bluuebunny/crossref_metadata_2025 huggingface dataset:
von Hippel-Lindau Disease: an Update
Authors: Maher Eamonn R , Sandford Richard N
Published: November 2019

Purpose of Review

In this review, we discuss the key molecular and clinical developments in VHL disease that have the potential to impact on the natural history of the disease and improve patient outcomes.

Recent Findings

Identifiable mutations inVHLunderlie most cases of VHL and define clear genotype-phenotype correlations. Detailed clinical and molecular characterisation has allowed the implementation of lifelong screening programmes that have improved clinical outcomes. Functional characterisation of the VHL protein complex has revealed its role in oxygen sensing and the mechanisms of tumourigenesis that are now being exploited to develop novel therapies for VHL and renal cancer.

The molecular and cellular landscape of VHL-associated tumours is revealing new opportunities to modify the natural history of the disease and develop therapies. Drugs are now entering clinical trials and combined with improved clinical and molecular diagnosis, and lifelong surveillance programmes, further progress towards reducing the morbidity and mortality associated with VHL disease is anticipated.
Roles of egos’ and siblings’ perceptions of maternal favoritism in adult children’s depressive symptoms: A within-family network approach
Authors: Suitor J. Jill , Gilligan Megan , Rurka Marissa , Hou Yifei
Published: November 2019

It is well documented that intergenerational ties play important roles in adults’ well-being. However, most studies focus on the impact of individuals’ own perceptions of their ties without considering whether family members’ assessments of these ties affect well-being. We address this question using data from 296 adult children nested within 95 later-life families in which all offspring were interviewed. Applying a mixed-method within-family approach, we explored whether the effect of perceived maternal favoritism on depressive symptoms was increased when siblings shared ego’s perceptions. Multilevel regression analyses revealed that ego’s own perceptions predicted depressive symptoms, but only among daughters. Siblings’ perceptions that egos were most close to mothers did not affect the well-being of daughters or sons. Qualitative analyses suggested that differential effects of perceived favoritism by gender reflected differences in the meaning sons and daughters associated with being favored children. Favored daughters were more likely than favored sons to report that they were emotional caregivers to their mothers; this pattern was especially strong when siblings reinforced egos’ perceptions of being “best suited” for this role. These findings emphasize the salience of egos’ own perceptions, relative to those of family network members, in shaping role embracement and psychological well-being, especially among women.
The origin of the coding metaphor in neuroscience
Authors: Garson Justin
Published: November 2019

To assess Brette's proposal to expunge “coding” from the neuroscientist's lexicon, we must consider its origins. The coding metaphor is due largely to British nerve physiologist Edgar Adrian. I suggest two ways that the coding metaphor fueled his research. I conclude that the debate today should not be about the “truth” of the metaphor but about its continuing utility.
Neural code: Another breach in the wall?
Authors: Huetz Chloé , Souffi Samira , Adenis Victor , Edeline Jean-Marc
Published: November 2019

Brette presents arguments that query the existence of the neural code. However, he has neglected certain evidence that could be viewed as proof that a neural code operates in the brain. Albeit these proofs show a link between neural activity and cognition, we discuss why they fail to demonstrate the existence of an invariant neural code.
Generative models as parsimonious descriptions of sensorimotor loops
Authors: Baltieri Manuel , Buckley Christopher L.
Published: November 2019

The Bayesian brain hypothesis, predictive processing, and variational free energy minimisation are typically used to describe perceptual processes based on accurate generative models of the world. However, generative models need not be veridical representations of the environment. We suggest that they can (and should) be used to describe sensorimotor relationships relevant for behaviour rather than precise accounts of the world.
Is coding a relevant metaphor for building AI?
Authors: Santoro Adam , Hill Felix , Barrett David , Raposo David , Botvinick Matt , Lillicrap Timothy
Published: November 2019

Brette contends that the neural coding metaphor is an invalid basis for theories of what the brain does. Here, we argue that it is an insufficient guide for building an artificial intelligence that learns to accomplish short- and long-term goals in a complex, changing environment.
The Bayesian brain: What is it and do humans have it?
Authors: Rahnev Dobromir
Published: November 2019

It has been widely asserted that humans have a “Bayesian brain.” Surprisingly, however, this term has never been defined and appears to be used differently by different authors. I argue that Bayesian brain should be used to denote the realist view that brains are actual Bayesian machines and point out that there is currently no evidence for such a claim.
Abandoning the code metaphor is compatible with semiotic process
Authors: Deacon Terrence W. , Rączaszek-Leonardi Joanna
Published: November 2019

We agree with Brette's assessment that the coding metaphor has become more problematic than helpful for theories of brain and cognitive functioning. In an effort to aid in constructing an alternative, we argue that joining the insights from the dynamical systems approach with the semiotic framework of C. S. Peirce can provide a fruitful perspective.
Neural coding: The bureaucratic model of the brain
Authors: Brette Romain
Published: November 2019

The neural coding metaphor is so ubiquitous that we tend to forget its metaphorical nature. What do we mean when we assert that neurons encode and decode? What kind of causal and representational model of the brain does the metaphor entail? What lies beneath the neural coding metaphor, I argue, is a bureaucratic model of the brain.
Escaping Fatou components of transcendental self-maps of the punctured plane
Authors: MARTÍ-PETE DAVID
Published: November 2019

We study the iteration of transcendental self-maps of $\mathcal{C}^*:\=\mathcal{C}\{0}$, that is, holomorphic functions $\fnof:\mathcal{C}^*:\rarr\mathcal{C}^*$ for which both zero and infinity are essential singularities. We use approximation theory to construct functions in this class with escaping Fatou components, both wandering domains and Baker domains, that accumulate to $\{0},\infin$ in any possible way under iteration. We also give the first explicit examples of transcendental self-maps of $\mathcal{C}^*$ with Baker domains and with wandering domains. In doing so, we developed a sufficient condition for a function to have a simply connected escaping wandering domain. Finally, we remark that our results also provide new examples of entire functions with escaping Fatou components.
An In‐Depth Seismological Analysis Revealing a Causal Link Between the 2017 MW 5.5 Pohang Earthquake and EGS Project
Authors: Woo J.‐U. , Kim M. , Sheen D.‐H. , Kang T.‐S. , Rhie J. , Grigoli F. , Ellsworth W. L. , Giardini D.
Published: November 2019

Hydraulic injection by the Pohang enhanced geothermal systems (EGSs) has been suspected to trigger the 2017 moment magnitude (MW) 5.5 Pohang earthquake in South Korea. The last stimulation experiment in the EGS was conducted only 2 months before the disaster, which has led to this suspicion. In this study, we conducted a seismic analysis on the earthquakes that have occurred around the EGS site in the past 10 years. The study included the construction of a velocity model, earthquake detection, the determination of hypocenters, magnitudes, focal mechanisms, and stress inversion, and a clustering analysis. No seismic activity was detected near the study area until November 2015 when there was a loss of a large quantity of heavy drilling mud. For three stimulations of a geothermal well, earthquakes sequentially migrated to the southwest along a fault plane, leading to the location of the mainshock. The delineated fault plane crossed the injection well at approximately 3,800 m, which corresponds to the borehole interval of not only the mud loss but also the breakage of the well's casing due to the mainshock rupture. These findings can be treated as empirical evidence for the hypothesis that the 2017 MW 5.5 Pohang earthquake was initiated on a critically stressed fault zone by the anthropogenic activity of fluid injection, consequentially releasing accumulated strain energy via tectonic loading.
Upscaling of Elastic Properties in Carbonates: A Modeling Approach Based on a Multiscale Geophysical Data Set
Authors: Bailly C. , Fortin J. , Adelinet M. , Hamon Y.
Published: November 2019

Linking ultrasonic measurements made on samples, with sonic logs and seismic subsurface data, is a key challenge for the understanding of carbonate reservoirs. To deal with this problem, we investigate the elastic properties of dry lacustrine carbonates. At one study site, we perform a seismic refraction survey (100 Hz), as well as “sonic” (54 kHz) and ultrasonic (250 kHz) measurements directly on outcrop and ultrasonic measurements on samples (500 kHz). By comparing the median of each data set, we show that the P wave velocity decreases from laboratory to seismic scale. Nevertheless, the median of the sonic measurements acquired on outcrop surfaces seems to fit with the seismic data, meaning that sonic acquisition may be representative of seismic scale. To explain the variations due to upscaling, we relate the concept of representative elementary volume with the wavelength of each scale of study. Indeed, with upscaling, the wavelength varies from millimetric to pluri‐metric. This change of scale allows us to conclude that the behavior of P wave velocity is due to different geological features (matrix porosity, cracks, and fractures) related to the different wavelengths used. Based on effective medium theory, we quantify the pore aspect ratio at sample scale and the crack/fracture density at outcrop and seismic scales using a multiscale representative elementary volume concept. Results show that the matrix porosity that controls the ultrasonic P wave velocities is progressively lost with upscaling, implying that crack and fracture porosity impacts sonic and seismic P wave velocities, a result of paramount importance for seismic interpretation based on deterministic approaches.
Intergranular Clay Films Control Inelastic Deformation in the Groningen Gas Reservoir: Evidence From Split‐Cylinder Deformation Tests
Authors: Pijnenburg R. P. J. , Verberne B. A. , Hangx S. J. T. , Spiers C. J.
Published: November 2019

Production of oil and gas from sandstone reservoirs leads to small elastic and inelastic strains in the reservoir, which may induce surface subsidence and seismicity. While the elastic component is easily described, the inelastic component, and any rate‐sensitivity thereof remain poorly understood in the relevant small strain range (≤1.0%). To address this, we performed a sequence of five stress/strain‐cycling plus strain‐marker‐imaging experiments on a single split‐cylinder sample (porosity 20.4%) of Slochteren sandstone from the seismogenic Groningen gas field. The tests were performed under in situ conditions of effective confining pressure (40 MPa) and temperature (100 °C), exploring increasingly large differential stresses (up to 75 MPa) and/or axial strains (up to 4.8%) in consecutive runs. At the small strains relevant to producing reservoirs (≤1.0%), inelastic deformation was largely accommodated by deformation of clay‐filled grain contacts. High axial strains (>1.4%) led to pervasive intragranular cracking plus intergranular slip within localized, conjugate bands. Using a simplified sandstone model, we show that the magnitude of inelastic deformation produced in our experiments at small strains (≤1.0%) and stresses relevant to the Groningen reservoir can indeed be roughly accounted for by clay film deformation. Thus, inelastic compaction of the Groningen reservoir is expected to be largely governed by clay film deformation. Compaction by this mechanism is shown to be rate insensitive on production timescales and is anticipated to halt when gas production stops. However, creep by other processes cannot be eliminated. Similar, clay‐bearing sandstone reservoirs occur widespread globally, implying a wide relevance of our results.
Simulating a Mesoscale Convective System Using WRF With a New Spectral Bin Microphysics: 1: Hail vs Graupel
Authors: Shpund Jacob , Khain Alexander , Lynn Barry , Fan Jiwen , Han Bin , Ryzhkov Alexander , Snyder Jeffrey , Dudhia Jimy , Gill Dave
Published: November 2019

A modified Fast Spectral Bin Microphysics scheme (FSBM‐2) embedded into the Weather Research and Forecasting (WRF) model is used to simulate a mesoscale deep convective system observed during the Midlatitude Continental Convective Clouds Experiment (MC3E). FSBM‐2 uses modified source codes as compared to the current FSBM (FSBM‐1). In contrast to FSBM‐1, FSBM‐2 can simulate hail of several centimeters in diameter and includes additional processes such as spontaneous breakup of raindrops and aerosol regeneration by drop evaporation. It is shown that allowing large hail particles of diameters exceeding about 1 cm substantially increases the agreement between the simulated and observed squall‐line structures in both the convective and stratiform regions. In contrast, if graupel particles are used to represent high‐density hydrometeors in convective areas, the ratio of convective‐to‐stratiform areas diverges from the ratio seen in observations and maximum radar reflectivities are substantially underestimated. Analysis of snow size distributions in the stratiform area shows an important link between the ice crystals formed by homogeneous freezing in the convective area to ice particle number concentration in the stratiform region. Simulated raindrop size distributions in the stratiform area below the melting level from FSBM‐2 show a good agreement with observations. The regeneration of cloud condensational nuclei (CCN) by droplet evaporation and detrainment of these CCN to the stratiform region increases the concentration of CCN there up to 8‐ to 9‐km altitude; the additional CCN penetrate clouds and produce new droplets, leading to some convection intensification.
Running exercise protects oligodendrocytes in the medial prefrontal cortex in chronic unpredictable stress rat model
Authors: Luo Yanmin , Xiao Qian , Wang Jin , Jiang Lin , Hu Menglan , Jiang Yanhong , Tang Jing , Liang Xin , Qi Yingqiang , Dou Xiaoyun , Zhang Yi , Huang Chunxia , Chen Linmu , Tang Yong
Published: November 2019

Previous postmortem and animal studies have shown decreases in the prefrontal cortex (PFC) volume and the number of glial cells in the PFC of depression. Running exercise has been shown to alleviate depressive symptoms. However, the effects of running exercise on the medial prefrontal cortex (mPFC) volume and oligodendrocytes in the mPFC of depressed patients and animals have not been investigated. To address these issues, adult male rats were subjected to chronic unpredictable stress (CUS) for 5 weeks, followed by treadmill running for 6 weeks. Then, the mPFC volume and the mPFC oligodendrocytes were investigated using stereology, immunohistochemistry, immunofluorescence and western blotting. Using a CUS paradigm that allowed for the analysis of anhedonia, we found that running exercise alleviated the deficits in sucrose preference, as well as the decrease in the mPFC volume. Meanwhile, we found that running exercise significantly increased the number of CNPase+oligodendrocytes and Olig2+oligodendrocytes, reduced the ratio between Olig2+/NG2+oligodendrocytes and Olig2+oligodendrocytes and increased myelin basic protein (MBP), CNPase and Olig2 protein expression in the mPFC of the CUS rat model. However, running exercise did not change NG2+oligodendrocyte number in the mPFC in these rats. These results indicated that running exercise promoted the differentiation of oligodendrocytes and myelin-forming ability in the mPFC in the context of depression. These findings suggest that the beneficial effects of running exercise on mPFC volume and oligodendrocytes in mPFC might be an important structural basis for the antidepressant effects of running exercise.
Dissection of gene expression datasets into clinically relevant interaction signatures via high-dimensional correlation maximization
Authors: Grau Michael , Lenz Georg , Lenz Peter
Published: November 2019

Gene expression is controlled by many simultaneous interactions, frequently measured collectively in biology and medicine by high-throughput technologies. It is a highly challenging task to infer from these data the generating effects and cooperating genes. Here, we present an unsupervised hypothesis-generating learning concept termed signal dissection by correlation maximization (SDCM) that dissects large high-dimensional datasets into signatures. Each signature captures a particular signal pattern that was consistently observed for multiple genes and samples, likely caused by the same underlying interaction. A key difference to other methods is our flexible nonlinear signal superposition model, combined with a precise regression technique. Analyzing gene expression of diffuse large B-cell lymphoma, our method discovers previously unidentified signatures that reveal significant differences in patient survival. These signatures are more predictive than those from various methods used for comparison and robustly validate across technological platforms. This implies highly specific extraction of clinically relevant gene interactions.
Integrating electric field modeling and neuroimaging to explain inter-individual variability of tACS effects
Authors: Kasten Florian H. , Duecker Katharina , Maack Marike C. , Meiser Arnd , Herrmann Christoph S.
Published: November 2019

Transcranial electrical stimulation (tES) of the brain can have variable effects, plausibly driven by individual differences in neuroanatomy and resulting differences of the electric fields inside the brain. Here, we integrated individual simulations of electric fields during tES with source localization to predict variability of transcranial alternating current stimulation (tACS) aftereffects on α-oscillations. In two experiments, participants received 20-min of either α-tACS (1 mA) or sham stimulation. Magnetoencephalogram (MEG) was recorded for 10-min before and after stimulation. tACS caused a larger power increase in the α-band compared to sham. The variability of this effect was significantly predicted by measures derived from individual electric field modeling. Our results directly link electric field variability to variability of tACS outcomes, underline the importance of individualizing stimulation protocols, and provide a novel approach to analyze tACS effects in terms of dose-response relationships.
A database of high-resolution MS/MS spectra for lichen metabolites
Authors: Olivier-Jimenez Damien , Chollet-Krugler Marylène , Rondeau David , Beniddir Mehdi A. , Ferron Solenn , Delhaye Thomas , Allard Pierre-Marie , Wolfender Jean-Luc , Sipman Harrie J. M. , Lücking Robert , Boustie Joël , Le Pogam Pierre
Published: November 2019

While analytical techniques in natural products research massively shifted to liquid chromatography-mass spectrometry, lichen chemistry remains reliant on limited analytical methods, Thin Layer Chromatography being the gold standard. To meet the modern standards of metabolomics within lichenochemistry, we announce the publication of an open access MS/MS library with 250 metabolites, coined LDB for Lichen DataBase, providing a comprehensive coverage of lichen chemodiversity. These were donated by the Berlin Garden and Botanical Museum from the collection of Siegfried Huneck to be analyzed by LC-MS/MS. Spectra at individual collision energies were submitted to MetaboLights (https://www.ebi.ac.uk/metabolights/MTBLS999) while merged spectra were uploaded to the GNPS platform (CCMSLIB00004751209 to CCMSLIB00004751517). Technical validation was achieved by dereplicating three lichen extracts using a Molecular Networking approach, revealing the detection of eleven unique molecules that would have been missed without LDB implementation to the GNPS. From a chemist’s viewpoint, this database should help streamlining the isolation of formerly unreported metabolites. From a taxonomist perspective, the LDB offers a versatile tool for the chemical profiling of newly reported species.
Wedge prism approach for simultaneous multichannel microscopy
Authors: Cai Hanna , Wang Yao L. , Wainner Richard T. , Iftimia Nicusor V. , Gabel Christopher V. , Chung Samuel H.
Published: November 2019

Multichannel (multicolor) imaging has become a powerful technique in biology research for performing in vivo neuronal calcium imaging, colocalization of fluorescent labels, non-invasive pH measurement, and other procedures. We describe a novel add-on approach for simultaneous multichannel optical microscopy based on simple wedge prisms. Our device requires no alignment and is simple, robust, user-friendly, and less expensive than current commercial instruments based on switchable filters or dual-view strategies. Point spread function measurements and simulations in Zemax indicate a reduction in resolution in the direction orthogonal to the wedge interface and in the axial direction, without introducing aberration. These effects depend on the objective utilized and are most significant near the periphery of the field of view. We tested a two-channel device on C. elegans neurons in vivo and demonstrated comparable signals to a conventional dual-view instrument. We also tested a four-channel device on fixed chick embryo Brainbow samples and identified individual neurons by their spectra without extensive image postprocessing. Therefore, we believe that this technology has the potential for broad use in microscopy.
Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization
Authors: Ronzier Elsa , Parks Xiaorong Xu , Qudsi Haani , Lopes Coeli M.
Published: November 2019

Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.
pH-depended protein shell dis- and reassembly of ferritin nanoparticles revealed by atomic force microscopy
Authors: Stühn Lukas , Auernhammer Julia , Dietz Christian
Published: November 2019

Ferritin, a protein that is present in the human body for a controlled iron storage and release, consists of a ferrihydrite core and a protein shell. Apoferritin, the empty shell of ferritin, can be modified to carry tailored properties exploitable for targeted and direct drug delivery. This protein shell has the ability to dis- and reassemble depending on the pH value of the liquid environment and can thus be filled with the desired substance. Here we observed the dis- and reassembly process of the protein shell of ferritin and apoferritin in situ and in real space using atomic force microscopy. Ferritin and apoferritin nanoparticles adsorbed on a mica substrate exhibited a change in their size by varying the pH value of the surrounding medium. Lowering the pH value of the solution led to a decrease in size of the nanoparticles whereas a successive increase of the pH value increased the particle size again. The pH dependent change in size could be related to the dis- and reassembling of the protein shell of ferritin and apoferritin. Supplementary imaging by bimodal magnetic force microscopy of ferritin molecules accomplished in air revealed a polygonal shape of the core and a three-fold symmetry of the protein shell providing valuable information about the substructure of the nanoparticles.
Unraveling Determinants of Affinity Enhancement in Dimeric Aptamers for a Dimeric Protein
Authors: Manochehry Sepehr , McConnell Erin M. , Li Yingfu
Published: November 2019

High-affinity aptamers can be derived de novo by using stringent conditions in SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments or can be engineered post SELEX via dimerization of selected aptamers. Using electrophoretic mobility shift assays, we studied a series of heterodimeric and homodimeric aptamers, constructed from two DNA aptamers with distinct primary sequences and secondary structures, previously isolated for VEGF-165, a homodimeric protein. We investigated four factors envisaged to impact the affinity of a dimeric aptamer to a dimeric protein: (1) length of the linker between two aptamer domains, (2) linking orientation, (3) binding-site compatibility of two component aptamers in a heterodimeric aptamer, and (4) steric acceptability of the two identical aptamers in a homodimeric aptamer. All heterodimeric aptamers for VEGF-165 were found to exhibit monomeric aptamer-like affinity and the lack of affinity enhancement was attributed to binding-site overlap by the constituent aptamers. The best homodimeric aptamer showed 2.8-fold better affinity than its monomeric unit (Kd = 13.6 ± 2.7 nM compared to 37.9 ± 14 nM), however the barrier to further affinity enhancement was ascribed to steric interference of the constituent aptamers. Our findings point to the need to consider the issues of binding-site compatibility and spatial requirement of aptamers for the development of dimeric aptamers capable of bivalent recognition. Thus, determinants highlighted herein should be assessed in future multimerization efforts.
Carprofen-induced depletion of proton motive force reverses TetK-mediated doxycycline resistance in methicillin-resistant Staphylococcus pseudintermedius
Authors: Magnowska Zofia , Jana Bimal , Brochmann Rikke Prejh , Hesketh Andrew , Lametsch Rene , De Gobba Cristian , Guardabassi Luca
Published: November 2019

We previously showed that doxycycline (DOX) and carprofen (CPF), a veterinary non-steroidal anti-inflammatory drug, have synergistic antimicrobial activity against methicillin-resistant Staphylococcus pseudintermedius (MRSP) carrying the tetracycline resistance determinant TetK. To elucidate the molecular mechanism of this synergy, we investigated the effects of the two drugs, individually and in combination, using a comprehensive approach including RNA sequencing, two-dimensional differential in-gel electrophoresis, macromolecule biosynthesis assays and fluorescence spectroscopy. Exposure of TetK-positive MRSP to CPF alone resulted in upregulation of pathways that generate ATP and NADH, and promote the proton gradient. We showed that CPF is a proton carrier that dissipates the electrochemical potential of the membrane. In the presence of both CPF and DOX, the energy compensation strategy was attenuated by downregulation of all the processes involved, such as citric acid cycle, oxidative phosphorylation and ATP-providing arginine deiminase pathway. Furthermore, protein biosynthesis inhibition increased from 20% under DOX exposure alone to 75% upon simultaneous exposure to CPF. We conclude that synergistic interaction of the drugs restores DOX susceptibility in MRSP by compromising proton-motive-force-dependent TetK-mediated efflux of the antibiotic. MRSP is unable to counterbalance CPF-mediated PMF depletion by cellular metabolic adaptations, resulting in intracellular accumulation of DOX and inhibition of protein biosynthesis.
µ-opioid receptor-mediated downregulation of midline thalamic pathways to basal and central amygdala
Authors: Goedecke L. , Bengoetxea X. , Blaesse P. , Pape H.-C. , Jüngling K.
Published: November 2019

Brain µ-opioid receptors (MOR) mediate reward and help coping with pain, social rejection, anxiety and depression. The dorsal midline thalamus (dMT) integrates visceral/emotional signals and biases behavior towards aversive or defensive states through projections to the amygdala. While a dense MOR expression in the dMT has been described, the exact cellular and synaptic mechanisms of µ-opioidergic modulation in the dMT-amygdala circuitry remain unresolved. Here, we hypothesized that MORs are important negative modulators of dMT-amygdala excitatory networks. Using retrograde tracers and targeted channelrhodopsin expression in combination with patch-clamp electrophysiology, we found that projections of dMT neurons onto both basal amygdala principal neurons (BA PN) and central amygdala (CeL) neurons are attenuated by stimulation of somatic or synaptic MORs. Importantly, dMT efferents to the amygdala drive feedforward excitation of centromedial amygdala neurons (CeM), which is dampened by MOR activation. This downregulation of excitatory activity in dMT-amygdala networks puts the µ-opioid system in a position to ameliorate aversive or defensive behavioral states associated with stress, withdrawal, physical pain or social rejection.
A downsampling strategy to assess the predictive value of radiomic features
Authors: Dirand Anne-Sophie , Frouin Frédérique , Buvat Irène
Published: November 2019

Many studies are devoted to the design of radiomic models for a prediction task. When no effective model is found, it is often difficult to know whether the radiomic features do not include information relevant to the task or because of insufficient data. We propose a downsampling method to answer that question when considering a classification task into two groups. Using two large patient cohorts, several experimental configurations involving different numbers of patients were created. Univariate or multivariate radiomic models were designed from each configuration. Their performance as reflected by the Youden index (YI) and Area Under the receiver operating characteristic Curve (AUC) was compared to the stable performance obtained with the highest number of patients. A downsampling method is described to predict the YI and AUC achievable with a large number of patients. Using the multivariate models involving machine learning, YI and AUC increased with the number of patients while they decreased for univariate models. The downsampling method better estimated YI and AUC obtained with the largest number of patients than the YI and AUC obtained using the number of available patients and identifies the lack of information relevant to the classification task when no such information exists.
Transcriptional control of central carbon metabolic flux in Bifidobacteria by two functionally similar, yet distinct LacI-type regulators
Authors: Lanigan Noreen , Kelly Emer , Arzamasov Aleksandr A. , Stanton Catherine , Rodionov Dmitry A. , van Sinderen Douwe
Published: November 2019

Bifidobacteria resident in the gastrointestinal tract (GIT) are subject to constantly changing environmental conditions, which require rapid adjustments in gene expression. Here, we show that two predicted LacI-type transcription factors (TFs), designated AraQ and MalR1, are involved in regulating the central, carbohydrate-associated metabolic pathway (the so-called phosphoketolase pathway or bifid shunt) of the gut commensal Bifidobacterium breve UCC2003. These TFs appear to not only control transcription of genes involved in the bifid shunt and each other, but also seem to commonly and directly affect transcription of other TF-encoding genes, as well as genes related to uptake and metabolism of various carbohydrates. This complex and interactive network of AraQ/MalR1-mediated gene regulation provides previously unknown insights into the governance of carbon metabolism in bifidobacteria.
Study of the interactions of a novel monoclonal antibody, mAb059c, with the hPD-1 receptor
Authors: Liu Jingxian , Wang Guiqun , Liu Liu , Wu Runjie , Wu Yi , Fang Cheng , Zhou Xinhong , Jiao Jing , Gu Ying , Zhou He , Xie Zhenhui , Sun Zhiwu , Chen Dakai , Dai Ken , Wang Dongxu , Tang Wei , Yang Teddy Tat Chi
Published: November 2019

Programmed cell death 1 (PD-1) monoclonal antibodies have been approved by regulatory agencies for the treatment of various types of cancer, and the mechanism involves the restoration of T cell functions. We report herein the X-ray crystal structure of a fully human monoclonal antibody mAb059c fragment antigen-binding (Fab) in complex with the PD-1 extracellular domain (ECD) at a resolution of 1.70 Å. Structural analysis indicates 1) an epitope, comprising fragments from the C’D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C’D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact – ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds. Interface analysis reveals that N-glycosylation sites 49, 74 and 116 on PD-1 do not contact mAb059c; while N58 in the BC loop is recognized by mAb059c heavy chain CDR1 and CDR2. Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs.
Improving the Real-time Marine Forecasting of the Northern South China Sea by Assimilation of Glider-observed T/S Profiles
Authors: Peng Shiqiu , Zhu Yuhang , Li Zhijin , Li Yineng , Xie Qiang , Liu Shijie , Luo Yeteng , Tian Yu , Yu Jiancheng
Published: November 2019

Prediction of marine conditions is notoriously challenging in the northern South China Sea (NSCS) due to inadequate observations in the region. The underwater gliders that were developed during the past decade may provide observing platforms that could produce required observations. During a field experiment, temperature/salinity (T/S) profiles from a set of underwater gliders were assimilated into a real-time marine forecasting system, along with the assimilation of climatological monthly mean Argo data to constrain the basin-wide model biases. The results show that, in addition to the reduction of the basin-wide model biases by the assimilation of the climatological monthly mean Argo data, the assimilation of glider-observed T/S profiles is efficient to reduce the local biases of the NSCS marine forecasting by as much as 28–31% (19–36%) in 24 h to 120 h forecasts for temperature (salinity) from sea surface to a depth of 1000 m. Our results imply that the real-time marine forecasting for the NSCS can largely benefit from a sustainable glider observing network of the NSCS in the future.
Author Correction: Mapping the Dynamic Functions and Structural Features of AcrB Efflux Pump Transporter Using Accelerated Molecular Dynamics Simulations
Authors: Jamshidi Shirin , Sutton J. Mark , Rahman Khondaker Miraz
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Inducing oculomotor plasticity to disclose the functional link between voluntary saccades and endogenous attention deployed perifoveally
Authors: Nicolas Judith , Bidet-Caulet Aurélie , Pélisson Denis
Published: November 2019

To what extent oculomotor and attention systems are linked remains strongly debated. Previous studies suggested that saccadic adaptation, a well-studied model of oculomotor plasticity, and orienting of attention rely on overlapping networks in the parietal cortex and can functionally interact. Using a Posner-like paradigm in healthy human subjects, we demonstrate for the first time that saccadic adaptation boosts endogenous attention orienting. Indeed, the discrimination of perifoveal targets benefits more from central cues after backward adaptation of leftward voluntary saccades than after a control saccade task. We propose that the overlap of underlying neural networks actually consists of neuronal populations co-activated by oculomotor plasticity and endogenous attention deployed perifoveally. The functional coupling demonstrated here plaids for conceptual models not belonging to the framework of the premotor theory of attention as the latter has been rejected precisely for this voluntary/endogenous modality. These results also open new perspective for rehabilitation of visuo-attentional deficits.
A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer
Authors: Block C. James , Dyson Gregory , Campeanu Ion John , Watza Donovan , Ratnam Manohar , Wu Guojun
Published: November 2019

The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. However, these studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. In this study, we comprehensively dissect the associations between multiple EMT transcription factors and EMT markers with stromal and immune tumor infiltration. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. We derive a stroma-corrected ZEB1-activated transcriptional signature and demonstrate that this signature includes several known inhibitors of inflammation, including BMPR2. Finally, multivariate survival analysis reveals that ZEB1 and its expression signature are significantly associated with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content.
Characterization and assessment of barnacle larval settlement-inducing activity of extracellular polymeric substances isolated from marine biofilm bacteria
Authors: Siddik Aboobucker , Satheesh Sathianeson
Published: November 2019

Extracellular polymeric substances (EPSs) are the hydrated gelatinous matrix produced by microorganisms for attachment in a biofilm environment. In this study, the compositional variation between EPSs of three marine biofilm bacteria (Pseudoalteromonas shioyasakiensis, Vibrio harveyi and Planomicrobium sp.) were analysed by GC-MS, 1H NMR, FT-IR and XRD and SEM. The ecological significance of exopolymers was assessed in vivo using marine model organism barnacle larvae for their settlement-inducing activity. Chemical analysis revealed the presence of glycan fucosylated oligosaccharides, tetraose, trisaccharides, iso-B-Pentasaccharides, sialyllactose, oligomannose, galacto-N-biose, difucosyl-para-lacto-N-neohexaose, 3′-sialyl N-acetyllactosamine and isoglobotriaose-β-N(Acetyl)-Propargyl in all extracted EPSs. Bioassay results indicated that treatment of the barnacle larvae with EPSs from three bacterial strains enhanced settlement on substrates. In conclusion, this study highlighted the role of water-soluble EPSs in the invertebrate larval settlement on artificial materials.
Navigated transcranial magnetic stimulation of the supplementary motor cortex disrupts fine motor skills in healthy adults
Authors: Schramm Severin , Albers Lucia , Ille Sebastian , Schröder Axel , Meyer Bernhard , Sollmann Nico , Krieg Sandro M.
Published: November 2019

Navigated transcranial magnetic stimulation (nTMS) over the supplementary motor area (SMA) may impact fine motor skills. This study evaluates different nTMS parameters in their capacity to affect fine motor performance on the way to develop an SMA mapping protocol. Twenty healthy volunteers performed a variety of fine motor tests during baseline and nTMS to the SMA using 5 Hz, 10 Hz, and theta-burst stimulation (TBS). Effects on performance were measured by test completion times (TCTs), standard deviation of inter-tap interval (SDIT), and visible coordination problems (VCPs). The predominant stimulation effect was slowing of TCTs, i.e. a slowdown of test performances during stimulation. Furthermore, participants exhibited VCPs like accidental use of contralateral limbs or inability to coordinate movements. More instances of significant differences between baseline and stimulation occurred during stimulation of the right hemisphere compared to left-hemispheric stimulation. In conclusion, nTMS to the SMA could enable new approaches in neuroscience and enable structured mapping approaches. Specifically, this study supports interhemispheric differences in motor control as right-hemispheric stimulation resulted in clearer impairments. The application of our nTMS-based setup to assess the function of the SMA should be applied in patients with changed anatomo-functional representations as the next step, e.g. among patients with eloquent brain tumors.
Barley-ß-glucans reduce systemic inflammation, renal injury and aortic calcification through ADAM17 and neutral-sphingomyelinase2 inhibition
Authors: Arcidiacono Maria Vittoria , Carrillo-López Natalia , Panizo Sara , Castro-Grattoni Anabel L. , Valcheva Petya , Ulloa Catalina , Rodríguez-Carrio Javier , Cardús Anna , Quirós-Caso Covadonga , Martínez-Arias Laura , Martínez-Salgado Carlos , Motilva María José , Rodriguez-Suarez Carmen , Cannata-Andía Jorge B. , Dusso Adriana S.
Published: November 2019

In chronic kidney disease (CKD), hyperphosphatemia-induced inflammation aggravates vascular calcification (VC) by increasing vascular smooth muscle cell (VSMC) osteogenic differentiation, ADAM17-induced renal and vascular injury, and TNFα-induction of neutral-sphingomyelinase2 (nSMase2) to release pro-calcifying exosomes. This study examined anti-inflammatory β-glucans efficacy at attenuating systemic inflammation in health, and renal and vascular injury favoring VC in hyperphosphatemic CKD. In healthy adults, dietary barley β-glucans (Bβglucans) reduced leukocyte superoxide production, inflammatory ADAM17, TNFα, nSMase2, and pro-aging/pro-inflammatory STING (Stimulator of interferon genes) gene expression without decreasing circulating inflammatory cytokines, except for γ-interferon. In hyperphosphatemic rat CKD, dietary Bβglucans reduced renal and aortic ADAM17-driven inflammation attenuating CKD-progression (higher GFR and lower serum creatinine, proteinuria, kidney inflammatory infiltration and nSMase2), and TNFα-driven increases in aortic nSMase2 and calcium deposition without improving mineral homeostasis. In VSMC, Bβglucans prevented LPS- or uremic serum-induced rapid increases in ADAM17, TNFα and nSMase2, and reduced the 13-fold higher calcium deposition induced by prolonged calcifying conditions by inhibiting osteogenic differentiation and increases in nSMase2 through Dectin1-independent actions involving Bβglucans internalization. Thus, dietary Bβglucans inhibit leukocyte superoxide production and leukocyte, renal and aortic ADAM17- and nSMase2 gene expression attenuating systemic inflammation in health, and renal injury and aortic calcification despite hyperphosphatemia in CKD.
Partitioning of amino acids and proteins into decanol using phase transfer agents towards understanding life in non-polar liquids
Authors: Thompson Brooke , Burt Kayla , Lee Andrew , Lingard Kyle , Maurer Sarah E.
Published: November 2019

Water has many roles in the context of life on Earth, however throughout the universe, other liquids may be able to support the emergence of life. We looked at the ability of amino acids, peptides, a depsipeptide, and proteins to partition into a non-polar decanol phase, with and without the addition of a phase transfer agent. Partitioning evaluated using UV detection, or with HPLC coupled to either charged aerosol detection or ESI-MS. For amino acids and short peptides, phase transfer agents were used to move the biomolecules to the decanol phase, and this transfer was pH dependent. For larger molecules, phase transfer agents did not seem to affect the transfer. Both the depsipetide, valinomycin, and the protein Taq DNA polymerase had solubility in the decanol phase. Additionally, valinomycin appeared to retain its biological ability to bind to potassium ions. These results show that most terrestrial biological molecules are not compatible with non-polar solvents, but it is possible to find and perhaps evolve polymers that are functional in such phases.
Violence reduces attention to faces and draws attention to points of contact
Authors: Scrivner Coltan , Choe Kyoung Whan , Henry Joseph , Lyu Muxuan , Maestripieri Dario , Berman Marc G.
Published: November 2019

Although violence is a frequently researched topic, little is known about how different social features influence information gathering from violent interactions. Regions of an interaction that provide contextual information should receive more attention. We predicted the most informative features of a violent social interaction would be faces, points of contact, and objects being held. To test this, we tracked the eyes of 90 participants as they viewed images of social interactions that varied with respect to violence. When viewing violent interactions, participants attended significantly less to faces and significantly more to points of contact. Moreover, first-fixation analysis suggests that some of these biases are present from the beginning of scene-viewing. These findings are the first to demonstrate the visual relevance of faces and contact points in gathering information from violent social interactions. These results also question the attentional dominance of faces in active social scenes, highlighting the importance of using a variety of stimuli and contexts in social cognition research.