bluuebunny/crossref_metadata_2025 huggingface dataset:
Entorhinal cortex receptive fields are modulated by spatial attention, even without movement
Authors: Wilming Niklas , König Peter , König Seth , Buffalo Elizabeth A.
Published: September 2017

Grid cells have been identified in the entorhinal cortex in a variety of species and allow for the precise decoding of position in space (1–7). Along with potentially playing an important role in navigation, grid cells have recently been hypothesized to make a general contribution to mental operations, including remembering the past and thinking about the future (8,9). A prerequisite for this hypothesis is that grid cell activity does not critically depend on physical movement. Directed attention, which contributes to virtually all mental operations and can be separated from physical movement provides a good test case to investigate this hypothesis. Overt attention in the form of fixational eye movements leads to grid-like firing fields in the monkey entorhinal cortex (3). Here we show that movement of covert attention, without any physical movement, also elicits spatial receptive fields with a triangular tiling of the space. In monkeys trained to maintain central fixation while covertly attending to a stimulus moving in the periphery we identified a significant population (20/141, 14% neurons at a FDR<5%) of entorhinal cells with spatially structured receptive fields. Further, we were able to identify a population of neurons that were labeled as grid cells on an individual basis. This contrast with our recordings obtained in the hippocampus, where grid-like representations were not observed. Our results provide compelling evidence that neurons in macaque entorhinal cortex do not rely on physical movement. Notably, these results support the notion that grid cells may be capable of serving a variety of different cognitive functions and suggest that grid cells are a versatile component of many neural algorithms.
SwarmSight: Real-Time Tracking of Insect Antenna Movements and Proboscis Extension Reflex using a Common Preparation and Conventional Hardware
Authors: Birgiolas Justas , Jernigan Christopher M. , Gerkin Richard C. , Smith Brian H. , Crook Sharon M.
Published: September 2017

Many scientifically and agriculturally important insects use antennae to detect the presence of volatile chemical compounds and extend their proboscis during feeding. The ability to rapidly obtain high-resolution measurements of natural antenna and proboscis movements and assess how they change in response to chemical, developmental, and genetic manipulations can aid the understanding of insect behavior. By extending our previous work on assessing aggregate insect swarm or animal group movements from natural and laboratory videos using video analysis software SwarmSight, we developed a novel, free, and open-source software module, SwarmSight Appendage Tracking (SwarmSight.org) for frame-by-frame tracking of insect antenna and proboscis positions from conventional web camera videos using conventional computers. The software processes frames about 120 times faster than humans, performs at better than human accuracy, and, using 30 frames-per-second videos, can capture antennal dynamics up to 15 Hz. We used the software to track the antennal response of honey bees to two odors and found significant mean antennal retractions away from the odor source about 1 s after odor presentation. We observed antenna position density heat map cluster formation and cluster and mean angle dependence on odor concentration.
Development of an integrated genomic map for a threatened Caribbean coral (Orbicella faveolata)
Authors: Snelling Jacob , Dziedzic Katherine , Guermond Sarah , Meyer Eli
Published: September 2017

Genomic methods are powerful tools for studying evolutionary responses to selection, but the application of these tools in non-model systems threatened by climate change has been limited by the availability of genomic resources in those systems. High-throughput DNA sequencing has enabled development of genome and transcriptome assemblies in non-model systems including reef-building corals, but the fragmented nature of early draft assemblies often obscures the relative positions of genes and genetic markers, and limits the functional interpretation of genomic studies in these systems. To address this limitation and improve genomic resources for the study of adaptation to ocean warming in corals, we’ve developed a genetic linkage map for the mountainous star coral,Orbicella faveolata. We analyzed genetic linkage among multilocus SNP genotypes to infer the relative positions of markers, transcripts, and genomic scaffolds in an integrated genomic map. To illustrate the utility of this resource, we tested for genetic associations with bleaching responses and fluorescence phenotypes, and estimated genome-wide patterns of population differentiation. Mapping the significant markers identified from these analyses in the integrated genomic resource identified hundreds of genes linked to significant markers, highlighting the utility of this resource for genomic studies of corals. The functional interpretations drawn from genomic studies are often limited by the availability of genomic resources linking genes to genetic markers. The resource developed in this study provides a framework for comparing genetic studies ofO. faveolataacross genotyping methods or references, and illustrates an approach for integrating genomic resources that may be broadly useful in other non-model systems.
Sulforaphane modulates microRNA expression in colon cancer cells to implicate the regulation of oncogenes CDC25A, HMGA2 and MYC
Authors: Dacosta Christopher A. , Paicu Claudia , Mohorianu Irina , Wang Wei , Xu Ping , Dalmay Tamas , Bao Yongping
Published: September 2017

Colorectal cancer is an increasingly important cause of morbidity and mortality, whose incidence is associated with dietary and lifestyle factors, particularly inversely so with the consumption of cruciferous vegetables. These vegetables contain glucosinolates, from the breakdown of which are derived isothiocyanates, such as sulforaphane. Sulforaphane is well-characterised for wide-ranging tumour-suppressive and chemoprotective activitiesin vitro, yet deeper elucidation of its biological interactions would aid in better realising its potential in chemoprevention and/or chemotherapy. There is evidence to suggest that sulforaphane modulates microRNA expression in the colon, thus implying the potential for microRNA modulation to play a role in the anti-cancer effects of sulforaphane. Therefore, the effects of sulforaphane on microRNA expression profiles in the colonic adenocarcinoma Caco-2 and non-cancerous colonic CCD-841 cell lines were investigated by small RNA cloning and deep sequencing, followed by Northern Blot validation experiments. Sulforaphane upregulated let-7f-5p and let-7g-5p expression at 24 h in Caco-2 cells, but not in CCD-841. Such treatment also downregulated miR-29b-3p in Caco-2. Dual luciferase assays with a let-7f-5p mimic and inhibitor confirmed the binding of the miRNA to predicted binding sites in the mRNA transcript 3’-UTRs of cell division cycle 25A (CDC25A), high-mobility group AT-hook-2 (HMGA2) and MYC. Therefore, we hypothesize that let-7f-5p translationally represses CDC25A, HMGA2 and MYC, thereby playing a role in the tumour-suppressive effects of sulforaphane. The apparent selectivity of let-7f-5p induction towards tumour cells would be therapeutically desirable if applicablein vivo. MiR-29b-3p is predicted to target a number of tumour-suppressing genes, further investigation of which could be informative regarding the potential of sulforaphane to suppress tumour progression.
Brain structure mediates the association between height and cognitive ability
Authors: Vuoksimaa Eero , Panizzon Matthew S. , Franz Carol E. , Fennema-Notestine Christine , Hagler Donald J. , Lyons Michael J. , Dale Anders M. , Kremen William S.
Published: September 2017

Height and general cognitive ability (GCA) are positively associated, but the underlying mechanisms of this relationship are unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to study if the association between height and cognitive ability is mediated by cortical size. We used genetically, ontogenetically and phylogenetically distinct cortical metrics of cortical surface area (SA) and cortical thickness (CT). Our results indicate that the well-replicated height-GCA association is accounted for by individual differences in total cortical SA (highly heritable metric related to global brain size), and not mean CT, and that the genetic association between SA and GCA underlies the phenotypic height-GCA relationship.
Parsing the roles of neck-linker docking and tethered head diffusion in the stepping dynamics of kinesin
Authors: Zhang Zhechun , Goldtzvik Yonathan , Thirumalai D.
Published: September 2017

Kinesin walks processively on microtubules (MTs) in an asymmetric hand-over-hand manner consuming one ATP molecule per 16 nm step. The contributions due to docking of the approximately thirteen residue neck linker to the leading head (deemed to be the power stroke), and diffusion of the trailing head contribute in propelling the motor by 16 nm have not been quantified. We use molecular simulations by creating a new coarse-grained model of the microtubule-kinesin complex, which reproduces the measured stall force as well as the force required to dislodge the motor head from the MT, to show that nearly three quarters of the step occurs by bidirectional stochastic motion of the TH. However, docking of the neck linker to the leading head constrains the extent of diffusion and minimizes the probability that kinesin takes side steps implying that both the events are necessary in the motility of kinesin, and for the maintenance of processivity. Surprisingly, we find that during a single step the trailing head stochastically hops multiple times between the geometrically accessible neighboring sites on the MT prior to forming a stable interaction with the target binding site with correct orientation between the motor head and theα/ßtubulin dimer.

Significance Statement

Like all motors, the stepping of the two headed conventional Kinesin on the microtubule is facilitated by conformational changes in the motor domain upon ATP binding and hydrolysis. Numerous experiments have revealed that docking of the thirteen residue neck linker (NL) to the motor domain of the leading plays a critical role in propelling the trailing head towards the plus end of the microtubule by nearly 16 nm in a single step. Surprisingly our molecular simulations reveal that nearly three quarters of the step occurs by stochastic diffusion of the trailing head. Docking of the NL restricts the extent of diffusion, thus forcing the motor to walk with overwhelming probability on a single protofilament of the MT.
Clustering and compositionality of task representations in a neural network trained to perform many cognitive tasks
Authors: Yang Guangyu Robert , Song H. Francis , Newsome William T. , Wang Xiao-Jing
Published: September 2017

A neural system has the ability to flexibly perform many tasks, but the underlying mechanism cannot be elucidated in traditional experimental and modeling studies designed for one task at a time. Here, we trained a single network model to perform 20 cognitive tasks that may involve working memory, decision-making, categorization and inhibitory control. We found that after training, recurrent units developed into clusters that are functionally specialized for various cognitive processes. We introduce a measure to quantify relationships between single-unit neural representations of tasks, and report five distinct types of such relationships that can be tested experimentally. Surprisingly, our network developed compositionality of task representations, a critical feature for cognitive flexibility, whereby one task can be performed by recombining instructions for other tasks. Finally, we demonstrate how the network could learn multiple tasks sequentially. This work provides a computational platform to investigate neural representations of many cognitive tasks.
Nutrient stoichiometry shapes microbial coevolution
Authors: Larsen Megan L. , Wilhelm Steven W. , Lennon Jay T.
Published: September 2017

Coevolution is a force contributing to the generation and maintenance of biodiversity. It is influenced by environmental conditions including the scarcity of essential resources, which can drive the evolution of defense and virulence traits. We conducted a long-term chemostat experiment where the marine cyanobacteriumSynechococcuswas challenged with a lytic phage under nitrogen (N) or phosphorus (P) limitation. This manipulation of nutrient stoichiometry altered the stability of host-parasite interactions and the underlying mode of coevolution. By assessing infectivity with >18,000 pairwise challenges, we documented directional selection for increased phage resistance, consistent with arms-race dynamics while phage infectivity fluctuated through time, as expected when coevolution is driven by negative frequency-dependent selection. The resulting infection networks were 50 % less modular under N-versus P-limitation reflecting host-range contraction and asymmetric coevolutionary trajectories. Nutrient stoichiometry affects eco-evolutionary feedbacks in ways that may alter the dynamics and functioning of environmental and host-associated microbial communities.
Monetary feedback modulates performance and electrophysiological indices of belief updating in reward learning
Authors: Bennett Daniel , Sasmita Karen , Maloney Ryan T. , Murawski Carsten , Bode Stefan
Published: September 2017

Belief updating entails the incorporation of new information about the environment into internal models of the world. Bayesian inference is the statistically optimal strategy for performing belief updating in the presence of uncertainty. An important open question is whether the use of cognitive strategies that implement Bayesian inference is dependent upon motivational state and, if so, how this is reflected in electrophysiological signatures of belief updating in the brain. Here we recorded the electroencephalogram of participants performing a simple reward learning task with both monetary and non-monetary instructive feedback conditions. Our aim was to distinguish the influence of the rewarding properties of feedback on belief updating from the information content of the feedback itself. A Bayesian updating model allowed us to quantify different aspects of belief updating across trials, including the size of belief updates and the uncertainty of beliefs. Faster learning rates were observed in the monetary feedback condition compared to the instructive feedback condition, while belief updates were generally larger, and belief uncertainty smaller, with monetary compared to instructive feedback. Larger amplitudes in the monetary feedback condition were found for three event-related potential components: the P3a, the feedback-related negativity (FRN) and the late positive potential (LPP). These findings suggest that motivational state influences inference strategies in reward learning, and this is reflected in the electrophysiological correlates of belief updating.
Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides
Authors: Truttmann Matthias C. , Pincus David , Ploegh Hidde L.
Published: September 2017

Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation – a post-translational protein modification that has emerged as a powerful modulator of HSP70 activity – influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels inC.elegansdirectly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)- extended polypeptide and of α-synuclein (α-syn). Expression of a constitutively activeC. elegansAMPylase Fic-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Over-expression of Fic-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activityin vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cyto-protective, rather than a cytotoxic role for such protein aggregates.
Layered structure and complex mechanochemistry of a strong bacterial adhesive
Authors: Hernando-Pérez Mercedes , Setayeshgar Sima , Hou Yifeng , Temam Roger , Brun Yves V , Dragnea Bogdan , Berne Cécile
Published: September 2017

While designing adhesives that perform in aqueous environments has proven challenging for synthetic adhesives, microorganisms commonly produce bioadhesives that efficiently attach to a variety of substrates, including wet surfaces that remain a challenge for industrial adhesives. The aquatic bacteriumCaulobacter crescentususes a discrete polar polysaccharide complex, the holdfast, to strongly attach to surfaces and resist flow. The holdfast is extremely versatile and has an impressive adhesive strength. Here, we use atomic force microscopy (AFM) to unravel the complex structure of the holdfast and characterize its chemical constituents and their role in adhesion. We used purified holdfasts to dissect the intrinsic properties of this component as a biomaterial, without the effect of the bacterial cell body. Our data support a model where the holdfast is a heterogeneous material composed of two layers: a stiff nanoscopic core, covered by a sparse, flexible brush layer. These two layers contain not onlyN-acetyl-D-glucosamine (NAG), the only yet identified component present in the holdfast, but also peptides and DNA, which provide structure and adhesive character. Biochemical experiments suggest that, while polypeptides are the most important components for adhesive force, the presence of DNA mainly impacts the brush layer and initial adhesion, and NAG plays a primarily structural role within the core. Moreover, our results suggest that holdfast matures structurally, becoming more homogeneous over time. The unanticipated complexity of both the structure and composition of the holdfast likely underlies its distinctive strength as a wet adhesive and could inform the development of a versatile new family of adhesives.
Assessing actimeters for inclusion in the Healthy Brain Network
Authors: Clucas Jonathan , White Curt , Koo Bonhwang , Milham Michael , Klein Arno
Published: September 2017

Background

The Healthy Brain Network is an openly shared pediatric psychiatric biobank with a target of 10,000 participants between the ages of 5 and 21, inclusively In adding ecological actimetry to the Healthy Brain Network, we intend to use appropriate, accurate, reliable tools. Currently a wide range of personal activity trackers are commercially available, providing a wide variety of sensor configurations. For many of these devices, accelerometry provides the basis of measuring both physical activity and sleep with comparable derivative measures.

Results

In order to include an ecological biotracker in the Healthy Brain Network protocol, we first evaluated the specifications of a variety of actimeters available for purchase. We then acquired physical instances of 5 of these devices (ActiGraph wGT3X-BT, Empatica Embrace, Empatica E4, GENEActiv Original, and Wavelet Wristband) and wore each of them in our daily lives, annotating our activities and evaluating the reasonableness of the data from each device and the logistical affordances of each device.

Conclusions

We decided that the ActiGraph wGT3X-BT is the most appropriate device for inclusion in the Healthy Brain Network. However, none of the devices we evaluated was clearly superior or inferior to the rest; rather, each device seems to have use cases in which that device excels beyond the others.
Dissection of the molecular circuitry controlling virulence in Francisella tularensis
Authors: Cuthbert Bonnie J. , Ross Wilma , Rohlfing Amy E. , Dove Simon L. , Gourse Richard L. , Brennan Richard G. , Schumacher Maria A.
Published: September 2017

Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators—the heteromeric macrophage growth locus protein A (MglA)–stringent starvation protein A (SspA) complex and the DNA-binding protein pathogenicity island gene regulator (PigR)—activates FPI transcription and thus is essential for virulence. Intriguingly, the second messenger, guanosine–tetraphosphate (ppGpp), which is produced during infection, is also involved in coordinating Francisella virulence; however, its role has been unclear. Here we identify MglA–SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA–SspA. We demonstrate that MglA–SspA, which binds RNA polymerase (RNAP), also interacts with the C-terminal domain of PigR, thus anchoring the (MglA–SspA)–RNAP complex to the FPI promoter. Furthermore, we show that MglA–SspA must be bound to ppGpp to mediate high-affinity interactions with PigR. Thus, these studies unveil a novel pathway different from those described previously for regulation of transcription by ppGpp. The data also indicate that F. tularensis pathogenesis is controlled by a highly interconnected molecular circuitry in which the virulence machinery directly senses infection via a small molecule stress signal.
HT‐SuperSAGE of the gut tissue of a Vip3Aa‐resistant Heliothis virescens (Lepidoptera: Noctuidae) strain provides insights into the basis of resistance
Authors: Ayra‐Pardo Camilo , Ochagavía Maria E. , Raymond Ben , Gulzar Asim , Rodríguez‐Cabrera Lianet , Rodríguez de la Noval Claudia , Morán Bertot Ivis , Terauchi Ryohei , Yoshida Kentaro , Matsumura Hideo , Téllez Rodríguez Pilar , Hernández Hernández Daily , Borrás‐Hidalgo Orlando , Wright Denis J.
Published: September 2017

Multitoxin Bt‐crops expressing insecticidal toxins with different modes of action, for example, Cry and Vip, are expected to improve resistance management in target pests. While Cry1A resistance has been relatively well characterized in some insect species, this is not the case for Vip3A, for which no mechanism of resistance has yet been identified. Here we applied HT‐SuperSAGE to analyze the transcriptome of the gut tissue of tobacco budworm Heliothis virescens (F.) laboratory‐selected for Vip3Aa resistance. From a total of 1 324 252 sequence reads, 5 895 126‐bp tags were obtained representing 17 751 nonsingleton unique transcripts (UniTags) from genetically similar Vip3Aa‐resistant (Vip–Sel) and susceptible control (Vip–Unsel) strains. Differential expression was significant (≥2.5 fold or ≤0.4; P < 0.05) for 1989 sequences (11.2% of total UniTags), where 420 represented overexpressed (OE) and 1569 underexpressed (UE) genes in Vip–Sel. BLASTN searches mapped 419 UniTags to H. virescens sequence contigs, of which, 416 (106 OE and 310 UE) were unambiguously annotated to proteins in NCBI nonredundant protein databases. Gene Ontology distributed 345 of annotated UniTags in 14 functional categories with metabolism (including serine‐type hydrolases) and translation/ribosome biogenesis being the most prevalent. A UniTag homologous to a particular member of the REsponse to PAThogen (REPAT) family was found among most overexpressed, while UniTags related to the putative Vip3Aa‐binding ribosomal protein S2 (RpS2) were underexpressed. qRT‐PCR of a subset of UniTags validated the HT‐SuperSAGE data. This study is the first providing lepidopteran gut transcriptome associated with Vip3Aa resistance and a foundation for future attempts to elucidate the resistance mechanism.
DNA barcoding of invasive plants in China: A resource for identifying invasive plants
Authors: Xu Song‐Zhi , Li Zhen‐Yu , Jin Xiao‐Hua
Published: September 2017

Invasive plants have aroused attention globally for causing ecological damage and having a negative impact on the economy and human health. However, it can be extremely challenging to rapidly and accurately identify invasive plants based on morphology because they are an assemblage of many different families and many plant materials lack sufficient diagnostic characteristics during border inspections. It is therefore urgent to evaluate candidate loci and build a reliable genetic library to prevent invasive plants from entering China. In this study, five common single markers (ITS, ITS2, matK, rbcL and trnH‐psbA) were evaluated using 634 species (including 469 invasive plant species in China, 10 new records to China, 16 potentially invasive plant species around the world but not introduced into China yet and 139 plant species native to China) based on three different methods. Our results indicated that ITS2 displayed largest intra‐ and interspecific divergence (1.72% and 91.46%). Based on NJ tree method, ITS2, ITS, matK, rbcL and trnH‐psbA provided 76.84%, 76.5%, 63.21%, 52.86% and 50.68% discrimination rates, respectively. The combination of ITS + matK performed best and provided 91.03% discriminatory power, followed by ITS2 + matK (85.78%). For identifying unknown individuals, ITS + matK had 100% correct identification rate based on our database, followed by ITS/ITS2 (both 93.33%) and ITS2 + matK (91.67%). Thus, we propose ITS/ITS2 + matK as the most suitable barcode for invasive plants in China. This study also demonstrated that DNA barcoding is an efficient tool for identifying invasive species.
Estimating species colonization dates using DNA in lake sediment
Authors: Olajos Fredrik , Bokma Folmer , Bartels Pia , Myrstener Erik , Rydberg Johan , Öhlund Gunnar , Bindler Richard , Wang Xiao‐Ru , Zale Rolf , Englund Göran
Published: September 2017

Detection of DNA in lake sediments holds promise as a tool to study processes like extinction, colonization, adaptation and evolutionary divergence. However, low concentrations make sediment DNA difficult to detect, leading to high false negative rates. Additionally, contamination could potentially lead to high false positive rates. Careful laboratory procedures can reduce false positive and negative rates, but should not be assumed to completely eliminate them. Therefore, methods are needed that identify potential false positive and negative results, and use this information to judge the plausibility of different interpretations of DNA data from natural archives.

We developed a Bayesian algorithm to infer the colonization history of a species using records of DNA from lake‐sediment cores, explicitly labelling some observations as false positive or false negative. We illustrate the method by analysing DNA of whitefish (Coregonus lavaretus L.) from sediment cores covering the past 10,000 years from two central Swedish lakes. We provide the algorithm as an R‐script, and the data from this study as example input files.

In one lake, Stora Lögdasjön, where connectivity with the proto‐Baltic Sea and the degree of whitefish ecotype differentiation suggested colonization immediately after deglaciation, DNA was indeed successfully recovered and amplified throughout the post‐glacial sediment. For this lake, we found no loss of detection probability over time, but a high false negative rate. In the other lake, Hotagen, where connectivity and ecotype differentiation suggested colonization long after deglaciation, DNA was amplified only in the upper part of the sediment, and colonization was estimated at 2,200 bp based on the assumption that successful amplicons represent whitefish presence. Here the earliest amplification represents a false positive with a posterior probability of 41%, which increases the uncertainty in the estimated time of colonization.

Complementing careful laboratory procedures aimed at preventing contamination, our method estimates contamination rates from the data. By combining these results with estimates of false negative rates, our models facilitate unbiased interpretation of data from natural DNA archives.
Prenatal Alcohol Exposure Leads to Enhanced Serine 9 Phosphorylation of Glycogen Synthase Kinase‐3β (GSK‐3β) in the Hippocampal Dentate Gyrus of Adult Mouse
Authors: Cunningham Lee Anna , Newville Jessie , Li Lu , Tapia Phillip , Allan Andrea M. , Valenzuela C. Fernando
Published: September 2017

Background

The goal of this study was to evaluate the expression and serine 9 phosphorylation of glycogen synthase kinase (GSK‐3β) within the adult hippocampal dentate gyrus (DG) in a preclinical mouse model of fetal alcohol spectrum disorders. GSK‐3β is a multifunctional kinase that modulates many hippocampal processes affected by gestational alcohol, including synaptic plasticity and adult neurogenesis. GSK‐3β is a constitutively active kinase that is negatively regulated by phosphorylation at the serine 9 residue.

Methods

We utilized a well‐characterized limited access “drinking‐in‐the‐dark” paradigm of prenatal alcohol exposure (PAE) and measured p(Ser9)GSK‐3β and total GSK‐3β within adult DG by Western blot analysis. In addition, we evaluated the expression pattern of both p(Ser9)GSK‐3β and total GSK‐3β within the adult hippocampal dentate of PAE and control mice using high‐resolution confocal microscopy.

Results

Our findings demonstrate a marked 2.0‐fold elevation of p(Ser9)GSK‐3β in PAE mice, concomitant with a more moderate 36% increase in total GSK‐3β. This resulted in an approximate 63% increase in the p(Ser9)GSK‐3β/GSK‐3β ratio. Immunostaining revealed robust GSK‐3β expression within Cornu Ammonis (CA) pyramidal neurons, hilar mossy cells, and a subset of GABAergic interneurons, with low levels of expression within hippocampal progenitors and dentate granule cells.

Conclusions

These findings suggest that PAE may lead to a long‐term disruption of GSK‐3β signaling within the DG, and implicate mossy cells, GABAergic interneurons, and CA primary neurons as major targets of this dysregulation.
Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine
Authors: Castberg I. , Westin A. A. , Skogvoll E. , Spigset O.
Published: September 2017

Objective

To investigate serum concentrations of second‐generation antipsychotics in relation to age and gender in a population ranging from 18 to 100 years.

Method

Results from a routine therapeutic drug monitoring database were retrieved, and 43 079 samples from 11 968 patients were included (17 249 samples for clozapine, 16 171 samples for olanzapine, 5343 samples for risperidone, and 4316 samples for quetiapine). The dose‐adjusted concentration was used as the primary target variable. A linear mixed model was used to allow the inclusion of multiple samples from each patient.

Results

Age had a significant impact on the concentrations of all four drugs. At the age of 80, the dose‐adjusted concentrations were up to twice those of the age of 40. At the age of 90, dose‐adjusted concentrations were two‐ to three‐fold higher. Age‐related increases were largest for clozapine (+108% at 80 years; +197% at 90 years) and smallest for olanzapine (+28% at 80 years; +106% at 90 years). Females generally had dose‐adjusted concentrations 20–30% higher than males.

Conclusion

The effect of age on the serum concentrations of the antipsychotics studied becomes pronounced with advanced age. The patient population aged above 70 should be subdivided according to exact age, and considerable dose reductions are recommended.
A developmental‐based motivational intervention to reduce alcohol and marijuana use among non‐treatment‐seeking young adults: a randomized controlled trial
Authors: Stein Michael D. , Caviness Celeste M. , Morse Emily F. , Grimone Kristin R. , Audet Daniel , Herman Debra S. , Moitra Ethan , Anderson Bradley J.
Published: September 2017

Aims

To test the hypothesis that among non‐treatment‐seeking emerging adults (EA) who both use marijuana and have alcohol binges, a brief, longitudinally delivered, developmentally based motivational intervention would show greater reductions in the use of these two substances compared with a health education control condition.

Design

Parallel, two‐group, randomized controlled trial with follow‐up interventions conducted at 1, 3, 6 and 9 months and final assessments at 12 and 15 months.

Setting

Hospital‐based research unit in the United States.

Participants

Community‐based 18–25‐year‐olds who reported at least monthly binge drinking and at least weekly marijuana use.

Intervention

Motivational intervention (EA‐MI) focused primarily on themes of emerging adulthood (identity exploration, instability, self‐focus, feeling in‐between, a sense of possibilities) and the subjects' relationship to substance use (n = 110) compared with an attention‐matched health education control condition (n = 116).

Measurements

The primary outcomes were days of binge alcohol, marijuana and dual use day as measured using the timeline follow‐back method analysing the treatment by time interaction to determine relative differences in the rate of change between intervention arms.

Findings

At baseline, the mean rate (days/30) of binge drinking was 5.23 (± 4.31) of marijuana use was 19.4 (± 10.0) and of dual (same day) use was 4.11 (± 4.13). Relative to baseline, there were reductions in the rate of binge alcohol use, marijuana use and days of combined binge alcohol and marijuana use (P < 0.001) at all follow‐up assessments. However, the treatment × time interaction was not statistically significant for alcohol (P = 0.37), for marijuana (P = 0.07) or for dual use (P = 0.55). Averaged over all follow‐ups, mean reductions in binge, marijuana and dual use days were 1.16, 1.45 and 1.08, respectively, in the health education arm, and 1.06, 1.69 and 0.96 in EA‐MI. Bayes factors were < 0.01 for frequency of binge alcohol use and frequency of dual binge alcohol and marijuana and 0.016 for marijuana use.

Conclusions

A brief, longitudinally delivered, developmentally based motivational intervention for young adults did not produce reductions in binge alcohol, marijuana use or dual use days relative to a control condition.
Hen's egg allergen in house and bed dust is significantly increased after hen's egg consumption—A pilot study
Authors: Trendelenburg V. , Tschirner S. , Niggemann B. , Beyer K.
Published: September 2017

Environmental exposure to food allergens may be a risk factor for cutaneous sensitization. Previous studies could detect peanut allergen in house dust. In this pilot study, we wanted to investigate whether hen's egg allergen is detectable in house dust collected from different household areas and whether levels are increased after intentional hen's egg consumption. Hen's egg protein levels of dust samples were measured using ELISA. In 8 of 8 households, hen's egg was detectable in dust samples of eating area and bed. Forty‐eight hours after intentional hen's egg consumption, hen's egg protein levels were significantly increased in both. Still, further research is necessary to investigate whether hen's egg allergen in house and bed dust plays a role in sensitization via skin.
Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours
Authors: Tachibana Masaya , Papadopoulos Kyriakos P. , Strickler John H. , Puzanov Igor , Gajee Roohi , Wang Yibin , Zahir Hamim
Published: September 2017

Aims

This phase 1, open‐label, crossover study sought to evaluate drug–drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P‐glycoprotein.

Methods

The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S‐warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P‐glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily.

Results

The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration–time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89–1.05) for caffeine, 0.88 (0.76–1.02) for S‐warfarin, 0.89 (0.60–1.31) for omeprazole, 0.83 (0.67–1.02) for midazolam, and 0.69 (0.51–0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60–0.95).

Conclusions

The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 substrates, and decreases the systemic exposure of P‐glycoprotein substrates when administered with tivantinib.
Differential regulation of PD‐1 and its ligands in allergic asthma
Authors: Bratke K. , Fritz L. , Nokodian F. , Geißler K. , Garbe K. , Lommatzsch M. , Virchow J. C.
Published: September 2017

Background

Targeting PD‐1/PD‐1 ligand signalling is an established treatment option for cancer. The role of these molecules in allergic asthma has been investigated in several mouse studies yielding conflicting results. However, human studies investigating the expression and regulation of PD‐1 and its ligands in allergic inflammation are lacking.

Objective

To analyse the expression and regulation of PD‐1 and its ligands in human allergic asthma.

Methods

The well‐established human asthma model of segmental allergen challenge (SAC) was used to analyse the regulation of PD‐1 and its ligands PD‐L1 and PD‐L2 on T lymphocytes and dendritic cells by flow cytometry. The impact of immunoglobulin E (IgE)‐mediated signalling on PD‐L1 expression was analysed on isolated plasmacytoid dendritic cells (pDCs).

Results

PD‐1 expression by blood CD4+ T cells was negatively associated with total and specific (against the allergen used for provocation) IgE serum concentrations. Twenty‐four hours after SAC, a small decrease in endobronchial PD‐1+CD4+ T cells was accompanied by an increase in PD‐L1 expression on endobronchial myeloid dendritic cells (mDCs) and pDCs. The PD‐L1 up‐regulation on pDCs was not induced by IgE‐mediated mechanisms. In contrast, PD‐L2 was only detected on endobronchial mDCs and was significantly down‐regulated 24 hours after SAC.

Conclusion and clinical relevance

This study shows, for the first time, an association of a low PD‐1 expression by circulating CD4+ T cells with high total and specific (against the allergen used for provocation) IgE concentrations in allergic asthma. In addition, we demonstrate a differential regulation of PD‐1 ligands on endobronchial DCs after allergen challenge which may favour Th2 inflammation. Therefore, modulating PD‐1 ligand‐mediated pathways might be a promising target in allergic asthma.
Adverse effects produced by different drugs used in the treatment of Parkinson's disease: A mixed treatment comparison
Authors: Li Bao‐Dong , Bi Zhen‐Yun , Liu Jing‐Feng , Si Wei‐Jun , Shi Qian‐Qian , Xue Li‐Peng , Bai Jing
Published: September 2017

Objective

This mixed treatment comparison is used to compare the adverse effects of eleven different drugs used to treat Parkinson's disease (PD). The drugs that we compare include the following: ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil, pergolide, and levodopa.

Methods

PubMed, EMBASE, and Cochrane Library were searched from the inception to December 2015. Our analysis combines the evidences of direct comparison and indirect comparison between various literatures. We evaluated the merging odds ratios (OR) value and surface under the cumulative ranking curves (SUCRA) of each of the drugs and used this as a mode of comparison.

Results

Twenty‐four randomized controlled trials (RCTs) were included in this study. Our results demonstrated that the incidence of adverse reactions of ropinirole, rotigotine, entacapone, and sumanirole were obviously higher in terms of nausea compared to the placebo. Ropinirole produced the highest incidence rates of dyskinesia side effects, whereas pramipexole was significantly higher in terms of patients’ hallucination. In addition, the SUCRA values of all the drugs showed that the incidence of adverse reaction of pergolide was relatively high (nausea: 83.5%; hallucination: 79.8%); for dyskinesia and somnolence, the incidence of ropinirole was higher (dyskinesia: 80.5%; somnolence: 69.4%); the incidence of adverse reaction of piribedil was higher on PD in terms of dizziness (67.0%); and the incidence of bromocriptine was relatively high in terms of constipation (62.3%).

Conclusions

This mixed treatment comparison showed that the drugs ropinirole, bromocriptine, and piribedil produced the highest incidence rates of nausea, dyskinesia, hallucination, dizziness, constipation, and somnolence symptoms. Thus, we conclude that as these three drugs produced the most frequent symptoms, they are not recommended for the treatment of patients with Parkinson's disease.
What does Brunei teach us about using Human Development Index rankings as a policy tool?
Authors: Michael Bryane
Published: September 2017

The Bruneian Government has set an ambitious target to achieve a top 10 ranking on the United Nations Development Programme's (UNDP) Human Development Index (HDI) by 2035. To achieve its objective (described in a national strategy document called the Wawasan 2035), Brunei's economy needs to grow by 6% to 7%. Is setting an HDI target a good way to govern Brunei's policy‐making? Is it a good way to govern any country's policy‐making? In this article, we look at the role of HDI‐rank targets in economic and fiscal policy. We show that such a headline target (much like a profit target in a private company) automatically sets targets for growth in various economic sectors and fiscal policy targets. As such, HDI‐rank targeting may provide a useful mechanism for co‐ordinating development policies and for monitoring progress against a wide range of development goals using only one number.
‘Collar propagation’ as an alternative propagation method for rhizomatous miscanthus
Authors: Mangold Anja , Lewandowski Iris , Xue Shuai , Kiesel Andreas
Published: September 2017

The demand for perennial nonfood crops, such as miscanthus, is increasing steadily, as fossil resources are replaced by biomass. However, as the establishment of miscanthus is very expensive, its cultivation area in Europe is still small. The most common propagation method for miscanthus is via rhizomes, the harvesting of which is very labour‐intensive. Seed propagation is promising, but not suitable for sterile genotypes. In this study, a new vegetative propagation method, ‘collar propagation’, was tested in field and controlled environment studies. Collars are built at the junction between rhizome and stem. They can be harvested in a less destructive way than rhizomes by pulling out the stems from winter‐dormant miscanthus plants. One genotype of each of the species M. sacchariflorus, M. × giganteus, M. sinensis in combination with three fragment types (collars, rhizomes, collars + rhizomes) were tested for establishment success and plant performance. The performance (e.g. dry matter yield) of collar‐propagated plants was either better than or not significantly different from rhizome‐propagated plants. Pregrown plantlets transplanted into the field showed no significant differences in establishment success between the fragments within a genotype. When directly planted into the field however, the fragment ‘rhizome+collar’ had a significantly better establishment success than the other two. The winter survival rate of the fragment ‘rhizome+collar’ was 70% for M. sacchariflorus and 75% for M. × giganteus. Emergence success from collar‐derived plants was not affected by harvest date (harvested monthly from November to February). This study showed that miscanthus propagation via collars is feasible and a promising alternative to rhizome propagation, as the multiplication rate of collars is comparable to that of rhizome propagation. Collar propagation is the more suitable method for the tested genotypes of the species M. sachariflorus and M. × giganteus, but not for M. sinensis genotypes, which may be better propagated by seeds.
Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment
Authors: Ando Yusuke , Ishigami Masatoshi , Ishizu Yoji , Kuzuya Teiji , Honda Takashi , Hayashi Kazuhiko , Ishikawa Tetsuya , Nakano Isao , Hirooka Yoshiki , Goto Hidemi
Published: September 2017

Aim

Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)‐DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment.

Methods

A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV‐DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV‐DNA disappearance.

Results

Thirteen patients developed HCC during the follow‐up period. The 1‐, 3‐, and 5‐year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220–17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438–21.519; P = 0.013), and higher HBV core‐related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683–108.815; P = 0.014) at the time of HBV‐DNA disappearance were significantly associated with the development of HCC.

Conclusion

Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV‐DNA disappearance.