bluuebunny/crossref_metadata_2025 huggingface dataset:
Interspecific plant competition mediates the metabolic and ecological signature of a plant-herbivore interaction under warming and elevated CO2
Authors: Van De Velde Helena , AbdElgawad Hamada , Asard Han , Beemster Gerrit T. S. , Selim Samy , Nijs Ivan , Bonte Dries
Published: September 2018

Biotic interactions shape community evolution, but we lack mechanistic insights on how metabolic and ecological processes under climate change are altered by biotic interactions.

We used a two-trophic model community consisting of the aphidDysaphis plantagineafeeding on the forbPlantago lanceolata, and a grass competitorLolium perennethat does not experience herbivory by the aphid. Monocultures and mixtures were exposed to the herbivory treatment and to three relevant simulated environmental changes as prevalent under current climate change (increased temperature, CO2, and increased temperature and CO2)

Elevated CO2reduced the nitrogen content ofP. lanceolata, while simultaneous increases of CO2and temperature modified the plant metabolic component and the magnitude of these responses in different directions. Elevated CO2enhanced defence systems inP. lanceolata, but these effects were not altered by warming. Interspecific plant competition did, however, neutralise these responses. There were no indirect effects of climate change on aphid population growth despite changes in plant defense, nutritional quality and biomass induced by our environmental change scenarios.

We thus demonstrate interactions between abiotic and biotic processes on plant metabolite profiles, but more importantly, that climate change effect on a selection of the metabolic pathways are altered by herbivory and competition. Our experiment under semi-natural conditions thus demonstrates the non-additive and often neutralizing effects of biotic interactions on plant metabolism and species performance under climate-associated environmental change.
Honey bee workers reared in a neonicotinoid contaminated in-hive environment
Authors: Odemer Richard , Odemer Franziska
Published: September 2018

With the currently updated risk assessment of three neonicotinoid pesticides, the European Food Safety Authority has confirmed that different applications of these substances represent a risk to wild and managed bees and their use was therefore severely restricted. However, to close further gaps in knowledge, this experiment covers exposure of honey bee worker brood reared in a neonicotinoid contaminated in-hive environment with focus on the individual. In a worst case scenario, mini-hives were fed chronically with a sublethal concentration of clothianidin (15 µg/kg), which is highly toxic to bees already in small amounts. Freshly hatched workers from these colonies were subsequently marked and introduced into non-contaminated colonies, where their lifespan and behavior was monitored. Nineteen days after exposure, clothianidin treated bees had no reduced lifespan or showed any signs of behavioral impairment when compared to the control, demonstrating that social buffering is not a simple substitution of dead bees by rearing more brood. Our results suggest that the social environment plays a crucial role for the individual in terms of “superorganism resilience”. These findings are discussed in context with the current use of lower tier test systems in risk assessment and contrary results obtained from laboratory experiments.

HIGHLIGHTS

Sublethal clothianidin treatment did not affect lifespan nor behavior of workers.

Effects on individual bees reared within a mini-hive are translatable to full-sized colonies.

“Superorganism resilience” is not a simple substitution of dead bees by rearing more brood.

Laboratory testing in the risk assessment of plant protection products bears severe weaknesses.
Anoxygenic Photosynthesis and Dark Carbon Metabolism under micro-oxic conditions in the Purple Sulfur Bacterium “Thiodictyon syntrophicum” nov. strain Cad16T
Authors: Luedin Samuel M , Storelli Nicola , Danza Francesco , Roman Samuele , Wittwer Matthias , Pothier Joël F , Tonolla Mauro
Published: September 2018

1.

The microbial ecosystem of the meromictic Lake Cadagno (Ticino, Swiss Alps) has been studied intensively to understand metabolic functions driven by the highly abundant anoxygenic phototrophic sulfur bacteria of the families Chromatiaceae and Chlorobiaceae. It was found that the sequenced isolate “Thiodictyon syntrophicum” nov. sp. str. Cad16T, belonging to the Chromatiaceae, may fix 26% of all bulk inorganic carbon in the chemocline at day and night. With this study, we elucidated the mode of dark carbon fixation of str. Cad16Twith a combination of long-term monitoring of key physicochemical parameters with CTD,14C-incorporation experiments and quantitative proteomics ofin situdialysis bag incubations of pure cultures. Regular vertical CTD profiling during the study period in summer 2017 revealed that the chemocline sank from 12 to 14 m which was accompanied by a bloom of cyanobacteria and the subsequent oxygenation of the deeper water column. Sampling was performed both day and night in September. While CO2assimilation rates were higher during the light period, the relative change in the proteome (663 quantified proteins) was only 1% of all CDS encoded in str. Cad16T. Oxidative respiration was thereby upregulated at light, whereas stress-related mechanisms prevailed during the night. These results indicate that the low light availability due to high cell concentrations and the oxygenation of the chemocline induced a mixotrophic growth in str. Cad16T.

The complete proteome data have been deposited to the ProteomeXchange with identifier PXD010641.
Identification of Kinase Inhibitors that Regulate Nuclear Receptor Nurr1 (NR4A2) Cellular Activity
Authors: Williams Kenya L. , Wells Carrow I. , Moore John T.
Published: September 2018

The ability to regulate the activity NR4A subfamily of nuclear receptors would be potentially useful in the treatment of multiple diseases, but to date, few regulators have been reported. This is likely due to the fact that the NR4A subfamily does not have a typical unoccupied nuclear receptor ligand binding pocket, but rather a pocket that is occupied with hydrophobic side chains of adjacent amino acids. It follows that traditional nuclear receptor assays that seek to identify ligands that bind within the ligand binding pocket would not be successful. We have thus focused on an alternate assay to identify NR4A regulators based on the fact that regulation of NR4A, at least partially, results from phosphorylation/dephosphorylation of the amino terminal region of the protein. We developed a medium throughput cellular assay using a fusion of the amino terminus of Nurr1 (NR4A2) with luciferase reporter and used the assay to screen a large and diverse protein kinase inhibitor set (PKIS). We identified multiple kinase inhibitor compounds from PKIS that significantly increased or decreased the cellular activity of Nurr1. These molecules serve as starting points to discover selective tools for regulation of Nurr1/Nurr1pathway.
The effects of demography and genetics on the neutral distribution of quantitative traits
Authors: Koch Evan M.
Published: September 2018

1

Neutral models for quantitative trait evolution are useful for identifying phenotypes under selection in natural populations. Models of quantitative traits often assume phenotypes are normally distributed. This assumption may be violated when a trait is affected by relatively few genetic variants or when the effects of those variants arise from skewed or heavy-tailed distributions. Traits such as gene expression levels and other molecular phenotypes may have these properties. To accommodate deviations from normality, models making fewer assumptions about the underlying trait genetics and patterns of genetic variation are needed. Here, we develop a general neutral model for quantitative trait variation using a coalescent approach by extending the framework developed by Schraiberand Landis(2015). This model allows interpretation of trait distributions in terms of familiar population genetic parameters because it is based on the coalescent. We show how the normal distribution resulting from the infinitesimal limit, where the number of loci grows large as the effect size per mutation becomes small, depends only on expected pairwise coalescent times. We then demonstrate how deviations from normality depend on demography through the distribution of coalescence times as well as through genetic parameters. In particular, population growth events exacerbate deviations while bottlenecks reduce them. This model also has practical applications, which we demonstrate by designing an approach to simulate from the null distribution of QST, the ratio of the trait variance between subpopulations to that in the overall population. We further show that it is likely impossible to distinguish sparsity from skewed or heavy-tailed distributions of mutational effects using only trait values sampled from a population. The model analyzed here greatly expands the parameter space for which neutral trait models can be designed.
Wdr5, Brca1 and Bard1 link the DNA damage response to the mesenchymal-to-epithelial transition during early reprogramming
Authors: Peñalosa-Ruiz Georgina , Bousgouni Vicky , Gerlach Jan Patrick , Waarlo Susan , de Ven Joris V. van , Veenstra Tim E. , Silva José C.R. , van Heeringen Simon J. , Bakal Chris , Mulder Klaas W. , Veenstra Gert Jan C.
Published: September 2018

Differentiated cells are epigenetically stable, but can be reprogrammed to pluripotency by expression of the OSKM transcription factors. Despite significant effort, relatively little is known about the cellular requirements for reprogramming and how they affect the properties of induced pluripotent stem cells (iPSC). We have performed high-content screening with siRNAs targeting 300 chromatin-associated factors. We used colony features, such as size and shape, as well as strength and homogeneity of marker gene expression to define five colony phenotypes in early reprogramming. We identified transcriptional signatures associated with these phenotypes in a secondary RNA sequencing screen. One of these phenotypes involves large colonies and an early block of reprogramming. Double knockdown epistasis experiments of the genes involved, revealed that Brca1, Bard1 and Wdr5 functionally interact and are required for both the DNA damage response and the mesenchymal-to-epithelial transition (MET), linking these processes. Moreover, the data provide a resource on the role of chromatin-associated factors in reprogramming and underline colony morphology as an important high dimensional readout for reprogramming quality.
Surface color and predictability determine contextual modulation of V1 firing and gamma oscillations
Authors: Peter Alina , Uran Cem , Klon-Lipok Johanna , Roese Rasmus , van Stijn Sylvia , Barnes William , Dowdall Jarrod R , Singer Wolf , Fries Pascal , Vinck Martin
Published: September 2018

The integration of direct bottom-up inputs with contextual information is a canonical motif in neocortical circuits. In area V1, neurons may reduce their firing rates when the (classical) receptive field input can be predicted by the spatial context. We previously hypothesized that gamma-synchronization (30-80Hz) provides a complementary signal to rates, encoding whether stimuli are predicted from spatial context by preferentially synchronizing neuronal populations receiving predictable inputs. Here we investigated how rates and synchrony are modulated by predictive context. Large uniform surfaces, which have high spatial predictability, strongly suppressed firing yet induced prominent gamma-synchronization, but only when they were colored. Yet, chromatic mismatches between center and surround, breaking predictability, strongly reduced gamma-synchronization while increasing firing rates. Differences between colors, including strong gamma-responses to red, arose because of stimulus adaptation to a full-screen background, with a prominent difference in adaptation between M- and L-cone signaling pathways. Thus, synchrony signals whether RF inputs are predicted from spatial context and may encode relationships across space, while firing rates increase when stimuli are unpredicted from the context.
Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation
Authors: Glinos Dafni A. , Soskic Blagoje , Jostins Luke , Sansom David M. , Trynka Gosia
Published: September 2018

T cell activation is a critical driver of immune response and if uncontrolled, it can result in failure to respond to infection or in excessive inflammation and autoimmunity. CD28 costimulatory pathway is an essential regulator of CD4 T cell responses. To deconvolute how T cell receptor (TCR) and CD28 orchestrate activation of human CD4 T cells we stimulated cells using varying intensities of TCR and CD28 signals followed by gene expression profiling. We demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Strikingly, cell cycle and cell division are sensitive to CD28 in memory cells, but under TCR control in naive cells, in contrast to the paradigm that memory cells are CD28-independent. Using a combination of chromatin accessibility and enhancer profiling, we observe that IRFs and Blimp-1 (PRDM1) motifs are enriched in naive and memory T cells in response to TCR. In contrast, memory cells initiate AP1 transcriptional regulation only when both TCR and CD28 are engaged, implicating CD28 as an amplifier of transcriptional programmes in memory cells. Lastly, we show that CD28-sensitive genes are enriched in autoimmune disease loci, pointing towards the role of memory cells and the regulation of T cell activation through CD28 in autoimmune disease development. This study provides important insights into the differential role of CD28 in naive and memory T cell responses and offers a new platform for design and interpretation of costimulatory based therapies.

One-sentence summary

Genomic profiling of CD4 T cell activation reveals a sensitivity switch from TCR in naive to CD28 in memory cells.
Can machine learning automatically detect the aligned trunk in sitting directly from raw video using a depth camera?
Authors: Sanchez Maria Beatriz , Cunningham Ryan , Butler Penelope B , Loram Ian
Published: September 2018

Background

The Segmental Assessment of Trunk Control (SATCo) evaluates sitting control at seven separate trunk segments, making a judgement based on their position in space relative to a defined, aligned posture. SATCo is in regular clinical and research use and is a Recommended Instrument for Cerebral Palsy and Spinal Cord Injury-Paediatric by The National Institute of Neurological Disorders and Stroke (US). However, SATCo remains a subjective assessment.

Research question

This study tests the feasibility of providing an objective, automated identification of frames containing the aligned, reference trunk posture using deep convolutional neural network (DCNN) analysis of raw high definition and depth (HD+D) images.

Methods

A SATCo was conducted on sixteen healthy male adults and recorded using a Kinect V2. For each of seven segments tested, two different trials were collected (control and no-control) to simulate a range of alignment configurations. For all images, classification of alignment obtained from a trained and validated DCNN was compared to expert clinician’s labelling.

Results

Using leave-one-out testing, at the optimal operating threshold, the DCNN correctly classified individual images (alignment v misaligned) with average precision 92.7±16% (mean±SD).

Significance

These results show for the first time, automation of a key component of the SATCo test, namely identification of aligned trunk posture directly from raw images (HD+D). This demonstrates the potential of machine learning to provide a fully automated, objective SATCo test to enhance assessment of trunk control in children and adults for research and treatment of various conditions including neurodisability and stroke.
wnt4apromotes female development and reproductive duct elongation in zebrafish
Authors: Kossack Michelle E. , High Samantha K. , Hopton Rachel E. , Yan Yi-lin , Postlethwait John H. , Draper Bruce W.
Published: September 2018

In laboratory strains of zebrafish, sex determination occurs in the absence of a typical sex chromosome and it is not known what regulates the proportion of animals that develop as male or female. Many sex determination and differentiation genes that act downstream of a sex chromosome are well conserved among vertebrates, but studies that test their contribution to this process have mostly been limited to mammalian models. In mammals, WNT4 is a signaling ligand that is essential for ovary and Müllerian duct development, where it function, in part, to antagonize the male-promoting FGF9 signal. Wnt4 is highly conserved in non-mammalian vertebrates, but it is not known if Wnt4 plays a role in sex determination and/or the differentiation of sex organs outside of mammals. This is an especially interesting question in teleost, such as zebrafish, because they lack an Fgf9 ortholog. Here we show thatwnt4ais the ortholog of mammalianWnt4,and thatwnt4bwas present in the last common ancestor of humans and zebrafish, but was lost in mammals. We found thatwnt4ais expressed in the somatic cells of juvenile gonads during the time sex determination likely occurs. We show thatwnt4aloss-of-function mutants develop predominantly as males and conclude thatwnt4aactivity promotes female sex determination in zebrafish. Additionally, both male and femalewnt4amutants are sterile because their reproductive ducts do not connect to the vent, wherewnt4ais normally expressed. Yet when dissected from homozygouswnt4amutant gonads, both sperm and eggs can produce fertile offspring. Together these results strongly argue that Wnt4a is a conserved regulator of female sex determination and reproductive duct development in non-mammalian vertebrates.

Wnt4 is a key regulator of ovary development in mammals, but it is not known if it plays a similar role in other vertebrates. Here we show that zebrafishwnt4ais the ortholog of mammalianWnt4. We show thatwnt4ais expressed in zebrafish somatic gonad cells during the time sex determination likely occurs. Through analysis ofwnt4amutants, we show that Wnt4a promotes female sex determination and the development of the male and female reproductive. We conclude that Wnt4/Wnt4a is likely a conserved regulator of ovarian and reproductive duct development in all vertebrates
Intuitive planning: global navigation through cognitive maps based on grid-like codes
Authors: Baram Alon B. , Muller Timothy H. , Whittington James C.R. , Behrens Timothy E.J.
Published: September 2018

It is proposed that a cognitive map encoding the relationships between objects supports the ability to flexibly navigate the world. Place cells and grid cells provide evidence for such a map in a spatial context. Emerging evidence suggests analogous cells code for non-spatial information. Further, it has been shown that grid cells resemble the eigenvectors of the relationship between place cells and can be learnt from local inputs. Here we show that these locally-learnt eigenvectors contain not only local information but also global knowledge that can provide both distributions over future states as well as a global distance measure encoding approximate distances between every object in the world. By simply changing the weights in the grid cell population, it is possible to switch between computing these different measures. We demonstrate a simple algorithm can use these measures to globally navigate arbitrary topologies without searching more than one step ahead. We refer to this as intuitive planning.
Opposing roles of dopamine receptor D1- and D2-expressing neurons in the anteromedial olfactory tubercle in acquisition of place preference in mice
Authors: Murata Koshi , Kinoshita Tomoki , Fukazawa Yugo , Kobayashi Kenta , Yamanaka Akihiro , Hikida Takatoshi , Manabe Hiroyuki , Yamaguchi Masahiro
Published: September 2018

Olfaction induces adaptive motivated behaviors. Odors associated with food induce attractive behavior, whereas those associated with dangers induce aversive behavior. We previously reported that learned odor-induced attractive and aversive behaviors accompany activation of the olfactory tubercle (OT) in a domainand cell type-specific manner. Odor cues associated with a sugar reward induced attractive behavior and c-fos expression in the dopamine receptor D1-expressing neurons (D1 neurons) in the anteromedial OT. In contrast, odor cues associated with electrical shock induced aversive behavior and c-fos expression in the D2 neurons in the anteromedial OT, as well as the D1 neurons in the lateral OT. Here, we investigated whether the D1 and D2 neurons in the anteromedial OT play distinct roles in attractive or aversive behaviors, using optogenetic stimulation and real-time place preference (RTPP) tests. Mice expressing ChETA (ChR2/E123T)-EYFP in the D1 neurons in the anteromedial OT spent a longer time in the photo-stimulation side of the place preference chamber than the control mice expressing EYFP. On the other hand, upon optogenetic stimulation of the D2 neurons in the anteromedial OT, the mice spent a shorter time in the photo-stimulation side than the control mice. Local neural activation in the anteromedial OT during the RTPP tests was confirmed by c-fos mRNA expression. These results suggest that the D1 and D2 neurons in the anteromedial OT play distinct roles in attractive and aversive behaviors, respectively.
Drosophila insulin-like peptide 1 (DILP1) promotes organismal growth and catabolic energy metabolism during the non-feeding pupal stage
Authors: Liao Sifang , Post Stephanie , Lehmann Philipp , Veenstra Jan A , Tatar Marc , Nassel Dick R
Published: September 2018

The insulin/IGF-signaling pathway is central in control of nutrient-dependent growth during development, and in adult physiology and longevity. Eight insulin-like peptides (DILP1-8) have been identified in Drosophila and several of these are known to regulate growth, metabolism, reproduction, stress responses and lifespan. However, the functional role of DILP1 is far from understood. Previous work has shown that dilp1/DILP1 is transiently expressed mainly during the non-feeding pupal stage and the first days of adult life. Here we show that mutation of dilp1 diminishes organismal weight during pupal development, whereas overexpression increases it, similar to dilp6 manipulations. No growth effects of dilp1 or dilp6 manipulations were detected during larval development. We next show that dilp1 and dilp6 increase metabolic rate in the late pupa and promote lipids as the primary source of catabolic energy. This lipid mobilization in the pupa is not correlated with transcriptional changes of adipokinetic hormone. The effects of dilp1 manipulations carry over to the adult fly. In newly eclosed flies, survival during starvation is strongly diminished in dilp1 mutants, but not in dilp2 and dilp1-dilp2 double mutants, whereas in older flies only double mutants display reduced starvation resistance. In conclusion, dilp1 and dilp6 promote growth of adult tissues during the non-feeding pupal stage, likely by utilization of stored lipids. This results in larger newly-eclosed flies with reduced stores of pupal-derived nutrients and diminished starvation tolerance and fecundity.
RAB18 impacts autophagy via lipid droplet-derived lipid transfer and is rescued by ATG9A
Authors: Bekbulat Fazilet , Schmitt Daniel , Feldmann Anne , Huesmann Heike , Eimer Stefan , Juretschke Thomas , Beli Petra , Behl Christian , Kern Andreas
Published: September 2018

Autophagy is a lysosomal degradation pathway that mediates protein and organelle turnover and maintains cellular homeostasis. Autophagosomes transport cargo to lysosomes and their formation is dependent on an appropriate lipid supply. Here, we show that the knockout of the RAB GTPase RAB18 interferes with lipid droplet (LD) metabolism, resulting in an impaired fatty acid mobilization. The reduced LD-derived lipid availability influences autophagy and provokes adaptive modifications of the autophagy network, which include increased ATG2B expression and ATG12-ATG5 conjugate formation as well as enhanced ATG2B and ATG9A phosphorylation. Phosphorylation of ATG9A directs this transmembrane protein to the site of autophagosome formation and this particular modification is sufficient to rescue autophagic activity under basal conditions in the absence of RAB18. However, it is incapable of enabling an increased autophagy under inductive conditions. Thus, we illustrate the role of RAB18 in connecting LDs and autophagy, further emphasize the importance of LD-derived lipids for the degradative pathway, and characterize an ATG9A phosphorylation-dependent autophagy rescue mechanism as an adaptive response that maintains autophagy under conditions of reduced LD-derived lipid availability.
Neural correlates of reward anticipation in 2000 children aged 9-10 years: relation to psychotic-like experiences and depressive symptoms
Authors: Ronan Lisa , Murray Graham K.
Published: September 2018

Background

Schizophrenia spectrum disorders and depression have been associated with reductions in brain activation during reward anticipation. It is not known whether brain signals associated with reward anticipation relate to psychopathology dimensions of depression or schizophrenia in childhood prior to adolescence.

Method

We examined whether fMRI brain correlates of reward anticipation related to psychotic-like experiences and symptoms of depression, in 2129 children from the ABCD study aged 9-10 years.Psychotic-like experiences and depression were assessed using the Prodromal Questionnaire Brief Child version and the K-SADS. We fused regional MRI summary statistics for reward anticipation activation in the ABCD study data release 1.0 (contrast of expected large reward versus neutral expectation). Relations between brain activation and psychopathology were assessed using linear regressions in R for 82 brain regions, corrected for multiple comparisons for the number of regions using false discovery rate.

Results

From several regressions, there was an isolated unilateral association between right parsorbitalis activation and psychotic-like experiences, but no other significant associations between brain activation and psychopathology.

Conclusions

In 9-10 year old children, reward anticipation is not strongly related to psychotic-like experiences or depression. As previous evidence links depression and schizophrenia to reduced reward anticipation in adults and older adolescents, it appears likely that such associations develop over the adolescent period: this can be tested in follow-up studies of the ABCD cohort.
Network analysis of whole-brain fMRI dynamics: A new framework based on dynamic communicability
Authors: Gilson Matthieu , Kouvaris Nikos E. , Deco Gustavo , Mangin Jean-François , Poupon Cyril , Lefranc Sandrine , Rivière Denis , Zamora-López Gorka
Published: September 2018

Neuroimaging techniques such as MRI have been widely used to explore the associations between brain areas. Structural connectivity (SC) captures the anatomical pathways across the brain and functional connectivity (FC) measures the correlation between the activity of brain regions. These connectivity measures have been much studied using network theory in order to uncover the distributed organization of brain structures, in particular FC for task-specific brain communication. However, the application of network theory to study FC matrices is often “static” despite the dynamic nature of time series obtained from fMRI. The present study aims to overcome this limitation by introducing a network-oriented analysis applied to whole-brain effective connectivity (EC) useful to interpret the brain dynamics. Technically, we tune a multivariate Ornstein-Uhlenbeck (MOU) process to reproduce the statistics of the whole-brain resting-state fMRI signals, which provides estimates for MOU-EC as well as input properties (similar to local excitabilities). The network analysis is then based on the Green function (or network impulse response) that describes the interactions between nodes across time for the estimated dynamics. This model-based approach provides time-dependent graph-like descriptor, named communicability, that characterize the roles that either nodes or connections play in the propagation of activity within the network. They can be used at both global and local levels, and also enables the comparison of estimates from real data with surrogates (e.g. random network or ring lattice). In contrast to classical graph approaches to study SC or FC, our framework stresses the importance of taking the temporal aspect of fMRI signals into account. Our results show a merging of functional communities over time (in which input properties play a role), moving from segregated to global integration of the network activity. Our formalism sets a solid ground for the analysis and interpretation of fMRI data, including task-evoked activity.
Does alpha-tocopherol flip-flop help to protect membranes against oxidation?
Authors: Boonnoy Phansiri , Karttunen Mikko , Wong-ekkabut Jirasak
Published: September 2018

Alpha-tocopherols (α-toc) are crucial in protecting biological membranes against oxidation by free radicals. We investigate the behavior of α-toc molecules in lipid bilayers containing oxidized lipids by molecular dynamics (MD) simulations. To verify the approach, the location and orientation of α-toc are first shown to be in agreement with previous experimental results. The simulations further show that α-toc molecules stay inside the lipid bilayer with their hydroxyl groups in contact with the bilayer surface. Interestingly, interbilayer α-toc flip-flop was observed in both oxidized and non-oxidized bilayers with significantly higher frequency in aldehyde lipid bilayer. Free energy calculations were performed and estimates of the flip-flop rates across the bilayers were determined. As the main finding, our results show that the presence of oxidized lipids leads to a significant decrease of free energy barriers and that the flip-flop rates depend on the type of oxidized lipid present. Our results suggest that α-toc molecules could potentially act as high efficacy scavengers of free radicals to protect membranes from oxidative attack and help stabilize them under oxidative stress.
Traumatic Brain Injury-Associated Micrgoglia Adopt Longitudinal Transcriptional Changes Consistent with Long-Term Depression of Synaptic Strength
Authors: Makinde Hadijat M. , Just Talia B. , Winter Deborah R. , Schwulst Steven J.
Published: September 2018

Traumatic brain injury (TBI) is an under-recognized public health threat. Even mild brain injury, or concussions, may lead to long-term neurologic impairment. Microglia play a fundamental role in the development and progression of this subsequent neurologic impairment. Despite this, a microglia-specific injury signature has yet to be identified. In the current study we hypothesized that TBI-associated microglia would adopt longitudinal changes in their transcriptional profile associated with pathways linked to the development of motor, cognitive, and behavioral disorders. C57BL/6 mice underwent TBI via a controlled cortical impact and were followed longitudinally. FACSorted microglia from TBI mice were subjected to RNA-sequencing at 7, 30, and 90 days post-injury. We identified 4 major patterns of gene expression corresponding to the host defense response, synaptic potentiation, lipid remodeling, and membrane polarization. In particular, significant upregulation of genes involved in long-term synaptic potentiation including Ptpn5, Shank3, and Sqstm1 were observed offering new insight into a previously unknown role of microglia in the weakening of synaptic efficacy between neurons after brain injury.
Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson’s disease
Authors: Milanese Chiara , Payan-Gomez Cesar , Galvani Marta , González Nicolás Molano , Tresini Maria , Abdellah Soraya Nait , Roon-Mom Willeke M.C. van , Figini Silvia , Marinus Johan , van Hilten Jacobus J. , Mastroberardino Pier G.
Published: September 2018

Background

Parkinson disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patients stratification. Mitochondrial function - which is impaired in and central to PD pathogenesis - may represent one of such surrogate indicators.

Methods

Mitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n=47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine learning based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. Effects of mitochondrial respiration on alpha-synuclein stress was assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions.

Results

Bioenergetics properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients and correlation is stronger with predominantly non-dopaminergic signs. Bioenergetics analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients’ fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors alpha-synuclein stress in different cellular experimental systems. Machine learning-based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration.

Conclusion

Suppression of mitochondrial activity in Parkinson disease may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures are potential biomarkers to follow disease progression.
Network of small no-take marine reserves reveal greater abundance and body size of fisheries target species
Authors: Rolim Fernanda A. , Langlois Tim , Rodrigues Pedro F. C. , Bond Todd , Motta Fábio S. , Neves Leonardo M. , Gadig Otto B. F.
Published: September 2018

No-take marine reserves (NTRs), i.e. areas with total fishing restrictions, have been established worldwide aiming to provide biodiversity and ecosystem conservation. Brazil has established NTRs, but currently lacks scientific knowledge and understanding of their ecological role, particularly regarding rocky reefs in subtropical regions. Consequently, this study aimed to contrast NTR, from the 30 year old Tupinambás Ecological Station, and comparable fished sites across a coastal biogeographic gradient to investigate the effect of fishing and habitat variability on the abundance and body-size of rocky reef fish. We used Baited Remote Underwater stereo-Video (stereo-BRUVs) and Diver Operated stereo-Video (stereo-DOVs) systems to simultaneously sample reef fish and habitat. Model selection and results identified habitat and biogeographic variables, such as distance from shore, as important predictor variables, explaining several aspects of the fish assemblage. The effect of protection was important in determining the abundance and body-size of targeted species, in particular for epinephelids and carangids. Conversely, species richness was correlated with habitat complexity and not with protection status. This is the first study to publish data using these novel survey methods in the Southeastern Atlantic and demonstrate their utility, in combination with an established network of NTR’s, to provide benchmarks for conservation and fisheries management.
Targeted genome fragmentation with CRISPR/Cas9 enables fast and efficient enrichment of small genomic regions and ultra-accurate sequencing with low DNA input (CRISPR-DS)
Authors: Nachmanson Daniela , Lian Shenyi , Schmidt Elizabeth K. , Hipp Michael J. , Baker Kathryn T. , Zhang Yuezheng , Tretiakova Maria , Loubet-Senear Kaitlyn , Kohrn Brendan F. , Salk Jesse J. , Kennedy Scott R. , Risques Rosa Ana
Published: September 2018

Next-generation sequencing methods suffer from low recovery, uneven coverage, and false mutations. DNA fragmentation by sonication is a major contributor to these problems because it produces randomly sized fragments, PCR amplification bias, and end artifacts. In addition, oligonucleotide-based hybridization capture, a common target enrichment method, has limited efficiency for small genomic regions, contributing to low recovery. This becomes a critical problem in clinical applications, which value cost-effective approaches focused on the sequencing of small gene panels. To address these issues, we developed a targeted genome fragmentation approach based on CRISPR/Cas9 digestion that produces DNA fragments of similar length. These fragments can be enriched by a simple size selection, resulting in targeted enrichment of up to approximately 49,000-fold. Additionally, homogenous length fragments significantly reduce PCR amplification bias and maximize read usability. We combined this novel target enrichment approach with Duplex Sequencing, which uses double-strand molecular tagging to correct for sequencing errors. The approach, termed CRISPR-DS, enables efficient target enrichment of small genomic regions, even coverage, ultra-accurate sequencing, and reduced DNA input. As proof of principle, we applied CRISPR-DS to the sequencing of the exonic regions of TP53 and performed side-by-side comparisons with standard Duplex Sequencing. CRISPR-DS detected previously reported pathogenic TP53 mutations present as low as 0.1% in peritoneal fluid of women with ovarian cancer, while using 10- to 100-fold less DNA than standard Duplex Sequencing. Whether used as standalone enrichment or coupled with high-accuracy sequencing methods, CRISPR-based fragmentation offers a simple solution for fast and efficient small target enrichment.
Crystal packing control of a trifluoromethyl-substituted furan/phenylene co-oligomer
Authors: Sonina Alina A. , Koskin Igor P. , Sherin Peter S. , Rybalova Tatyana V. , Shundrina Inna K. , Mostovich Evgeny A. , Kazantsev Maxim S.
Published: September 2018

Furan/phenylene co-oligomer single crystals are considered as future materials for organic optoelectronics. Here, the effects of trifluoromethyl substituents on the crystallization, structure and optical properties of furan/phenylene co-oligomer 1,4-bis{5-[4-(trifluoromethyl)phenyl]furan-2-yl}benzene are studied systematically. The solution growth methods and physical vapor transport result in the formation of three polymorphs depending on the growth method and the solvent. Single-crystal X-ray analysis reveals the crystal structures to correspond to H-, J- or mixed aggregates. All obtained crystals exhibit high photoluminescence efficiency and have optical properties which strongly depend on the crystal packing. Variable-temperature X-ray powder diffraction analysis shows the thermal transition of two forms (H- and J-aggregates) into a third one (mixed aggregate). Terminal trifluoromethyl groups induce weak intermolecular interactions which control the crystal packing and optical properties of co-oligomer single crystals.
Crystal structure of the ribonuclease-P-protein subunit from Staphylococcus aureus
Authors: Ha Lisha , Colquhoun Jennifer , Noinaj Nicholas , Das Chittaranjan , Dunman Paul M. , Flaherty Daniel P.
Published: September 2018

Staphylococcus aureus ribonuclease-P-protein subunit (RnpA) is a promising antimicrobial target that is a key protein component for two essential cellular processes, RNA degradation and transfer-RNA (tRNA) maturation. The first crystal structure of RnpA from the pathogenic bacterial species, S. aureus, is reported at 2.0 Å resolution. The structure presented maintains key similarities with previously reported RnpA structures from bacteria and archaea, including the highly conserved RNR-box region and aromatic residues in the precursor-tRNA 5′-leader-binding domain. This structure will be instrumental in the pursuit of structure-based designed inhibitors targeting RnpA-mediated RNA processing as a novel therapeutic approach for treating S. aureus infections.
Conformational changes on substrate binding revealed by structures of Methylobacterium extorquens malate dehydrogenase
Authors: González Javier M. , Marti-Arbona Ricardo , Chen Julian C.-H. , Broom-Peltz Brian , Unkefer Clifford J.
Published: September 2018

Three high-resolution X-ray crystal structures of malate dehydrogenase (MDH; EC 1.1.1.37) from the methylotroph Methylobacterium extorquens AM1 are presented. By comparing the structures of apo MDH, a binary complex of MDH and NAD+, and a ternary complex of MDH and oxaloacetate with ADP-ribose occupying the pyridine nucleotide-binding site, conformational changes associated with the formation of the catalytic complex were characterized. While the substrate-binding site is accessible in the enzyme resting state or NAD+-bound forms, the substrate-bound form exhibits a closed conformation. This conformational change involves the transition of an α-helix to a 310-helix, which causes the adjacent loop to close the active site following coenzyme and substrate binding. In the ternary complex, His284 forms a hydrogen bond to the C2 carbonyl of oxaloacetate, placing it in a position to donate a proton in the formation of (2S)-malate.
Structure of glyoxysomal malate dehydrogenase (MDH3) fromSaccharomyces cerevisiae
Authors: Moriyama Shu , Nishio Kazuya , Mizushima Tsunehiro
Published: September 2018

Malate dehydrogenase (MDH), a carbohydrate and energy metabolism enzyme in eukaryotes, catalyzes the interconversion of malate to oxaloacetate (OAA) in conjunction with that of nicotinamide adenine dinucleotide (NAD+) to NADH. Three isozymes of MDH have been reported inSaccharomyces cerevisiae: MDH1, MDH2 and MDH3. MDH1 is a mitochondrial enzyme and a member of the tricarboxylic acid cycle, whereas MDH2 is a cytosolic enzyme that functions in the glyoxylate cycle. MDH3 is a glyoxysomal enzyme that is involved in the reoxidation of NADH, which is produced during fatty-acid β-oxidation. The affinity of MDH3 for OAA is lower than those of MDH1 and MDH2. Here, the crystal structures of yeast apo MDH3, the MDH3–NAD+complex and the MDH3–NAD+–OAA ternary complex were determined. The structure of the ternary complex suggests that the active-site loop is in the open conformation, differing from the closed conformations in mitochondrial and cytosolic malate dehydrogenases.
Crystal structure of mutant carboxypeptidase T from Thermoactinomyces vulgaris with an implanted S1′ subsite from pancreatic carboxypeptidase B
Authors: Akparov Valery Kh. , Timofeev Vladimir I. , Kuranova Inna P. , Rakitina Tatiana V.
Published: September 2018

A site-directed mutagenesis method has been used to obtain the G215S/A251G/T257A/D260G/T262D mutant of carboxypeptidase T from Thermoactinomyces vulgaris (CPT), in which the amino-acid residues of the S1′ subsite are substituted by the corresponding residues from pancreatic carboxypeptidase B (CPB). It was shown that the mutant enzyme retained the broad, mainly hydrophobic selectivity of wild-type CPT. The mutant containing the implanted CPB S1′ subsite was crystallized and its three-dimensional structure was determined at 1.29 Å resolution by X-ray crystallography. A comparison of the three-dimensional structures of CPT, the G215S/A251G/T257A/D260G/T262D CPT mutant and CPB showed that the S1′ subsite of CPT has not been distorted by the mutagenesis and adequately reproduces the structure of the CPB S1′ subsite. The CPB-like mutant differs from CPB in substrate selectivity owing to differences between the two enzymes outside the S1′ subsite. Moreover, the difference in substrate specificity between the enzymes was shown to be affected by residues other than those that directly contact the substrate.
The leading small group: an institutional innovation for PPP projects in China
Authors: Zhang Yajian , Tan Willie
Published: September 2018

Purpose

It is widely recognized that large-scale public–private partnership (PPP) projects require an effective coordination mechanism among various stakeholders throughout the project life cycle. The purpose of this paper is to provide an insight into how this may be achieved through the leading small group (LSG), which is a distinctive informal Chinese institution for coordination among various public agencies.

Design/methodology/approach

An in-depth case study using secondary data and five in-depth interviews with two staff members from the developer and three government officials involved is used to probe into how the LSG functions during the various development phases of the Yangzhou Teda Waste-to-Energy project.

Findings

The main finding is that, conditional on its capacity, the LSG coordinated various public agencies to promote fast project implementation and ensure its smooth operation by making high-level decisions, facilitating quick permits and approvals, and mitigating the risks. However, formalization and participation from other stakeholders are needed to ensure good governance.

Research limitations/implications

Because it is an exploratory case study, the findings cannot be readily generalized. Further research can be done to compare the performance of LSGs in different Chinese cities and PPP projects.

Practical implications

It is supposed that this paper can provide implications of designing effective coordination mechanisms for managing large-scale PPP projects.

Originality/value

This paper provides an account of the LSG as a distinctive Chinese coordination mechanism that has been rarely studied.
Back to basics
Authors: Lucky Shannon , Harkema Craig
Published: September 2018

Purpose

To describe how academic libraries can support digital humanities (DH) research by leveraging established library values and strengths to provide support for preservation and access and physical and digital spaces for researchers and communities, specifically focused on cultural heritage collections.

Design/methodology/approach

The experiences of the authors in collaborating with DH scholars and community organizations is discussed with references to the literature. The paper suggests how research libraries can use existing expertise and infrastructure to support the development of digital cultural heritage collections and DH research.

Findings

Developing working collaborations with DH researchers and community organizations is a productive way to engage in impactful cultural heritage digital projects. It can aid resource allocation decisions to support active research, strategic goals, community needs and the development and preservation of unique, locally relevant collections. Libraries do not need to radically transform themselves to do this work, they have established strengths that can be effective in meeting the challenges of DH research.

Practical implications

Academic libraries should strategically direct the work they already excel at to support DH research and work with scholars and communities to build collections and infrastructure to support these initiatives.

Originality/value

The paper recommends practical approaches, supported by literature and local examples, that could be taken when building DH and community-engaged cultural heritage projects.