeducation courses have gained some empirical support as effective early intervention strategies. Many of these courses reflect traditional cognitive behaviour therapy (CBT) thinking but psychoeducation courses based on other approaches are beginning to emerge. One such course, ‘ACTivate Your Life’, is based on acceptance and commitment therapy (ACT). The aim of this preliminary investigation is to evaluate a four-session (eight-hour) ACT psychoeducation intervention delivered within the Abertawe Bro Morgannwg University (ABMU) Health Board. Participants were invited to complete four outcome measures (assessing depression, anxiety, self-esteem and life satisfaction) and two process measures (assessing mindfulness self-efficacy and psychological flexibility) at pre- and post-intervention. Statistical analysis indicated that participants’ scores across each of the measured domains showed highly significant changes. These results suggest that a brief psychoeducation ACT course may be useful in helping people in need of early psychological intervention, and that further research is now needed to provide a definitive evaluation of its effectiveness.
Cosmic Ray Neutrons Reveal Mountain Snowpacks
Authors: Cook Terri
Published: September 2017

The first application of aboveground neutron sensing to evaluate alpine snowpacks indicates that this method can reliably detect average snow depth and water content across intermediate distances.
Airborne Platforms Help Answer Questions in Polar Geosciences
Authors: Scheinert Mirko , Eagles Graeme , Tinto Kirsty
Published: September 2017

International Workshop on Airborne Geodesy and Geophysics with Focus on Polar Applications; Dresden, Germany, 19–21 April 2017
To Understand Future Solar Activity, One Has to Know the Past
Authors: Pevtsov Alexei , Clette Frédéric
Published: September 2017

Short-term funding strategies present serious problems for programs like solar activity studies, where observations and analysis span decades or longer.
Laterally extended atomically precise graphene nanoribbons with improved electrical conductivity for efficient gas sensing
Authors: Mehdi Pour Mohammad , Lashkov Andrey , Radocea Adrian , Liu Ximeng , Sun Tao , Lipatov Alexey , Korlacki Rafal A. , Shekhirev Mikhail , Aluru Narayana R. , Lyding Joseph W. , Sysoev Victor , Sinitskii Alexander
Published: October 2017

Narrow atomically precise graphene nanoribbons hold great promise for electronic and optoelectronic applications, but the previously demonstrated nanoribbon-based devices typically suffer from low currents and mobilities. In this study, we explored the idea of lateral extension of graphene nanoribbons for improving their electrical conductivity. We started with a conventional chevron graphene nanoribbon, and designed its laterally extended variant. We synthesized these new graphene nanoribbons in solution and found that the lateral extension results in decrease of their electronic bandgap and improvement in the electrical conductivity of nanoribbon-based thin films. These films were employed in gas sensors and an electronic nose system, which showed improved responsivities to low molecular weight alcohols compared to similar sensors based on benchmark graphitic materials, such as graphene and reduced graphene oxide, and a reliable analyte recognition. This study shows the methodology for designing new atomically precise graphene nanoribbons with improved properties, their bottom-up synthesis, characterization, processing and implementation in electronic devices.
Upstream watershed condition predicts rural children’s health across 35 developing countries
Authors: Herrera Diego , Ellis Alicia , Fisher Brendan , Golden Christopher D. , Johnson Kiersten , Mulligan Mark , Pfaff Alexander , Treuer Timothy , Ricketts Taylor H.
Published: October 2017

Diarrheal disease (DD) due to contaminated water is a major cause of child mortality globally. Forests and wetlands can provide ecosystem services that help maintain water quality. To understand the connections between land cover and childhood DD, we compiled a database of 293,362 children in 35 countries with information on health, socioeconomic factors, climate, and watershed condition. Using hierarchical models, here we find that higher upstream tree cover is associated with lower probability of DD downstream. This effect is significant for rural households but not for urban households, suggesting differing dependence on watershed conditions. In rural areas, the effect of a 30% increase in upstream tree cover is similar to the effect of improved sanitation, but smaller than the effect of improved water source, wealth or education. We conclude that maintaining natural capital within watersheds can be an important public health investment, especially for populations with low levels of built capital.
A three-dimensional view of structural changes caused by deactivation of fluid catalytic cracking catalysts
Authors: Ihli J. , Jacob R. R. , Holler M. , Guizar-Sicairos M. , Diaz A. , da Silva J. C. , Ferreira Sanchez D. , Krumeich F. , Grolimund D. , Taddei M. , Cheng W. -C. , Shu Y. , Menzel A. , van Bokhoven J. A.
Published: October 2017

Since its commercial introduction three-quarters of a century ago, fluid catalytic cracking has been one of the most important conversion processes in the petroleum industry. In this process, porous composites composed of zeolite and clay crack the heavy fractions in crude oil into transportation fuel and petrochemical feedstocks. Yet, over time the catalytic activity of these composite particles decreases. Here, we report on ptychographic tomography, diffraction, and fluorescence tomography, as well as electron microscopy measurements, which elucidate the structural changes that lead to catalyst deactivation. In combination, these measurements reveal zeolite amorphization and distinct structural changes on the particle exterior as the driving forces behind catalyst deactivation. Amorphization of zeolites, in particular, close to the particle exterior, results in a reduction of catalytic capacity. A concretion of the outermost particle layer into a dense amorphous silica–alumina shell further reduces the mass transport to the active sites within the composite.
Interconnected subsets of memory follicular helper T cells have different effector functions
Authors: Asrir Assia , Aloulou Meryem , Gador Mylène , Pérals Corine , Fazilleau Nicolas
Published: October 2017

Follicular helper T cells regulate high-affinity antibody production. Memory follicular helper T cells can be local in draining lymphoid organs and circulate in the blood, but the underlying mechanisms of this subdivision are unresolved. Here we show that both memory follicular helper T subsets sustain B-cell responses after reactivation. Local cells promote more plasma cell differentiation, whereas circulating cells promote more secondary germinal centers. In parallel, local memory B cells are homogeneous and programmed to become plasma cells, whereas circulating memory B cells are able to rediversify. Local memory follicular helper T cells have higher affinity T-cell receptors, which correlates with expression of peptide MHC-II at the surface of local memory B cells only. Blocking T-cell receptor–peptide MHC-II interactions induces the release of local memory follicular helper T cells in the circulating compartment. Our studies show that memory follicular helper T localization is highly intertwined with memory B cells, a finding that has important implications for vaccine design.
PNLDC1 is essential for piRNA 3′ end trimming and transposon silencing during spermatogenesis in mice
Authors: Ding Deqiang , Liu Jiali , Dong Kunzhe , Midic Uros , Hess Rex A. , Xie Huirong , Demireva Elena Y. , Chen Chen
Published: October 2017

Piwi-interacting RNAs are small regulatory RNAs with key roles in transposon silencing and regulation of gametogenesis. The production of mature piwi-interacting RNAs requires a critical step of trimming piwi-interacting RNA intermediates to achieve optimally sized piwi-interacting RNAs. The poly(A)-specific ribonuclease family deadenylase PNLDC1 is implicated in piwi-interacting RNA trimming in silkworms. The physiological function of PNLDC1 in mammals remains unknown. Using Pnldc1-deficient mice, here we show that PNLDC1 is required for piwi-interacting RNA biogenesis, transposon silencing, and spermatogenesis. Pnldc1 mutation in mice inhibits piwi-interacting RNA trimming and causes accumulation of untrimmed piwi-interacting RNA intermediates with 3′ end extension, leading to severe reduction of mature piwi-interacting RNAs in the testis. Pnldc1 mutant mice exhibit disrupted LINE1 retrotransposon silencing and defect in spermiogenesis. Together, these results define PNLDC1 as a mammalian piwi-interacting RNA biogenesis factor that protects the germline genome and ensures normal sperm production in mice.
Shuttling single metal atom into and out of a metal nanoparticle
Authors: Wang Shuxin , Abroshan Hadi , Liu Chong , Luo Tian-Yi , Zhu Manzhou , Kim Hyung J. , Rosi Nathaniel L. , Jin Rongchao
Published: October 2017

It has long been a challenge to dope metal nanoparticles with a specific number of heterometal atoms at specific positions. This becomes even more challenging if the heterometal belongs to the same group as the host metal because of the high tendency of forming a distribution of alloy nanoparticles with different numbers of dopants due to the similarities of metals in outmost electron configuration. Herein we report a new strategy for shuttling a single Ag or Cu atom into a centrally hollow, rod-shaped Au24 nanoparticle, forming AgAu24 and CuAu24 nanoparticles in a highly controllable manner. Through a combined approach of experiment and theory, we explain the shuttling pathways of single dopants into and out of the nanoparticles. This study shows that the single dopant is shuttled into the hollow Au24 nanoparticle either through the apex or side entry, while shuttling a metal atom out of the Au25 to form the Au24 nanoparticle occurs mainly through the side entry.
Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
Authors: Maniaci Chiara , Hughes Scott J. , Testa Andrea , Chen Wenzhang , Lamont Douglas J. , Rocha Sonia , Alessi Dario R. , Romeo Roberto , Ciulli Alessio
Published: October 2017

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for ‘proteolysis-targeting chimeras’). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.
Strict molecular sieving over electrodeposited 2D-interspacing-narrowed graphene oxide membranes
Authors: Qi Benyu , He Xiaofan , Zeng Gaofeng , Pan Yichang , Li Guihua , Liu Guojuan , Zhang Yanfeng , Chen Wei , Sun Yuhan
Published: October 2017

To separate small molecules/species, it’s crucial but still challenging to narrow the 2D-interspacing of graphene oxide (GO) membranes without damaging the membrane. Here the fast deposition of ultrathin, defect-free and robust GO layers is realized on porous stainless steel hollow fibers (PSSHFs) by a facile and practical electrophoresis deposition (ED) method. In this approach, oxygen-containing groups of GO are selectively reduced, leading to a controlled decrease of the 2D channels of stacked GO layers. The resultant ED-GO@PSSHF composite membranes featured a sharp cutoff between C2 (ethane and ethene) and C3 (propane and propene) hydrocarbons and exhibited nearly complete rejections for the smallest alcohol and ion in aqueous solutions. This demonstrates the versatility of GO based membranes for the precise separation of various types of mixtures. At the same time, a robust mechanical strength of the ED-GO@PSSHF membrane is also achieved due to the enhanced interaction at GO/support and GO/GO interfaces.
Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer
Authors: Woo Hyun Goo , Choi Ji-Hye , Yoon Sarah , Jee Byul A. , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Yoon Jung-Hwan , Yi Nam-Joon , Lee Kwang-Woong , Suh Kyung-Suk , Kim Yoon Jun
Published: October 2017

Hepatocellular carcinoma harbors numerous genomic and epigenomic aberrations of DNA copy numbers and DNA methylation. Transcriptomic deregulation by these aberrations plays key driver roles in heterogeneous progression of cancers. Here, we profile DNA copy numbers, DNA methylation, and messenger RNA expression levels from 64 cases of hepatocellular carcinoma specimens. We find that the frequencies of the aberrancies of the DNA copy-number-correlated (CNVcor) expression genes and the methylation-correlated expression (METcor) genes are co-regulated significantly. Multi-omics integration of the CNVcor and METcor genes reveal three prognostic subtypes of hepatocellular carcinoma, which can be validated by an independent data. The most aggressive subtype expressing stemness genes has frequent BAP1 mutations, implying its pivotal role in the aggressive tumor progression. In conclusion, our integrative analysis of genomic and epigenomic regulation provides new insights on the multi-layered pathobiology of hepatocellular carcinoma, which might be helpful in developing precision management for hepatocellular carcinoma patients.
A sexually dimorphic pre-stressed translational signature in CA3 pyramidal neurons of BDNF Val66Met mice
Authors: Marrocco Jordan , Petty Gordon H. , Ríos Mariel B. , Gray Jason D. , Kogan Joshua F. , Waters Elizabeth M. , Schmidt Eric F. , Lee Francis S. , McEwen Bruce S.
Published: October 2017

Males and females use distinct brain circuits to cope with similar challenges. Using RNA sequencing of ribosome-bound mRNA from hippocampal CA3 neurons, we found remarkable sex differences and discovered that female mice displayed greater gene expression activation after acute stress than males. Stress-sensitive BDNF Val66Met mice of both sexes show a pre-stressed translational phenotype in which the same genes that are activated without applied stress are also induced in wild-type mice by an acute stressor. Behaviourally, only heterozygous BDNF Val66Met females exhibit spatial memory impairment, regardless of acute stress. Interestingly, this effect is not observed in ovariectomized heterozygous BDNF Val66Met females, suggesting that circulating ovarian hormones induce cognitive impairment in Met carriers. Cognitive deficits are not observed in males of either genotype. Thus, in a brain region not normally associated with sex differences, this work sheds light on ways that genes, environment and sex interact to affect the transcriptome’s response to a stressor.
Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice
Authors: Sack Brandon K. , Mikolajczak Sebastian A. , Fishbaugher Matthew , Vaughan Ashley M. , Flannery Erika L. , Nguyen Thao , Betz Will , Jane Navarro Mary , Foquet Lander , Steel Ryan W. J. , Billman Zachary P. , Murphy Sean C. , Hoffman Stephen L. , Chakravarty Sumana , Sim B. Kim Lee , Behet Marije , Reuling Isaie J. , Walk Jona , Scholzen Anja , Sauerwein Robert W. , Ishizuka Andrew S. , Flynn Barbara , Seder Robert A. , Kappe Stefan H. I.
Published: October 2017

Abstract

A malaria vaccine that prevents infection will be an important new tool in continued efforts of malaria elimination, and such vaccines are under intense development for the major human malaria parasitePlasmodium falciparum(Pf). Antibodies elicited by vaccines can block the initial phases of parasite infection when sporozoites are deposited into the skin by mosquito bite and then target the liver for further development. However, there are currently no standardized in vivo preclinical models that can measure the inhibitory activity of antibody specificities againstPfsporozoite infection via mosquito bite. Here, we use human liver-chimeric mice as a challenge model to assess prevention of naturalPfsporozoite infection by antibodies. We demonstrate that these mice are consistently infected withPfby mosquito bite and that this challenge can be combined with passive transfer of either monoclonal antibodies or polyclonal human IgG from immune serum to measure antibody-mediated blocking of parasite infection using bioluminescent imaging. This methodology is useful to down-select functional antibodies and to investigate mechanisms or immune correlates of protection in clinical trials, thereby informing rational vaccine optimization.
Enhanced Therapeutic Treatment of Colorectal Cancer Using Surface-Modified Nanoporous Acupuncture Needles
Authors: Lee Bo Ram , Kim Hye-Rim , Choi Eun-Sook , Cho Jung-Hoon , Kim Nam-Jun , Kim Jung-Hee , Lee Kyeong-Min , Razzaq Abdul , Choi Hansaem , Hwang Yunju , Grimes Craig A. , Lee Bong-Hyo , Kim Eunjoo , In Su-Il
Published: October 2017

Acupuncture originated within the auspices of Oriental medicine, and today is used as an alternative method for treating various diseases and symptoms. The physiological mechanisms of acupuncture appear to involve the release of endogenous opiates and neurotransmitters, with the signals mediating through electrical stimulation of the central nervous system (CNS). Earlier we reported a nanoporous stainless steel acupuncture needle with enhanced therapeutic properties, evaluated by electrophysiological and behavioral responses in Sprague-Dawley (SD) rats. Herein, we investigate molecular changes in colorectal cancer (CRC) rats by acupuncture treatment using the nanoporous needles. Treatment at acupoint HT7 is found most effective at reducing average tumor size, β-catenin expression levels, and the number of aberrant crypt foci in the colon endothelium. Surface modification of acupuncture needles further enhances the therapeutic effects of acupuncture treatment in CRC rats.
Erratum: Sample-based approach can outperform the classical dynamical analysis - experimental confirmation of the basin stability method
Authors: Brzeski P. , Wojewoda J. , Kapitaniak T. , Kurths J. , Perlikowski P.
Published: October 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene
Authors: Gonda Xenia , Sarginson Jane , Eszlari Nora , Petschner Peter , Toth Zoltan G. , Baksa Daniel , Hullam Gabor , Anderson Ian M. , Deakin J. F. William , Juhasz Gabriella , Bagdy Gyorgy
Published: October 2017

Low GABA transmission has been reported in suicide, and GABRA6 rs3219151 T allele has been associated with greater physiological and endocrine stress response in previous studies. Although environmental stress also plays a role in suicide, the possible role of this allele has not been investigated in this respect. In our present study effect of rs3219151 of GABRA6 gene in interaction with recent negative life events on lifetime and current depression, current anxiety, as well as lifetime suicide were investigated using regression models in a white European general sample of 2283 subjects. Post hoc measures for phenotypes related to suicide risk were also tested for association with rs3219151 in interaction with environmental stress. No main effect of the GABRA6 rs3219151 was detected, but in those exposed to recent negative life events GABRA6 T allele increased current anxiety and depression as well as specific elements of suicide risk including suicidal and death-related thoughts, hopelessness, restlessness and agitation, insomnia and impulsiveness as measured by the STOP task. Our data indicate that stress-associated suicide risk is elevated in carriers of the GABRA6 rs3219151 T allele with several independent markers and predictors of suicidal behaviours converging to this increased risk.
Establishment of a repeated social defeat stress model in female mice
Authors: Takahashi Aki , Chung Jia-Ru , Zhang Song , Zhang Hongxing , Grossman Yael , Aleyasin Hossein , Flanigan Meghan E. , Pfau Madeline L. , Menard Caroline , Dumitriu Dani , Hodes Georgia E. , McEwen Bruce S. , Nestler Eric J. , Han Ming-Hu , Russo Scott J.
Published: October 2017

Numerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female mouse model of RSDS by inducing male aggression toward females through chemogenetic activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate that females susceptible to RSDS display social avoidance, anxiety-like behavior, reduction of body weight, and elevated levels of circulating interleukin 6. In contrast, a subset of mice we term resilient only display anxiety-like behaviors after RSDS. This model allows for investigation of sex differences in the neurobiological mechanisms of defeat‒induced depression‒like behaviors. A robust female social defeat model is a critical first step in the identification and development of novel therapeutic compounds to treat depression and anxiety disorders in women.
The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma
Authors: Bai Dou-Sheng , Zhang Chi , Chen Ping , Jin Sheng-Jie , Jiang Guo-Qing
Published: October 2017

The purpose of this study was to conduct a comprehensive study of the clinical correlation between the alpha-fetoprotein (AFP) level at diagnosis and pathological grades, progression, and survival of patients with hepatocellular carcinoma (HCC). A total of 78,743 patients in Surveillance, Epidemiology, and End Results Program (SEER)-registered HCC was analyzed. The AFP test results for patients with HCC were mainly recorded as AFP-negative and AFP-positive. Logistic regression analysis revealed that the AFP level at diagnosis was an independent risk factor of pathological grade (odds ratio [OR], 2.559; 95% confidence interval [CI], 2.075–3.157; P < 0.001), TNM-7 stage (OR, 2.794; CI, 2.407–3.242; P < 0.001), and tumor size (OR, 1.748; 95% CI, 1.574–1.941; P < 0.001). Multivariable Cox regression analyses identified AFP level as an independent predictor of survival risk of patients with HCC who did not undergo surgery (hazard ratio [HR], 1.660; 95% CI, 1.534–1.797; P < 0.001), and those who underwent surgery (HR, 1.534; 95% CI, 1.348–1.745; P < 0.001). The AFP level at diagnosis was an independent risk predictor associated with pathological grade, progression, and survival. Further, surgery may not significantly reverse the adverse effects of AFP-positive compared with AFP-negative.
DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes
Authors: Habibian Justine S. , Jefic Mitra , Bagchi Rushita A. , Lane Robert H. , McKnight Robert A. , McKinsey Timothy A. , Morrison Ron F. , Ferguson Bradley S.
Published: October 2017

Adipose tissue inflammation is a central pathological element that regulates obesity-mediated insulin resistance and type II diabetes. Evidence demonstrates that extracellular signal-regulated kinase (ERK 1/2) activation (i.e. phosphorylation) links tumor necrosis factor α (TNFα) to pro-inflammatory gene expression in the nucleus. Dual specificity phosphatases (DUSPs) inactivate ERK 1/2 through dephosphorylation and can thus inhibit inflammatory gene expression. We report that DUSP5, an ERK1/2 phosphatase, was induced in epididymal white adipose tissue (WAT) in response to diet-induced obesity. Moreover, DUSP5 mRNA expression increased during obesity development concomitant to increases in TNFα expression. Consistent with in vivo findings, DUSP5 mRNA expression increased in adipocytes in response to TNFα, parallel with ERK1/2 dephosphorylation. Genetic loss of DUSP5 exacerbated TNFα-mediated ERK 1/2 signaling in 3T3-L1 adipocytes and in adipose tissue of mice. Furthermore, inhibition of ERK 1/2 and c-Jun N terminal kinase (JNK) signaling attenuated TNFα-induced DUSP5 expression. These data suggest that DUSP5 functions in the feedback inhibition of ERK1/2 signaling in response to TNFα, which resulted in increased inflammatory gene expression. Thus, DUSP5 potentially acts as an endogenous regulator of adipose tissue inflammation; although its role in obesity-mediated inflammation and insulin signaling remains unclear.
Nuclear factor (erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox modulation in skeletal muscles
Authors: Oh Sechang , Komine Shoichi , Warabi Eiji , Akiyama Kentaro , Ishii Akiko , Ishige Kazunori , Mizokami Yuji , Kuga Keisuke , Horie Masaki , Miwa Yoshihiro , Iwawaki Takao , Yamamoto Masayuki , Shoda Junichi
Published: October 2017

Sulforaphane (SFN) plays an important role in preventing oxidative stress by activating the nuclear factor (erythroid derived 2)-like 2 (Nrf2) signalling pathway. SFN may improve exercise endurance capacity by counteracting oxidative stress-induced damage during exercise. We assessed running ability based on an exhaustive treadmill test (progressive-continuous all-out) and examined the expression of markers for oxidative stress and muscle damage. Twelve- to 13-week-old Male wild-type mice (Nrf2+/+) and Nrf2-null mice (Nrf2−/−) on C57BL/6J background were intraperitoneally injected with SFN or vehicle prior to the test. The running distance of SFN-injected Nrf2+/+ mice was significantly greater compared with that of uninjected mice. Enhanced running capacity was accompanied by upregulation of Nrf2 signalling and downstream genes. Marker of oxidative stress in SFN-injected Nrf2+/+ mice were lower than those in uninjected mice following the test. SFN produced greater protection against muscle damage during exhaustive exercise conditions in Nrf2+/+ mice than in Nrf2−/− mice. SFN-induced Nrf2 upregulation, and its antioxidative effects, might play critical roles in attenuating muscle fatigue via reduction of oxidative stress caused by exhaustive exercise. This in turn leads to enhanced exercise endurance capacity. These results provide new insights into SFN-induced upregulation of Nrf2 and its role in improving exercise performance.
A novel immunohistochemical score to predict early mortality in acute myeloid leukemia patients based on indoleamine 2,3 dioxygenase expression
Authors: Mangaonkar Abhishek , Mondal Ashis Kumar , Fulzule Sadanand , Pundkar Chetan , Park Eun Jeong , Jillella Anand , Kota Vamsi , Xu Hongyan , Savage Natasha M. , Shi Huidong , Munn David , Kolhe Ravindra
Published: October 2017

Indoleamine 2,3 dioxygenase-1 (IDO-1) is an enzyme in the kynurenine pathway which augments tumor-induced immune tolerance. Previous studies in childhood acute myeloid leukemia (AML) have shown a negative correlation of IDO-1 mRNA expression with outcomes. The aim of our study was to develop a practical and objective immunohistochemical technique to quantify IDO-1 expression on diagnostic bone marrow biopsies of AML patients in order to facilitate its use in routine clinical practice. IDO-1 mRNA was extracted from diagnostic bone marrow specimens from 29 AML patients. IDO-1 protein expression was assessed in 40 cases via immunohistochemistry and quantified by a novel ‘composite IDO-1 score’. In a univariate analysis, higher age (p = 0.0018), male gender (p = 0.019), high risk cytogenetics (p = 0.002), higher IDO-1 mRNA (p = 0.005), higher composite IDO-1 score (p < 0.0001) and not undergoing allogeneic stem cell transplant (SCT, p = 0.0005) predicted poor overall survival. In a multivariate model that included the aforementioned variables, higher composite IDO-1 score (p = 0.007) and not undergoing allogeneic SCT (p = 0.007) was found to significantly predict poor outcomes. Further, patients who failed induction had higher composite IDO-1 score (p = 0.01). In conclusion, ‘composite IDO-1 score’ is a prognostic tool that can help identify a certain subset of AML patients with ‘early mortality’. This unique subset of patients can potentially benefit from specific IDO-1 inhibitor therapy, currently in clinical trials.
Development of A Machine Learning Algorithm to Classify Drugs Of Unknown Fetal Effect
Authors: Boland Mary Regina , Polubriaginof Fernanda , Tatonetti Nicholas P.
Published: October 2017

Many drugs commonly prescribed during pregnancy lack a fetal safety recommendation – called FDA ‘category C’ drugs. This study aims to classify these drugs into harmful and safe categories using knowledge gained from chemoinformatics (i.e., pharmacological similarity with drugs of known fetal effect) and empirical data (i.e., derived from Electronic Health Records). Our fetal loss cohort contains 14,922 affected and 33,043 unaffected pregnancies and our congenital anomalies cohort contains 5,658 affected and 31,240 unaffected infants. We trained a random forest to classify drugs of unknown pregnancy class into harmful or safe categories, focusing on two distinct outcomes: fetal loss and congenital anomalies. Our models achieved an out-of-bag accuracy of 91% for fetal loss and 87% for congenital anomalies outperforming null models. Fifty-seven ‘category C’ medications were classified as harmful for fetal loss and eleven for congenital anomalies. This includes medications with documented harmful effects, including naproxen, ibuprofen and rubella live vaccine. We also identified several novel drugs, e.g., haloperidol, that increased the risk of fetal loss. Our approach provides important information on the harmfulness of ‘category C’ drugs. This is needed, as no FDA recommendation exists for these drugs’ fetal safety.
Quantifying the relative immune cell activation from whole tissue/organ-derived differentially expressed gene data
Authors: Wijaya Edward , Igarashi Yoshinobu , Nakatsu Noriyuki , Haseda Yasunari , Billaud Joel , Chen Yi-An , Mizuguchi Kenji , Yamada Hiroshi , Ishii Ken , Aoshi Taiki
Published: October 2017

Evaluation of immune responses in individual immune cell types is important for the development of new medicines. Here, we propose a computational method designated ICEPOP (Immune CEll POPulation) to estimate individual immune cell type responses from bulk tissue and organ samples. The relative gene responses are scored for each cell type by using the data from differentially expressed genes derived from control- vs drug-treated sample pairs, and the data from public databases including ImmGen and IRIS, which contain gene expression profiles of a variety of immune cells. By ICEPOP, we analysed cell responses induced by vaccine-adjuvants in the mouse spleen, and extended the analyses to human peripheral blood mononuclear cells and gut biopsy samples focusing on human papilloma virus vaccination and inflammatory bowel disease treatment with Infliximab. In both mouse and human datasets, our method reliably quantified the responding immune cell types and provided insightful information, demonstrating that our method is useful to evaluate immune responses from bulk sample-derived gene expression data. ICEPOP is available as an interactive web site (https://vdynamics.shinyapps.io/icepop/) and Python package (https://github.com/ewijaya/icepop).
Genetic status of KRAS modulates the role of Neuropilin-1 in tumorigenesis
Authors: Vivekanandhan Sneha , Yang Lijuan , Cao Ying , Wang Engfeng , Dutta Shamit K. , Sharma Anil K. , Mukhopadhyay Debabrata
Published: October 2017

Neuropilin-1 (NRP1), a non–tyrosine kinase receptor, is overexpressed in many cancers including pancreatic and lung cancers. Inhibition of NRP1 expression, however, has differing pro-tumor vs. anti-tumor effects, depending on the cancer types. To understand the differential role of NRP1 in tumorigenesis process, we utilized cells from two different cancer types, pancreatic and lung, each containing either wild type KRAS (KRASwt) or mutant KRAS (KRASmt). Inhibition of NRP1 expression by shRNA in both pancreatic and lung cancer cells containing dominant active KRASmt caused increased cell viability and tumor growth. On the contrary, inhibition of NRP1, in the tumor cells containing KRASwt showed decreased tumor growth. Importantly, concurrent inhibition of KRASmt and NRP1 in the tumor cells reverses the increased viability and leads to tumor inhibition. We found that NRP1 shRNA expressing KRASmt tumor cells caused increased cell viability by decreasing SMAD2 phosphorylation. Our findings demonstrate that the effects of NRP1 knockdown in cancer cells are dependent on the genetic status of KRAS.
Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
Authors: Ren Yin , Sagers Jessica E. , Landegger Lukas D. , Bhatia Sangeeta N. , Stankovic Konstantina M.
Published: October 2017

Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS.