bluuebunny/crossref_metadata_2025 huggingface dataset:
Finite amplitude analysis of non-isothermal parallel flow in a vertical channel filled with a highly permeable porous medium
Authors: Sharma Abhishek K. , Khandelwal Manish K. , Bera P.
Published: October 2018

This paper addresses the finite amplitude instability of stably stratified non-isothermal parallel flow in a vertical channel filled with a highly permeable porous medium. A cubic Landau equation is derived to study the limiting value of growth of instabilities under nonlinear effects. The non-Darcy model is considered to describe the flow instabilities in a porous medium. The nonlinear results are presented for air as well as water. The analysis is carried out in the vicinity of as well as away from the critical point (bifurcation point). It is found that when the medium is saturated by water then supercritical bifurcation is the only type of bifurcation at and beyond the bifurcation point. However, for air, depending on the strength of the flow and permeability of the medium, both supercritical and subcritical bifurcations are observed. The influence of nonlinear interaction of different harmonics on the heat transfer rate, friction coefficient, nonlinear kinetic energy spectrum and disturbance flow is also studied in both supercritical as well as subcritical regimes. The variation of neutral stability curves of parallel mixed convection flow of air with wavenumber reveals that a bifurcation that is supercritical for some wavenumber may be subcritical orvice versaat other nearby wavenumbers. The analysis of the nonlinear kinetic energy spectrum of the fundamental disturbance also supports the existence of supercritical/subcritical bifurcation at and away from the critical point. The effect of different harmonics on the pattern of secondary flow, based on linear stability theory, is also studied and a significant influence is found, especially in the subcritical regime.
Global energy fluxes in turbulent channels with flow control
Authors: Gatti Davide , Cimarelli Andrea , Hasegawa Yosuke , Frohnapfel Bettina , Quadrio Maurizio
Published: October 2018

This paper addresses the integral energy fluxes in natural and controlled turbulent channel flows, where active skin-friction drag reduction techniques allow a more efficient use of the available power. We study whether the increased efficiency shows any general trend in how energy is dissipated by the mean velocity field (mean dissipation) and by the fluctuating velocity field (turbulent dissipation). Direct numerical simulations (DNS) of different control strategies are performed at constant power input (CPI), so that at statistical equilibrium, each flow (either uncontrolled or controlled by different means) has the same power input, hence the same global energy flux and, by definition, the same total energy dissipation rate. The simulations reveal that changes in mean and turbulent energy dissipation rates can be of either sign in a successfully controlled flow. A quantitative description of these changes is made possible by a new decomposition of the total dissipation, stemming from an extended Reynolds decomposition, where the mean velocity is split into a laminar component and a deviation from it. Thanks to the analytical expressions of the laminar quantities, exact relationships are derived that link the achieved flow rate increase and all energy fluxes in the flow system with two wall-normal integrals of the Reynolds shear stress and the Reynolds number. The dependence of the energy fluxes on the Reynolds number is elucidated with a simple model in which the control-dependent changes of the Reynolds shear stress are accounted for via a modification of the mean velocity profile. The physical meaning of the energy fluxes stemming from the new decomposition unveils their inter-relations and connection to flow control, so that a clear target for flow control can be identified.
On the transient behaviour of a laminar rotor–stator cavity
Authors: Corral R. , Romera D.
Published: October 2018

The unsteady laminar flow between two large rotating disks when one of them is impulsively started is described using the von Kármán similarity analysis to reduce the solution of the Navier–Stokes equations to a set of ordinary differential equations. It is found that the transient phenomenon consists of three distinct phases. Firstly, the development of the Ekman boundary layer, where a quasi-steady Stewartson-type of flow is created. Secondly, angular momentum is initially diffused in the axial direction until the inward radial convection of angular momentum becomes dominating. Thirdly, a Batchelor flow is created once the Bödewadt boundary layer is developed and the entrainment of disk and stator boundary layers are balanced. The dependences of the characteristic dimensionless times on the Reynolds number based on the cavity gap for the second and third stages have been identified numerically and analytically. It is found that the diffusive part of the transient is bypassed if the flow, initially at rest, is perturbed with a small circumferential velocity. The flow and heat transfer transient during a ramp of finite duration has been computed numerically. The integral angular momentum and energy balances of the cavity have been performed in order to understand the energy and momentum budget of the cavity. It is concluded that the spin-up and the spin-down process of a rotor–stator cavity using a quasi-stationary approximation of the fluid, where the time derivatives are neglected, is questionable for realistic gas turbine applications. Finally, the self-similar solution is compared against two-dimensional axisymmetric, steady and unsteady, laminar simulations to assess the limitations and validity of the self-similar analysis. It has been identified that in a closed squared cavity the outer shroud modifies the physics of the transient, but the general conclusions drawn from the one-dimensional model are still valid.
The motion of a buoyant vortex filament
Authors: Chang Ching , Llewellyn Smith Stefan G.
Published: October 2018

We investigate the motion of a thin vortex filament in the presence of buoyancy. The asymptotic model of Moore & Saffman (Phil. Trans. R. Soc. Lond.A, vol. 272, 1972, pp. 403–429) is extended to take account of buoyancy forces in the force balance on a vortex element. The motion of a buoyant vortex is given by the transverse component of force balance, while the tangential component governs the dynamics of the structure in the core. We show that the local acceleration of axial flow is generated by the external pressure gradient due to gravity. The equations are then solved for vortex rings. An analytic solution for a buoyant vortex ring at a small initial inclination is obtained and asymptotically agrees with the literature.
Managing intensity in knowledge work: Self-leadership practices among Danish management consultants
Authors: Bäcklander Gisela , Rosengren Calle , Kaulio Matti
Published: October 2018

This paper examines the sources of knowledge workers’ work intensity and the self-leading strategies they apply to deal with it. The paper is based on focus group interviews with management consultants in a Danish management consultancy firm. Work intensity was identified as resulting from a combination of: (1) a results-only focus, (2) vagueness, (3) boundaryless work, and (4) low control of the quantitative load. A framework for self-leading strategies is developed based on the dimensions of reactive/proactive and self-focused/externally focused strategies in different combinations. The results indicate that while consultants expressed a belief in internal self-discipline strategies of a more reactive nature, in fact, external and proactive strategies were the most effective in practice. In conclusion, the paper contributes to an extension of self-leadership theory to better account for current research on self-control.
The External Validity of College Student Subject Pools in Experimental Research: A Cross-Sample Comparison of Treatment Effect Heterogeneity
Authors: Lupton Danielle L.
Published: October 2018

Are student subject experiment pools comparable across institutions? Despite repeated concerns over the “college sophomore problem,” many experiment-based studies still rely on student subject pools due to their convenience and accessibility. In this paper, I investigate whether student subject pools are comparable across universities by examining how respondents across three student subject pools at distinct educational institutions perform on the same survey experiment about crisis bargaining between states. I argue that, due to selection biases inherent in university matriculation and the self-selection of students into experimental protocols, respondents across these subject pools will exhibit key demographic differences. I also examine whether respondents across these subject pools think similarly about international politics and respond comparably to experimental treatments. I find that, while there are significant demographic differences across subject pools, subjects across institutions respond similarly to experimental treatments—with the key exception of information regarding the regime type of a state. Furthermore, there is little evidence that these demographic differences impact conditional average treatment effects across subgroups. These findings carry critical implications for the use of student samples across political science and within international relations more specifically, particularly regarding the current replication crisis in the discipline.
The frame of smashing tensor-ideals
Authors: BALMER PAUL , KRAUSE HENNING , STEVENSON GREG
Published: October 2018

We prove that every flat tensor-idempotent in the module category Mod- of a tensor-triangulated category comes from a unique smashing ideal in . We deduce that the lattice of smashing ideals forms a frame.
Complementary endozoochorous seed dispersal by large mammals in the Golestan National Park, Iran
Authors: Karimi Sorour , Hemami Mahmoud-Reza , Tarkesh Esfahani Mostafa , Akhani Hossein , Baltzinger Christophe
Published: October 2018

Large animals tend to disperse seeds over long distances via ingestion and defecation due to their large home range and capacity to move among different habitats for feeding. The aim of this study was to investigate the potential of endozoochorous seed dispersal by five herbivores: Ovis vignei, Capra aegagrus, Gazella subgutturosa, Cervus elaphus, Capreolus capreolus and two omnivores: Sus Scrofa and Ursus arctos in the Golestan National Park, northeast of Iran, by a greenhouse germination experiment. A total of 3107 seedlings belonging to 154 different plant taxa were germinated from 655 dung samples collected in three different habitats. Plant families that most frequently germinated were Poaceae and Brassicaceae. Urtica dioica was the most abundant germinating seed, accounting for 20% of all the seedlings recorded in our dung samples, whereas the most frequently observed species was Portulaca oleracea, which occurred in 24% of our samples. We showed that 54% of the seeds germinating were dispersed by only one of the mammals studied. Herbs and graminoids were the most frequently dispersed growth forms by the herbivores and the wild boar, whereas brown bears mostly dispersed shrubs. The seedling composition in the dung samples was strongly correlated with the local flora especially for non-selective feeders, like red deer. The differences observed in the number of plants and frequency of different growth forms dispersed among the studied mammals reflect their body size, digestive physiology, and dietary and habitat preferences. Our findings highlight the different and complementary roles of large herbivores and omnivores as long-distance seed dispersal vectors.
REVIEWERS FOR VOLUME 75
Authors: Editor Journal
Published: October 2018

Many papers submitted to the Edinburgh Journal of Botany are reviewed by members of the Editorial Board and Editorial Advisory Board. The members of both Boards wish to express their thanks to the following, who have also kindly reviewed papers during the preparation of this volume.
Online grocery shopping: promise and pitfalls for healthier food and beverage purchases
Authors: Jilcott Pitts Stephanie B , Ng Shu Wen , Blitstein Jonathan L , Gustafson Alison , Niculescu Mihai
Published: October 2018

Objectives

(i) To determine the current state of online grocery shopping, including individuals’ motivations for shopping for groceries online and types of foods purchased; and (ii) to identify the potential promise and pitfalls that online grocery shopping may offer in relation to food and beverage purchases.

Design

PubMed, ABI/INFORM and Google Scholar were searched to identify published research.

Setting

To be included, studies must have been published between 2007 and 2017 in English, based in the USA or Europe (including the UK), and focused on: (i) motivations for online grocery shopping; (ii) the cognitive/psychosocial domain; and (iii) the community or neighbourhood food environment domain.

Subjects

Our search yielded twenty-four relevant papers.

Results

Findings indicate that online grocery shopping can be a double-edged sword. While it has the potential to increase healthy choices via reduced unhealthy impulse purchases, nutrition labelling strategies, and as a method to overcome food access limitations among individuals with limited access to a brick-and-mortar store, it also has the potential to increase unhealthy choices due to reasons such as consumers’ hesitance to purchase fresh produce online.

Conclusions

Additional research is needed to determine the most effective ways to positively engage customers to use online grocery shopping to make healthier choices.
Estimating the Economic Value of Interannual Reservoir Storage in Water Resource Systems
Authors: Khadem M. , Rougé C. , Harou J. J. , Hansen K. M. , Medellin‐Azuara J. , Lund J. R.
Published: October 2018

Reservoir operators face pressures on timing releases of water. Releasing too much water immediately can threaten future supplies and costs, but not releasing enough creates immediate economic hardship downstream. This paper examines how the economic valuation of end‐of‐year carryover storage can lead to optimal amounts of carryover storage in complex large water resource systems. Economic carryover storage value functions (COSVFs) are developed to represent the value of storage in the face of interannual inflow uncertainty and variability within water resource optimization models. The approach divides a perfect foresight optimization problem into year‐long (limited foresight) subproblems solved sequentially by a within‐year optimization engine to find optimal short‐term operations. The final storage state from the previous year provides the initial condition to each annual problem, and end‐of‐year COSVFs are the final condition. Here the COSVF parameters that maximize the interannual benefits from river basin operations are found by evolutionary search. This generalized approach can handle nonconvexity in large‐scale water resources systems. The approach is illustrated with a regional model of the California Central Valley water system including 30 reservoirs, 22 aquifers, and 51 urban and agricultural demand sites. Head‐dependent pumping costs make the optimization problem nonconvex. Optimized interannual reservoir operation improves over more cautious operation in the historical approximation, reducing the average annual scarcity volume and costs by 80% and 98%, respectively, with more realistic representation of hydrologic foresight for California's Mediterranean climate. The economic valuation of storage helps inform water storage decisions.
Isotopic Constraints on Nitrogen Transformation Rates in the Deep Sedimentary Marine Biosphere
Authors: Buchwald C. , Homola K. , Spivack A. J. , Estes E. R. , Murray R. W. , Wankel S. D.
Published: October 2018

Little is known about the nature of microbial community activity contributing to the cycling of nitrogen in organic‐poor sediments underlying the expansive oligotrophic ocean gyres. Here we use pore water concentrations and stable N and O isotope measurements of nitrate and nitrite to constrain rates of nitrogen cycling processes over a 34‐m profile from the deep North Atlantic spanning fully oxic to anoxic conditions. Using a 1‐D reaction‐diffusion model to predict the distribution of nitrogen cycling rates, results converge on two distinct scenarios: (1) an exceptionally high degree of coupling between nitrite oxidation and nitrate reduction near the top of the anoxic zone or (2) an unusually large N isotope effect (~60‰) for nitrate reduction that is decoupled from the corresponding O isotope effect, which is possibly explained by enzyme‐level interconversion between nitrite and nitrate.
Early effects of exposure-based cognitive behaviour therapy on the neural correlates of anxiety
Authors: Reinecke Andrea , Thilo Kai V. , Croft Alison , Harmer Catherine J.
Published: October 2018

Exposure-based cognitive-behaviour therapy (CBT) for anxiety disorders is an effective intervention, but the brain mechanisms driving recovery are largely unknown. In this experimental medicine study, we investigated to what degree CBT affects neural markers of anxiety at an early stage of treatment, to identify dynamic mechanistic changes which might be crucial in the process of recovery as opposed to those seen following full treatment completion. In a randomised controlled trial, unmedicated patients with panic disorder either received four weekly sessions of exposure-based CBT (N = 14) or were allocated to a waiting group (N = 14). Symptom severity was measured before and after the intervention. During functional magnetic resonance imaging (fMRI), patients performed an emotion regulation task, either viewing negative images naturally, or intentionally down-regulating negative affect using previously taught strategies. Four-session CBT led to marked reductions in symptoms and 71% of patients reached recovery status (versus 7% in the control group). This intervention normalised brain hyperactivation previously seen in panic disorder, particularly in areas linked to threat monitoring, fear memory, and maladaptive emotion regulation, such as amygdala, dorsomedial and dorsolateral prefrontal cortex, and temporal gyrus. Our findings suggest that optimal treatment doses for panic disorder might be much lower than previously thought. Furthermore, this is the first study to show that neural markers of anxiety change very early during CBT, highlighting potential neural mechanisms that might drive clinical recovery. Such knowledge is important for the development of more compact combination treatments targeting these mechanisms more effectively. (Neural Effects of Cognitive-behaviour Therapy in Panic Disorder; clinicaltrials.gov; NCT03251235)
MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/mTOR axis in gastric cancer
Authors: Chen Sheng , Wu Jian , Jiao Kai , Wu Qiong , Ma Jiaojiao , Chen Di , Kang Jianqin , Zhao Guodong , Shi Yongquan , Fan Daiming , Zhao Guohong
Published: October 2018

Multidrug resistance (MDR) accounts for poor prognosis in gastric cancer (GC). MicroRNAs (miRNAs) are critical regulators of MDR via modulation of the target genes. The present study revealed that miR-495-3p could act via a target gene, GRP78, to regulate the process of autophagy and inhibit MDR. Based on the in vitro and in vivo gain-of-function or loss-of-function experiments, overexpression of miR-495-3p was sufficient to reverse the MDR to four chemotherapeutics in vitro and inhibit the tumor growth in vivo. Moreover, GRP78 was positively associated with the occurrence of autophagy. Thus, reducing the expression of GRP78 by siRNA resulted in autophagy-suppressive activity similar to that of miR-495-3p on mammalian target of rapamycin (mTOR) and its substrates activation and autophagy inhibition, while restoring GRP78 attenuated the anti-autophagy effects caused by miR-495-3p. Clinically, either miR-495-3p downregulation or GRP78 upregulation was associated with malignant phenotypes in patients with GC. In conclusion, these findings demonstrate that miR-495-3p is an important regulator of autophagy balance and MDR by modulating the GRP78/mTOR axis. In addition, miR-495-3p and GRP78 could be used as prognostic factors for overall survival in GC, which implicates miR-495-3p as a therapeutic target in cancer.
Activation of the interferon type I response rather than autophagy contributes to myogenesis inhibition in congenital DM1 myoblasts
Authors: Rizzo Milena , Beffy Pascale , Del Carratore Renata , Falleni Alessandra , Pretini Virginia , D’Aurizio Romina , Botta Annalisa , Evangelista Monica , Stoccoro Andrea , Coppedè Fabio , Furling Denis , Simili Marcella
Published: October 2018

Congenital myotonic dystrophy type 1 (CDM1) is characterized by severe symptoms that affect patients from birth, with 40% mortality in the neonatal period and impaired skeletal muscle development. In this paper, we examined the relationship between autophagy and abnormal myogenic differentiation of CDM1 myoblasts. We investigated these pathological features at both ultrastructural and molecular levels, utilizing two CDM1 foetal myoblasts, CDM13 and CDM15, with 1800 and 3200 repeats, respectively. The congenital nature of these CDM1 myoblasts was confirmed by the high methylation level at the DMPK locus. Our results indicated that abnormal autophagy was independent of myogenic differentiation, as CDM13 myoblasts differentiated as well as control myoblasts but underwent autophagy like CDM15, displaying impaired differentiation. miRNA expression profiles revealed that CDM15 myoblasts failed to upregulate the complex network of myo-miRNAs under MYOD and MEF2A control, while this network was upregulated in CDM13 myoblasts. Interestingly, the abnormal differentiation of CDM15 myoblasts was associated with cellular stress accompanied by the induction of the interferon type 1 pathway (innate immune response). Indeed, inhibition of the interferon (IFN) type I pathway restores myogenic differentiation of CDM15 myoblasts, suggesting that the inappropriate activation of the innate immune response might contribute to impaired myogenic differentiation and severe muscle symptoms observed in some CDM1 patients. These findings open up the possibility of new therapeutic approaches to treat CDM1.
AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields)
Authors: Shteingauz Anna , Porat Yaara , Voloshin Tali , Schneiderman Rosa S. , Munster Mijal , Zeevi Einav , Kaynan Noa , Gotlib Karnit , Giladi Moshe , Kirson Eilon D. , Weinberg Uri , Kinzel Adrian , Palti Yoram
Published: October 2018

Tumor Treating Fields (TTFields), an approved treatment modality for glioblastoma, are delivered via non-invasive application of low-intensity, intermediate-frequency, alternating electric fields. TTFields application leads to abnormal mitosis, aneuploidy, and increased cell granularity, which are often associated with enhancement of autophagy. In this work, we evaluated whether TTFields effected the regulation of autophagy in glioma cells. We found that autophagy is upregulated in glioma cells treated with TTFields as demonstrated by immunoblot analysis of the lipidated microtubule-associated protein light chain 3 (LC3-II). Fluorescence and transmission electron microscopy demonstrated the presence of LC3 puncta and typical autophagosome-like structures in TTFields-treated cells. Utilizing time-lapse microscopy, we found that the significant increase in the formation of LC3 puncta was specific to cells that divided during TTFields application. Evaluation of selected cell stress parameters revealed an increase in the expression of the endoplasmic reticulum (ER) stress marker GRP78 and decreased intracellular ATP levels, both of which are indicative of increased proteotoxic stress. Pathway analysis demonstrated that TTFields-induced upregulation of autophagy is dependent on AMP-activated protein kinase (AMPK) activation. Depletion of AMPK or autophagy-related protein 7 (ATG7) inhibited the upregulation of autophagy in response to TTFields, as well as sensitized cells to the treatment, suggesting that cancer cells utilize autophagy as a resistance mechanism to TTFields. Combining TTFields with the autophagy inhibitor chloroquine (CQ) resulted in a significant dose-dependent reduction in cell growth compared with either TTFields or CQ alone. These results suggest that dividing cells upregulate autophagy in response to aneuploidy and ER stress induced by TTFields, and that AMPK serves as a key regulator of this process.
Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation
Authors: Colonna Lucrezia , Peterson Christopher W. , Schell John B. , Carlson Judith M. , Tkachev Victor , Brown Melanie , Yu Alison , Reddy Sowmya , Obenza Willi M. , Nelson Veronica , Polacino Patricia S. , Mack Heather , Hu Shiu-Lok , Zeleski Katie , Hoffman Michelle , Olvera Joe , Furlan Scott N. , Zheng Hengqi , Taraseviciute Agne , Hunt Daniel J. , Betz Kayla , Lane Jennifer F. , Vogel Keith , Hotchkiss Charlotte E. , Moats Cassie , Baldessari Audrey , Murnane Robert D. , English Christopher , Astley Cliff A. , Wangari Solomon , Agricola Brian , Ahrens Joel , Iwayama Naoto , May Andrew , Stensland Laurence , Huang Meei-Li W. , Jerome Keith R. , Kiem Hans-Peter , Kean Leslie S.
Published: October 2018

Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.
RhoGAP domain-containing fusions and PPAPDC1A fusions are recurrent and prognostic in diffuse gastric cancer
Authors: Yang Hanna , Hong Dongwan , Cho Soo Young , Park Young Soo , Ko Woo Ri , Kim Ju Hee , Hur Hoon , Lee Jongkeun , Kim Su-Jin , Kwon Sun Young , Lee Jae-Hyuk , Park Do Youn , Song Kyu Sang , Chang Heekyung , Ryu Min-Hee , Cho Kye Soo , Kang Jeong Won , Kook Myeong-Cherl , Thiessen Nina , He An , Mungall Andy , Han Sang-Uk , Kim Hark Kyun
Published: October 2018

We conducted an RNA sequencing study to identify novel gene fusions in 80 discovery dataset tumors collected from young patients with diffuse gastric cancer (DGC). Twenty-five in-frame fusions are associated with DGC, three of which (CLDN18-ARHGAP26, CTNND1-ARHGAP26, and ANXA2-MYO9A) are recurrent in 384 DGCs based on RT-PCR. All three fusions contain a RhoGAP domain in their 3’ partner genes. Patients with one of these three fusions have a significantly worse prognosis than those without. Ectopic expression of CLDN18-ARHGAP26 promotes the migration and invasion capacities of DGC cells. Parallel targeted RNA sequencing analysis additionally identifies TACC2-PPAPDC1A as a recurrent and poor prognostic in-frame fusion. Overall, PPAPDC1A fusions and in-frame fusions containing a RhoGAP domain clearly define the aggressive subset (7.5%) of DGCs, and their prognostic impact is greater than, and independent of, chromosomal instability and CDH1 mutations. Our study may provide novel genomic insights guiding future strategies for managing DGCs.
Structural dynamics of the E6AP/UBE3A-E6-p53 enzyme-substrate complex
Authors: Sailer Carolin , Offensperger Fabian , Julier Alexandra , Kammer Kai-Michael , Walker-Gray Ryan , Gold Matthew G. , Scheffner Martin , Stengel Florian
Published: October 2018

Deregulation of the ubiquitin ligase E6AP is causally linked to the development of human disease, including cervical cancer. In complex with the E6 oncoprotein of human papillomaviruses, E6AP targets the tumor suppressor p53 for degradation, thereby contributing to carcinogenesis. Moreover, E6 acts as a potent activator of E6AP by a yet unknown mechanism. However, structural information explaining how the E6AP-E6-p53 enzyme-substrate complex is assembled, and how E6 stimulates E6AP, is largely missing. Here, we develop and apply different crosslinking mass spectrometry-based approaches to study the E6AP-E6-p53 interplay. We show that binding of E6 induces conformational rearrangements in E6AP, thereby positioning E6 and p53 in the immediate vicinity of the catalytic center of E6AP. Our data provide structural and functional insights into the dynamics of the full-length E6AP-E6-p53 enzyme-substrate complex, demonstrating how E6 can stimulate the ubiquitin ligase activity of E6AP while facilitating ubiquitin transfer from E6AP onto p53.
A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
Authors: Arnadottir Gudny A. , Norddahl Gudmundur L. , Gudmundsdottir Steinunn , Agustsdottir Arna B. , Sigurdsson Snaevar , Jensson Brynjar O. , Bjarnadottir Kristbjorg , Theodors Fannar , Benonisdottir Stefania , Ivarsdottir Erna V. , Oddsson Asmundur , Kristjansson Ragnar P. , Sulem Gerald , Alexandersson Kristjan F. , Juliusdottir Thorhildur , Gudmundsson Kjartan R. , Saemundsdottir Jona , Jonasdottir Adalbjorg , Jonasdottir Aslaug , Sigurdsson Asgeir , Manzanillo Paolo , Gudjonsson Sigurjon A. , Thorisson Gudmundur A. , Magnusson Olafur Th. , Masson Gisli , Orvar Kjartan B. , Holm Hilma , Bjornsson Sigurdur , Arngrimsson Reynir , Gudbjartsson Daniel F. , Thorsteinsdottir Unnur , Jonsdottir Ingileif , Haraldsson Asgeir , Sulem Patrick , Stefansson Kari
Published: October 2018

Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.
Women with prolonged nausea in pregnancy have increased risk for depressive symptoms postpartum
Authors: Iliadis Stavros I. , Axfors Cathrine , Johansson Sara , Skalkidou Alkistis , Mulic-Lutvica Ajlana
Published: October 2018

The aim of this population-based, longitudinal study was to assess the association between nausea and vomiting in pregnancy (NVP) and perinatal depressive symptoms. Pregnant women (N = 4239) undergoing routine ultrasound at gestational week (GW) 17 self-reported on NVP and were divided into those without nausea (G0), early (≤17 GW) nausea without medication (G1), early nausea with medication (G2), and prolonged (>17 GW) nausea (G3). The Edinburgh Postnatal Depression Scale at GW 17 and 32 (cut-off ≥13) and at six weeks postpartum (cut-off ≥12) was used to assess depressive symptoms. Main outcome measures were depressive symptoms at GW 32 and at six weeks postpartum. NVP was experienced by 80.7%. The unadjusted logistic regression showed a positive association between all three nausea groups and depressive symptoms at all time-points. After adjustment, significant associations with postpartum depressive symptoms remained for G3, compared to G0 (aOR = 1.66; 95% CI 1.1–2.52). After excluding women with history of depression, only the G3 group was at higher odds for postpartum depressive symptoms (aOR = 2.26; 95% CI 1.04–4.92). In conclusion, women with prolonged nausea have increased risk of depressive symptoms at six weeks postpartum, regardless of history of depression.
Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to-brain metastases
Authors: Zhang Wei , Zhang Cunlong , Liu Feng , Mao Yu , Xu Wei , Fan Tingting , Sun Qinsheng , He Shengnan , Chen Yuzong , Guo Wei , Tan Ying , Jiang Yuyang
Published: October 2018

Epidemiological observations have shown that schizophrenia patients after long-term drug treatment exhibited reduced tumor incidences. The potential anticancer effects of antipsychotic drugs are subsequently demonstrated. These drugs are of great interest as agents against untreatable brain metastases because of their ability to traverse the blood-brain barrier (BBB). Most drugs tested thus far are the first-generation antipsychotics (FGAs). But their clinical application may be limited due to high risks of deaths in elderly patients. There is an urgent need to find additional BBB-traversing anticancer agents with lower risks of deaths. In this work, we investigated antitumor activities of eight second-generation-antipsychotic (SGA) drugs, since they exhibit lower mortality rates than FGAs. We discovered that sertindole showed broad antiproliferative activities against seven cancer types including 29 cell-lines and exhibited potent effects toward breast cancer cell-lines, with half maximal concentration to inhibit proliferation by 50% (IC50) as low as 800 nM. We further found that sertindole caused cell death through autophagy-associated apoptosis and its directly-binding inhibition of 5-HT6 involved in this process. In xenotransplant mice, sertindole administration approaching maximal therapeutic dose attenuated breast-tumor growth by 22.7%. Therefore, our study reveals promising anticancer potentials of sertindole against breast cancers, with probable applications for breast-to-brain metastases.
Dynamic volume magnetic domain wall imaging in grain oriented electrical steel at power frequencies with accumulative high-frame rate neutron dark-field imaging
Authors: Harti Ralph P. , Strobl Markus , Schäfer Rudolf , Kardjilov Nikolay , Tremsin Anton S. , Grünzweig Christian
Published: October 2018

The mobility of magnetic domains forms the link between the basic physical properties of a magnetic material and its global characteristics such as permeability and saturation field. Most commonly, surface domain structure are studied using magneto-optical Kerr microscopy. The limited information depth of approx. 20 nanometers, however, allows only for an indirect interpretation of the internal volume domain structures. Here we show how accumulative high-frame rate dynamic neutron dark-field imaging is able for the first time to visualize the dynamic of the volume magnetic domain structures in grain oriented electrical steel laminations at power frequencies. In particular we studied the volume domain structures with a spatial resolution of ∼100 μm and successfully quantified domain sizes, wall velocities, domain annihilation and its duration and domain wall multiplication in real time recordings at power frequencies of 10, 25 and 50 Hz with ±262.5 A/m and ±525 A/m (peak to peak) applied field.
Nanogel tectonic porous 3D scaffold for direct reprogramming fibroblasts into osteoblasts and bone regeneration
Authors: Sato Yoshiki , Yamamoto Kenta , Horiguchi Satoshi , Tahara Yoshiro , Nakai Kei , Kotani Shin-ichiro , Oseko Fumishige , Pezzotti Giuseppe , Yamamoto Toshiro , Kishida Tsunao , Kanamura Narisato , Akiyoshi Kazunari , Mazda Osam
Published: October 2018

Transplantation of engineered three-dimensional (3D) bone tissue may provide therapeutic benefits to patients with various bone diseases. To achieve this goal, appropriate 3D scaffolds and cells are required. In the present study, we devised a novel nanogel tectonic material for artificial 3D scaffold, namely the nanogel-cross-linked porous (NanoCliP)-freeze-dried (FD) gel, and estimated its potential as a 3D scaffold for bone tissue engineering. As the osteoblasts, directly converted osteoblasts (dOBs) were used, because a large number of highly functional osteoblasts could be induced from fibroblasts that can be collected from patients with a minimally invasive procedure. The NanoCliP-FD gel was highly porous, and fibronectin coating of the gel allowed efficient adhesion of the dOBs, so that the cells occupied the almost entire surface of the walls of the pores after culturing for 7 days. The dOBs massively produced calcified bone matrix, and the culture could be continued for at least 28 days. The NanoCliP-FD gel with dOBs remarkably promoted bone regeneration in vivo after having been grafted to bone defect lesions that were artificially created in mice. The present findings suggest that the combination of the NanoCliP-FD gel and dOBs may provide a feasible therapeutic modality for bone diseases.
The mesophilic archaeon Methanosarcina acetivorans counteracts uracil in DNA with multiple enzymes: EndoQ, ExoIII, and UDG
Authors: Shiraishi Miyako , Ishino Sonoko , Heffernan Matthew , Cann Isaac , Ishino Yoshizumi
Published: October 2018

Cytosine deamination into uracil is one of the most prevalent and pro-mutagenic forms of damage to DNA. Base excision repair is a well-known process of uracil removal in DNA, which is achieved by uracil DNA glycosylase (UDG) that is found in all three domains of life. However, other strategies for uracil removal seem to have been evolved in Archaea. Exonuclease III (ExoIII) from the euryarchaeon Methanothermobacter thermautotrophicus has been described to exhibit endonuclease activity toward uracil-containing DNA. Another uracil-acting protein, endonuclease Q (EndoQ), was recently identified from the euryarchaeon Pyrococcus furiosus. Here, we describe the uracil-counteracting system in the mesophilic euryarchaeon Methanosarcina acetivorans through genomic sequence analyses and biochemical characterizations. Three enzymes, UDG, ExoIII, and EndoQ, from M. acetivorans exhibited uracil cleavage activities in DNA with a distinct range of substrate specificities in vitro, and the transcripts for these three enzymes were detected in the M. acetivorans cells. Thus, this organism appears to conduct uracil repair using at least three distinct pathways. Distribution of the homologs of these uracil-targeting proteins in Archaea showed that this tendency is not restricted to M. acetivorans, but is prevalent and diverse in most Archaea. This work further underscores the importance of uracil-removal systems to maintain genome integrity in Archaea, including ‘UDG lacking’ organisms.
Cell Transport Prompts the Performance of Low-Voltage Electroporation for Cell Inactivation
Authors: Huo Zheng-Yang , Li Guo-Qiang , Yu Tong , Feng Chao , Lu Yun , Wu Yin-Hu , Yu Cecilia , Xie Xing , Hu Hong-Ying
Published: October 2018

The inactivation of pathogens in liquids has broad applications, ranging from water disinfection to food pasteurization. However, common cell inactivation methods (e.g., chlorination, ultraviolet radiation and thermal treatment) have significant drawbacks such as carcinogenic byproduct formation, energy intensiveness and/or nutrient structure destruction. Here, we fabricated a new approach to address these challenges by applying a low-voltage electroporation disinfection cell (EDC) and investigate the critical mechanisms of cell transport to allow high inactivation performance. The EDC prototypes were equipped with two one-dimensional (1D) nanostructure-assisted electrodes that enabled high electric field strength (>107 V m−1) near the electrode surface with a low applied voltage (1 V). We have identified that during electroporation disinfection, electrophoresis, dielectrophoresis and hydraulic flow are the three major mechanisms which transport cells into the vicinity of the electrode surface to achieve superior disinfection performance. The EDC treated 70 ml of bacteria sample with an initial cell concentration of 107CFU ml−1and achieved complete bacteria inactivation (survival rate <0.00001%; no live bacteria detected). Our findings will help to establish a foundation for the future development and implementation of low-voltage electroporation for cell inactivation.
Utility of the Tympanic Membrane Pressure Waveform for Non-invasive Estimation of The Intracranial Pressure Waveform
Authors: Evensen Karen Brastad , Paulat Klaus , Prieur Fabrice , Holm Sverre , Eide Per Kristian
Published: October 2018

Time domain analysis of the intracranial pressure (ICP) waveform provides important information about the intracranial pressure-volume reserve capacity. The aim here was to explore whether the tympanic membrane pressure (TMP) waveform can be used to non-invasively estimate the ICP waveform. Simultaneous invasive ICP and non-invasive TMP signals were measured in a total of 28 individuals who underwent invasive ICP measurements as a part of their clinical work up (surveillance after subarachnoid hemorrhage in 9 individuals and diagnostic for CSF circulation disorders in 19 individuals). For each individual, a transfer function estimate between the invasive ICP and non-invasive TMP signals was established in order to explore the potential of the method. To validate the results, ICP waveform parameters including the mean wave amplitude (MWA) were computed in the time domain for both the ICP estimates and the invasively measured ICP. The patient-specific non-invasive ICP signals predicted MWA rather satisfactorily in 4/28 individuals (14%). In these four patients the differences between original and estimated MWA were <1.0 mmHg in more than 50% of observations, and <0.5 mmHg in more than 20% of observations. The study further disclosed that the cochlear aqueduct worked as a physical lowpass filter.
Characterization of transgenic rice expressing fusion protein Cry1Ab/Vip3A for insect resistance
Authors: Xu Chao , Cheng Jiahui , Lin Haiyan , Lin Chaoyang , Gao Jianhua , Shen Zhicheng
Published: October 2018

Management of resistance development of insect pests is of great importance for continued utilization of Bt crop. The high-dose/refuge and pyramid (gene stacking) strategy are commonly employed to delay the evolution of insect resistance. Due to the anticipated difficulty for deployment of mandatory refuge for transgenic crops in China, where the size of farmer is quite small, stacking of genes with different modes of action is a more feasible strategy. Here we report the development of transgenic rice expressing a fusion protein of Cry1Ab and Vip3A toxin. Analysis of trypsin proteolysis suggested that the fusion protein is equivalent to the combination of Cry1Ab and Vip3A protein. The transgenic plants expressing the fusion protein were found to be highly resistant to two major rice pests, Asiatic rice borer Chilo suppressalis (Lepidoptera: Crambidae) and rice leaf folder Cnaphalocrocis medinalis (Lepidoptera: Crambidae), while their agronomic performances showed no significant difference compared to the non-transgenic recipient rice. Therefore, the transgenic rice may be utilized for rice pest control in China.
A Network Model of Resilience Factors for Adolescents with and without Exposure to Childhood Adversity
Authors: Fritz J. , Fried E. I. , Goodyer I. M. , Wilkinson P. O. , van Harmelen A.-L.
Published: October 2018

Resilience factors (RFs) help prevent mental health problems after childhood adversity (CA). RFs are known to be related, but it is currently unknown how their interrelations facilitate mental health. Here, we used network analysis to examine the interrelations between ten RFs in 14-year-old adolescents exposed (‘CA’; n = 638) and not exposed to CA (‘no-CA’; n = 501). We found that the degree to which RFs are assumed to enhance each other is higher in the no-CA compared to the CA group. Upon correction for general distress levels, the global RF connectivity also differed between the two groups. More specifically, in the no-CA network almost all RFs were positively interrelated and thus may enhance each other, whereas in the CA network some RFs were negatively interrelated and thus may hamper each other. Moreover, the CA group showed more direct connections between the RFs and current distress. Therefore, CA seems to influence how RFs relate to each other and to current distress, potentially leading to a dysfunctional RF system. Translational research could explore whether intervening on negative RF interrelations so that they turn positive and RFs can enhance each other, may alter ‘RF-mental distress’ relations, resulting in a lower risk for subsequent mental health problems.
Selection, hybridization, and the evolution of morphology in the Lake Malaŵi endemic cichlids of the genus Labeotropheus
Authors: Pauers Michael J. , Fox Kelsey R. , Hall Robert A. , Patel Kesha
Published: October 2018

The cichlid fishes of Lake Malaŵi are the paramount example of adaptive radiation in vertebrates. Evidence of their astounding diversity is perhaps most visible in their adaptations for obtaining food; the genus Labeotropheus, due to their prominent snouts, are an interesting example of an extreme adaptation for feeding. Two different body types are found in this genus: a deep-bodied form (e.g., L. fuelleborni) found most often in turbulent shallow water; and a slender bodied form (e.g., L. trewavasae) found in structurally-complex deep water habitats. Here we test the hypothesis that L. trewavasae should suffer a loss in fitness, measured as growth rate, if raised in turbulence; additionally, we examined growth and morphology of L. fuelleborni and L. fuelleborni x L. trewavasae hybrids under these conditions. We did find the predicted loss of fitness in turbulent-raised L. trewavasae, but found no loss of fitness for L. fuelleborni in either condition; hybrids, due to an unusual morphology, performed better in turbulent as opposed to control conditions. Fitness in turbulent conditions was dependent upon morphology, with deeper bodies and upturned neurocrania allowing a greater growth rate under these conditions. Directional selection on morphology was crucial in the evolution of morphology in the Labeotropheus.
Milk Metabolomics Data Reveal the Energy Balance of Individual Dairy Cows in Early Lactation
Authors: Xu Wei , Vervoort Jacques , Saccenti Edoardo , van Hoeij Renny , Kemp Bas , van Knegsel Ariette
Published: October 2018

In early lactation, dairy cows typically have a negative energy balance which has been related to metabolic disorders, compromised health and fertility, and reduced productive lifespan. Assessment of the energy balance, however, is not easy on the farm. Our aims were to investigate the milk metabolic profiles of dairy cows in early lactation, and to obtain models to estimate energy balance from milk metabolomics data and milk production traits. Milk samples were collected in week 2 and 7 after calving from 31 dairy cows. For each cow, the energy balance was calculated from energy intake, milk production traits and body weight. A total of 52 milk metabolites were detected using LC-QQQ-MS. Data from different lactation weeks was analysed by partial least squares analysis, the top 15 most relevant variables from the metabolomics data related to energy balance were used to develop reduced linear models to estimate energy balance by forward selection regression. Milk fat yield, glycine, choline and carnitine were important variables to estimate energy balance (adjusted R2: 0.53 to 0.87, depending on the model). The relationship of these milk metabolites with energy balance is proposed to be related to their roles in cell renewal.