bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biased orientation representations can be explained by experience with non-uniform training set statistics
Authors: Henderson Margaret , Serences John 
Published: July 2020

AbstractVisual acuity is better for vertical and horizontal compared to other orientations. This cross-species phenomenon is often explained by “efficient coding”, whereby more neurons show sharper tuning for the orientations most common in natural vision. However, it is unclear if experience alone can account for such biases. Here, we measured orientation representations in a convolutional neural network, VGG-16, trained on modified versions of ImageNet (rotated by 0°, 22.5°, or 45° counter-clockwise of upright). Discriminability for each model was highest near the orientations that were most common in the network’s training set. Furthermore, there was an over-representation of narrowly tuned units selective for the most common orientations. These effects emerged in middle layers and increased with depth in the network. Biases emerged early in training, consistent with the possibility that non-uniform representations may play a functional role in the network’s task performance. Together, our results suggest that biased orientation representations can emerge through experience with a non-uniform distribution of orientations, supporting the efficient coding hypothesis.
Improved protein structure refinement guided by deep learning based accuracy estimation
Authors: Hiranuma Naozumi , Park Hahnbeom , Baek Minkyung , Anishchanka Ivan , Dauparas Justas , Baker David 
Published: July 2020

AbstractWe develop a deep learning framework (DeepAccNet) that estimates per-residue accuracy and residue-residue distance signed error in protein models and uses these predictions to guide Rosetta protein structure refinement. The network uses 3D convolutions to evaluate local atomic environments followed by 2D convolutions to provide their global contexts and outperforms other methods that similarly predict the accuracy of protein structure models. Overall accuracy predictions for X-ray and cryoEM structures in the PDB correlate with their resolution, and the network should be broadly useful for assessing the accuracy of both predicted structure models and experimentally determined structures and identifying specific regions likely to be in error. Incorporation of the accuracy predictions at multiple stages in the Rosetta refinement protocol considerably increased the accuracy of the resulting protein structure models, illustrating how deep learning can improve search for global energy minima of biomolecules.
Ecological load and balancing selection in circumboreal barnacles
Authors: Nunez Joaquin C. B. , Rong Stephen , Damian-Serrano Alejandro , Burley John T. , Elyanow Rebecca G. , Ferranti David A. , Neil Kimberly B. , Glenner Henrik , Rosenblad Magnus Alm , Blomberg Anders , Johannesson Kerstin , Rand David M. 
Published: July 2020

AbstractAcorn barnacle adults experience environmental heterogeneity at various spatial scales of their circumboreal habitat, raising the question of how adaptation to high environmental variability is maintained in the face of strong juvenile dispersal and mortality. Here we show that 4% of genes in the barnacle genome experience balancing selection across the entire range of the species. Many of these genes harbor mutations maintained across 2 million years of evolution between the Pacific and Atlantic oceans. These genes are involved in ion regulation, pain reception, and heat tolerance, functions which are essential in highly variable ecosystems. The data also reveal complex population structure within and between basins, driven by the trans-Arctic interchange and the last glaciation. Divergence between Atlantic and Pacific populations is high, foreshadowing the onset of allopatric speciation, and suggesting that balancing selection is strong enough to maintain functional variation for millions of years in the face of complex demography.
Basolateral amygdala CB1 receptors modulate HPA axis activation and context-cocaine memory strength during reconsolidation
Authors: Higginbotham Jessica A. , Jones Nicole M. , Wang Rong , McLaughlin Ryan J. , Fuchs Rita A. 
Published: July 2020

ABSTRACTRe-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. Cannabinoid type 1 receptor (CB1R) signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, it remains unclear whether CB1Rs in the BLA mediate this phenomenon. To investigate this question, we examined whether CB1R antagonist or agonist administration into the BLA immediately after cocaine-memory retrieval (i.e., during memory reconsolidation) alters cocaine-memory strength and subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of cocaine relapse. Intra-BLA administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) – during, but not after, memory reconsolidation – increased drug context-induced cocaine-seeking behavior three days later, while the CB1R agonist, WIN55,212-2 (0.5 µg/hemisphere) failed to alter this behavior. Furthermore, AM251 administration into the posterior caudate putamen (anatomical control region) during memory reconsolidation did not alter subsequent context-induced cocaine-seeking behavior. In a follow-up experiment, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by an increase in blood serum corticosterone concentration, and this response was selectively extended by intra-BLA AM251 administration during the putative time of memory reconsolidation relative to all control conditions. Together, these findings suggest that CB1R populations in the BLA gate memory strength or interfere with memory maintenance, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficiency of the memory reconsolidation process.
Comparative transcriptomics identifiesBotrytis cinereainduced conserved defences across different tissues ofFragaria vesca
Authors: Badmi Raghuram 
Published: July 2020

AbstractGrey mould is one of the most devastating plant diseases that causes huge losses to the agricultural sector worldwide.Botrytis cinerea, the causal pathogen of grey mould, is a generalist necrotrophic fungus with the ability to infect over 1000 species and influence a broad array of host’s physiological responses.B. cinereais capable of infecting a wide variety of tissues such as leaves, stem, flowers and fruits that adds to the already complex problem in controlling its spread. Understanding the pathogen induced transcriptional reprogramming in different tissues is important to identify key genes for targeted gene modifications. Identifying the genes that are common between different tissue infections will reveal similarities and differences between these pathogen-tissue pairs. In this study, the transcriptomic datasets of Botrytis infected white berries ofFragaria vesca(WhiteBc) and Botrytis infected red berries ofF. vesca(RedBc) were (re)mapped to the latestF. vescatranscriptome to enable direct comparisons with the Botrytis infectedF. vescaleaves (LeafBc). The genes involved in MAP kinase signalling, pathogenesis-related, allergens, cell-wall defences, detoxification and secondary metabolites wereCommonResponsive andUpregulated (CoReUp) betweenLeafBc,WhiteBcandRedBc, suggesting their important roles againstB. cinereainfection in all three tissues. These insights maybe helpful for generatingB. cinerearesistant varieties of strawberry.
Generation of ordered protein assemblies using rigid three-body fusion
Authors: Vulovic Ivan , Yao Qing , Park Young-Jun , Courbet Alexis , Norris Andrew , Busch Florian , Sahasrabuddhe Aniruddha , Merten Hannes , Sahtoe Danny D. , Ueda George , Fallas Jorge A. , Weaver Sara J. , Hsia Yang , Langan Robert A. , Plückthun Andreas , Wysocki Vicki H. , Veesler David , Jensen Grant J. , Baker David 
Published: July 2020

AbstractProtein nanomaterial design is an emerging discipline with applications in medicine and beyond. A longstanding design approach uses genetic fusion to join protein homo-oligomer subunits via α-helical linkers to form more complex symmetric assemblies, but this method is hampered by linker flexibility and a dearth of geometric solutions. Here, we describe a general computational method that performs rigid three-body fusion of homo-oligomer and spacer building blocks to generate user-defined architectures, while at the same time significantly increasing the number of geometric solutions over typical symmetric fusion. The fusion junctions are then optimized using Rosetta to minimize flexibility. We apply this method to design and test 92 dihedral symmetric protein assemblies from a set of designed homo-dimers and repeat protein building blocks. Experimental validation by native mass spectrometry, small angle X-ray scattering, and negative-stain single-particle electron microscopy confirms the assembly states for 11 designs. Most of these assemblies are constructed from DARPins (designed ankyrin repeat proteins), anchored on one end by α-helical fusion and on the other by a designed homo-dimer interface, and we explored their use for cryo-EM structure determination by incorporating DARPin variants selected to bind targets of interest. Although the target resolution was limited by preferred orientation effects, small scaffold size, and the low-order symmetry of these dihedral scaffolds, we found that the dual anchoring strategy reduced the flexibility of the target-DARPIN complex with respect to the overall assembly, suggesting that multipoint anchoring of binding domains could contribute to cryo-EM structure determination of small proteins.
Structure and function of the nervous system in nectophores of the siphonophoreNanomia bijuga
Authors: Norekian Tigran P. , Meech Robert W. 
Published: July 2020

SummaryAlthoughNanomianectophores are specialized for locomotion, their cellular elements and complex nerve structures suggest they have multiple subsidiary functions.The main nerve complex is a nerve ring, an adjacent columnar-shaped matrix plus two associated nerve projections. An upper nerve tract appears to provide a sensory input while a lower nerve tract connects with the rest of the colony.The nerve cell cluster that gives rise to the lower nerve tract may relay information from the colony stem.The structure of the extensively innervated “flask cells” located around the bell margin suggests a secretory function. They are ideally placed to release chemical messengers or toxins into the jet of water that leaves the nectophore during each swim.The numerous nematocytes present on exposed nectophore ridges appear to have an entangling rather than a penetrating role.Movements of the velum, produced by contraction of the Claus’ muscle system during backwards swimming, can be elicited by electrical stimulation of the surface epithelium even when the major nerve tracts serving the nerve ring have been destroyed (confirming Mackie, 1964).Epithelial impulses generated by electrical stimulation elicit synaptic potentials in Claus’ muscle fibres. Their amplitude suggests a neural input in the vicinity of the Claus’ muscle system. The synaptic delay is <1.3 ms (Temperature 11.5 to 15° C).During backward swimming radial muscle fibres in the endoderm contract isometrically providing the Claus’ fibres with a firm foundation.Summary StatementNanomia colonies have specialized swimming bells capable of backwards swimming; thrust is redirected by an epithelial signal that leads to muscle contraction via a synaptic rather than an electrotonic event.
Effect of shear and tensile loading on fibrin molecular structure revealed by coherent Raman microscopy
Authors: Wang Yujen , Kumar Sachin , Nisar Arsalan , Bonn Mischa , Rausch Manuel K. , Parekh Sapun H. 
Published: July 2020

AbstractBlood clots are essential biomaterials that prevent blood loss and provide a temporary scaffold for tissue repair. In their function, these materials must be capable of resisting mechanical forces from hemodynamic shear and contractile tension without rupture. Fibrin networks, the primary load-bearing element in blood clots, have unique nonlinear mechanical properties resulting from their hierarchical structure, which provides multiscale load bearing from fiber deformation to protein unfolding. Here, we study the fiber and molecular scale response of fibrin under shear and tensile loadsin situusing a combination of fluorescence and vibrational (molecular) microscopy. Imaging protein fiber orientation and molecular vibrations, we find that fiber orientation and molecular changes in fibrin appear at much larger strains under shear compared to uniaxial tension. Orientation levels reached at 150% shear strain were reached already at 60% tensile strain, and molecular unfolding of fibrin was only seen at shear strains above 300%, whereas fibrin unfolding began already at 20% tensile strain. Moreover, shear deformation caused progressive changes in vibrational modes consistent with increased protofibril and fiber packing that were already present even at very low tensile deformation. Together with a bioinformatic analysis of the fibrinogen primary structure, we propose a scheme for the molecular response of fibrin from low to high deformation, which may relate to the teleological origin of its resistance to shear and tensile forces.Graphical Abstract
A Sequence determinant in 3’UTR of mRNAs for Nuclear Retention by Paraspeckles
Authors: Jacq Audrey , Becquet Denis , Boyer Bénédicte , Guillen Séverine , Bello-Goutierrez Maria-Montserrat , Blanchard Marie-Pierre , Villard Claude , Belghazi Maya , Torres Manon , Franc Jean-Louis , François-Bellan Anne-Marie 
Published: July 2020

ABSTRACTParaspeckles are nuclear membraneless structures composed of a long non-coding RNA, Nuclear-Enriched-Abundant-Transcript-1 and RNA binding proteins, which associate numerous mRNAs. It is therefore believed that their cellular function is to sequester in the nucleus their associated proteins and/or target mRNAs. However, little is known about the molecular determinant in mRNA targets that allow their association to paraspeckles except that inverted repeats of Alu sequences (IRAlu) present in 3’UTR of mRNAs may allow this association. While in a previous study we established the list of paraspeckle target RNAs in a rat pituitary cell line, we didn’t find however, inverted repeated SINEs, the rat equivalent of primate IRAlus in 3’UTR of these RNAs. By developing a candidate gene strategy, we selected a paraspeckle target gene, namely calreticulin mRNA, and we searched for other potential RNA recruitment elements in its 3’UTR, since 3’UTRs usually contain the sequence recognition for nuclear localization. We found a 15-nucleotide sequence, present as a tandem repeat in 3’UTR of this mRNA, which is involved in the nuclear retention by paraspeckles. While being not overrepresented in the 3’UTR of the paraspeckle target RNAs, this recruitment element was present in near 30% of all 3’UTR mRNAs. In addition, since an oligonucleotide containing this sequence binds the paraspeckle protein component HNRNPK, it is proposed that HNRNPK may constitute a bridging protein between paraspeckles and target mRNAs.
3D Microwell Platforms for Control of Single Cell 3D Geometry and Intracellular Organization
Authors: Wilson Robin E. , Denisin Aleksandra K. , Dunn Alexander R. , Pruitt Beth L. 
Published: July 2020

AbstractIntroductionCell structure and migration is impacted by the mechanical properties and geometry of the cell adhesive environment. Most studies to date investigating the effects of 3D environments on cells have not controlled geometry at the single-cell level, making it difficult to understand the influence of 3D environmental cues on single cells. Here, we developed microwell platforms to investigate the effects of 2D vs 3D geometries on single-cell F-actin and nuclear organization.MethodsWe used microfabrication techniques to fabricate three polyacrylamide platforms: 3D microwells with a 3D adhesive environment (3D/3D), 3D microwells with 2D adhesive areas at the bottom only (3D/2D), and flat 2D gels with 2D patterned adhesive areas (2D/2D). We measured geometric swelling and Young’s modulus of the platforms. We then cultured C2C12 myoblasts on each platform and evaluated the effects of the engineered microenvironments on F-actin structure and nuclear shape.ResultsWe tuned the mechanical characteristics of the microfabricated platforms by manipulating the gel formulation. Crosslinker ratio strongly influenced geometric swelling whereas total polymer content primarily affected Young’s modulus. When comparing cells in these platforms, we found significant effects on F-actin and nuclear structures. Our analysis showed that a 3D/3D environment was necessary to increase actin and nuclear height. A 3D/2D environment was sufficient to increase actin alignment and nuclear aspect ratio compared to a 2D/2D environment.ConclusionsUsing our novel polyacrylamide platforms, we were able to decouple the effects of 3D confinement and adhesive environment, finding that both influenced actin and nuclear structure.
Biology and physics of heterochromatin-likedomains/complexes
Authors: Singh Prim B. , Belyakin Stepan N. , Laktionov Petr P. 
Published: July 2020

AbstractThe hallmarks of constitutive heterochromatin, HP1 and H3K9me2/3, assemble heterochromatin-likedomains/complexesoutsidecanonical constitutively heterochromatic territories where they regulate chromatin-templated processes. Domains are more than 100kb in size; complexes less than 100kb. They are present in the genomes of organisms ranging from fission yeast to man, with an expansion in size and number in mammals. Some of the likely functions of the domains/complexes include silencing of the donor mating type region in fission yeast, regulation of mammalian imprinted genes and the phylotypic progression during vertebrate development. Farcis- andtrans-contacts between micro-phase separated domains/complexes in mammalian nuclei contribute to the emergence of epigenetic compartmental domains (ECDs) detected in Hi-C maps. We speculate that a thermodynamic description of micro-phase separation of heterochromatin-likedomains/complexes will require a gestalt shift away from the monomer as the “unit of incompatibility”, where it is the choice of monomer that determines the sign and magnitude of the Flory-Huggins parameter, χ. Instead, a more dynamic structure, the oligo-nucleosomal “clutch”, consisting of between 2 to 10 nucleosomes is both the long sought-after secondary structure of chromatin and its unit of incompatibility. Based on this assumption we present a simple theoretical framework that enables an estimation of χ for domains/complexes flanked by euchromatin and thereby an indication of their tendency to phase separate. The degree of phase separation is specified by χN, where N is the number of “clutches” in a domain/complex. Our approach may provide an additional tool for understanding the biophysics of the 3D genome.
Modelling cortical laminar connectivity in the macaque brain
Authors: Shamir Ittai , Assaf Yaniv 
Published: July 2020

AbstractIn 1991, Felleman and Van Essen published their seminal study regarding hierarchical processing in the primate cerebral cortex. Their work encompassed a widescale analysis of connections reported through tracing between 35 regions in the macaque visual cortex, extending from cortical regions to the laminar level. In this work, we revisit laminar-level connectivity in the macaque brain using a whole-brain MRI-based approach. We use multi-modal ex-vivo MRI imaging of the macaque brain in both white and grey matter, which are then integrated via a simple model of laminar connectivity. This model uses a granularity-based approach to define a set of rules that expands cortical connections to the laminar level. Different fiber tracking routines are then examined in order to explore the ability of our model to infer laminar connectivity. The network of macaque cortical laminar connectivity resulting from the chosen routine is then validated in the visual cortex by comparison to findings from Felleman and Van Essen with an 83% accuracy level. By using a more comprehensive definition of the cortex that addresses its heterogenous laminar composition, we can explore a new avenue of structural connectivity on the laminar level.
Regression of Human Breast Carcinoma in Nude Mice After AdsfltGene Therapy is Mediated by Tumor Vascular Endothelial Cell Apoptosis
Authors: Felici Angelina , Bottaro Donald P. , Mangoni Antonella , Reusch Petra , Marmé Dieter , Kovesdi Imre , De Silva Dinuka M. , Lee Young H. , Capogrossi Maurizio C. , Mühlhauser Judith 
Published: July 2020

AbstractTwo vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibitin vivoneoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks tumors were injected either with Adsflt, or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Adsflt-infected group (33 ± 22 mm3) was decreased by 91% relative to that of the negative control group (388 ± 94 mm3;P<0.05). Moreover, 10 of 15 Adsflt-infected tumors exhibited complete regression. The vascular density in Adsflt-infected tumors was reduced by 50% relative to that of negative controls (P<0.05), consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Adsflt–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Adsfltintratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects.