bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coarse-grained implicit solvent lipid force field with a compatible resolution to the Cα protein representation
Authors: La Torre Diego Ugarte , Takada Shoji 
Published: September 2020

AbstractBiological membranes have been prominent targets for coarse-grained (CG) molecular dynamics (MD) simulations. While minimal CG lipid models with three-beads per lipid and quantitative CG lipid models with >10-beads per lipid have been well studied, in between them, CG lipid models with a compatible resolution to residue-level CG protein models are much less developed. Here, we extended a previously developed three-bead lipid model into a five-bead model and parametrized it for two phospholipids, POPC and DPPC. The developed model, iSoLF, reproduced the area per lipid, hydrophobic thickness, and phase behaviors of the target phospholipid bilayer membranes at the physiological temperature. The model POPC and DPPC membranes were in liquid and gel phases, respectively, in accordance with experiments. We further examined the spontaneous formation of a membrane bilayer, the temperature dependence of physical properties, vesicle dynamics, and the POPC/DPPC two-component membrane dynamics of the CG lipid model, showing some promise. Once combined with standard Cα protein models, the iSoLF model will be a powerful tool to simulate large biological membrane systems made of lipids and proteins.
Neuroglia Infection by Rabies Virus after Anterograde Virus Spread in Peripheral Neurons
Authors: Potratz Madlin , Zaeck Luca M. , Weigel Carlotta , Klein Antonia , Freuling Conrad M. , Müller Thomas , Finke Stefan 
Published: September 2020

AbstractThe highly neurotropic rabies virus (RABV) enters peripheral neurons at axon termini and requires long distance axonal transport and trans-synaptic spread between neurons for the infection of the central nervous system (CNS). Whereas laboratory strains are almost exclusively detected in neurons, recent 3D imaging of field RABV-infected brains revealed an remarkably high proportion of infected astroglia, indicating that in contrast to attenuated lab strains highly virulent field viruses are able to suppress astrocyte mediated innate immune responses and virus elimination pathways. While fundamental for CNS invasion,in vivofield RABV spread and tropism in peripheral tissues is understudied. Here, we used three-dimensional light sheet and confocal laser scanning microscopy to investigate thein vivodistribution patterns of a field RABV clone in cleared high-volume tissue samples after infection via a natural (intramuscular; hind leg) and an artificial (intracranial) inoculation route. Immunostaining of virus and host markers provided a comprehensive overview of RABV infection in the CNS and peripheral nerves after centripetal and centrifugal virus spread. Importantly, we identified non-neuronal,axon-ensheathing neuroglia (Schwann cells, SCs) in peripheral nerves of the hind leg and facial regions as a target cell population of field RABV. This suggest that virus release from axons and infected SCs is part of the RABVin vivocycle and may affect RABV-related demyelination of peripheral neurons and local innate immune responses. Detection of RABV in axon surrounding myelinating SCs after i.c. infection further provided evidence for anterograde spread of RABV, highlighting that RABV axonal transport and spread of infectious virus in peripheral nerves is not exclusively retrograde. Our data support a new model in which, comparable to CNS neuroglia, SC infection in peripheral nerves suppresses glia-mediated innate immunity and delays antiviral host responses required for successful transport from the peripheral infection sites to the brain.
Filopodia rotate and coil by actively generating twist in their actin shaft
Authors: Leijnse Natascha , Barooji Younes Farhangi , Verhagen Bram , Wullkopf Lena , Erler Janine Terra , Semsey Szabolcs , Nylandsted Jesper , Doostmohammadi Amin , Oddershede Lene Broeng , Bendix Poul Martin 
Published: September 2020

AbstractFilopodia are actin-rich structures, present on the surface of practically every known eukaryotic cell. These structures play a pivotal role in specific cell-cell and cell-matrix interactions by allowing cells to explore their environment, generate mechanical forces, perform chemical signaling, or convey signals via intercellular tunneling nano-bridges. The dynamics of filopodia appear quite complex as they exhibit a rich behavior of buckling, pulling, length and shape changes. Here, we find that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling of their actin rich core. Importantly, we show the rotational dynamics of the filamentous actin inside filopodia for a range of highly distinct and cognate cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist, and hence rotation, is an emergent phenomenon of active filaments confined in a narrow channel which points to a generic mechanism present in all cells. Our measurements confirm that filopodia exert traction forces and form helical buckles in a range of different cell types that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia.
HillTau: A fast, compact abstraction for model reduction in biochemical signaling networks
Authors: Bhalla Upinder S. 
Published: September 2020

AbstractSignaling networks mediate many aspects of cellular function. The conventional, mechanistically motivated approach to modeling such networks is through mass-action chemistry, which maps directly to biological entities and facilitates experimental tests and predictions. However such models are complex, need many parameters, and are computationally costly. Here we introduce the HillTau form for signaling models. HillTau retains the direct mapping to biological observables, but it uses far fewer parameters, and is 100 to over 1000 times faster than ODE-based methods. In the HillTau formalism, the steady-state concentration of signaling molecules is approximated by the Hill equation, and the dynamics by a time-coursetau. We demonstrate its use in implementing several biochemical motifs, including association, inhibition, feedforward and feedback inhibition, bistability, oscillations, and a synaptic switch obeying the BCM rule. The major use-cases for HillTau are system abstraction, model reduction, scaffolds for data-driven optimization, and fast approximations to complex cellular signaling.Author summaryChemical signals mediate many computations in cells, from housekeeping functions in all cells to memory and pattern selectivity in neurons. These signals form complex networks of interactions. Computer models are a powerful way to study how such networks behave, but it is hard to get all the chemical details for typical models, and it is slow to run them with standard numerical approaches to chemical kinetics. We introduce HillTau as a simplified way to model complex chemical networks. HillTau models condense multiple reaction steps into single steps defined by a small number of parameters for activation and settling time. As a result the models are simple, easy to find values for, and they run quickly. Remarkably, they fit the full chemical formulations rather well. We illustrate the utility of HillTau for modeling several signaling network functions, and for fitting complicated signaling networks.
Cardiniumsymbiosis as a potential confounder of mtDNA based phylogeographic inference inCulicoides imicola(Diptera: Ceratopogonidae), a vector of veterinary viruses
Authors: Pilgrim Jack , Siozios Stefanos , Baylis Matthew , Venter Gert , Garros Claire , Hurst Gregory D. D. 
Published: September 2020

AbstractCulicoides imicola(Diptera: Ceratopogonidae) is an important Afrotropical and Palearctic vector of disease, transmitting viruses of animal health and economic significance. The apparent incursions ofC. imicolainto mainland Europe via wind-movement events has made it important to trace this species to better predict new areas of arbovirus outbreaks. A widely used method for tracking dispersal patterns ofC. imicolaemploys a phylogeographic approach anchored on the mtDNA markerCOI(cytochrome c oxidase subunit I). However, a problem with this approach is that maternally-inherited symbiotic bacteria can alter the frequency ofCOImitochondrial haplotypes (mitotypes), masking the true patterns of movement and gene flow. In this study, we investigate possible associations of the symbiontCardiniumwithC. imicolamitotype distribution. Haplotype network analysis indicates the concordance of specific mitotypes withCardiniuminfection status inC. imicolapopulations from the Mediterranean basin and South Africa. This observation urges caution on the single usage of theCOImarker to determine population structure and movement inC. imicola, and instead suggests the complementary utilisation of additional molecular markers (e.g. microsatellites and nuclear markers).
DNA-Origami-Based Fluorescence Brightness Standards for Convenient and Fast Protein Counting in Live Cells
Authors: Williams Nathan D. , Landajuela Ane , Kasula Ravi Kiran , Zhou Wenjiao , Powell John T. , Xi Zhiqun , Isaacs Farren J. , Berro Julien , Toomre Derek , Karatekin Erdem , Lin Chenxiang 
Published: September 2020

AbstractFluorescence microscopy has been one of the most discovery-rich methods in biology. In the digital age, the discipline is becoming increasingly quantitative. Virtually all biological laboratories have access to fluorescence microscopes, but abilities to quantify biomolecule copy numbers are limited by the complexity and sophistication associated with current quantification methods. Here, we present DNA-origami-based fluorescence brightness standards for counting 5–300 copies of proteins in mammalian and bacterial cells, tagged with fluorescent proteins or organic dyes. Compared to conventional quantification techniques, our brightness standards are robust, straightforward to use, and compatible with nearly all fluorescence imaging applications, thereby providing a practical and versatile tool to quantify biomoleculesviafluorescence microscopy.
Transmission, tropism and biological impacts of torixRickettsiain the common bed bugCimex lectularius(Hemiptera: Cimicidae)
Authors: Thongprem Panupong , Evison Sophie EF , Hurst Gregory DD , Otti Oliver 
Published: September 2020

ABSTRACTThe torix group ofRickettsiahave been recorded from a wide assemblage of invertebrates, but details of transmission and biological impacts on the host have rarely been established. The common bed bug(Cimex lectularius)is a hemipteran insect which lives as an obligatory hematophagous pest of humans and is host to a primaryWolbachiasymbiont and two facultative symbionts, a BEV-like symbiont, and a torix groupRickettsia. In this study, we first note the presence of a singleRickettsiastrain in multiple laboratory bed bug isolates derived from Europe and Africa. Importantly, we discovered that theRickettsiahas segregated in two laboratory strains, providing infected and uninfected isogenic lines for this study. Crosses with these lines established transmission was purely maternal, in contrast to previous studies of torix infections in planthoppers where paternal infection status was also important. Fluorescencein-situhybridization analysis indicatesRickettsiainfected in oocytes and bacteriomes, and other somatic tissues. There was no evidence thatRickettsiainfection was associated with sex ratio distortion activity, butRickettsiainfected individuals developed from first instar to adult more slowly. The impact ofRickettsiaon fecundity and fertility were investigated.Rickettsiainfected females produced fewer fertile eggs, but there was no evidence for cytoplasmic incompatibility. These data imply the existence of an unknown benefit toC. lectulariuscarryingRickettsiathat awaits further research.
Ligand Modulation of the Conformational Dynamics of the A2AAdenosine Receptor Revealed by Single-Molecule Fluorescence
Authors: Fernandes Dennis D. , Neale Chris , Gomes Gregory-Neal W. , Li Yuchong , Malik Aimen , Pandey Aditya , Orazietti Alexander , Wang Xudong , Ye Libin , Prosser R. Scott , Gradinaru Claudiu C. 
Published: September 2020

ABSTRACTG protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins, making them an important target for therapeutics. Activation of these receptors is modulated by orthosteric ligands, which stabilize one or several states within a complex conformational ensemble. The intra-and inter-state dynamics, however, is not well documented. Here, we used single-molecule fluorescence to measure ligand-modulated conformational dynamics of the adenosine A2AReceptor (A2AR) on nanosecond to millisecond timescales. Experiments were performed on detergent-purified A2R in either the ligand-free (apo) state, or when bound to an inverse, partial or full agonist ligand. Single-molecule Förster resonance energy transfer (smFRET) was performed on detergent-solubilized A2AR to resolve active and inactive states via the separation between transmembrane (TM) helices 4 and 6. The ligand-dependent changes of the smFRET distributions are consistent with conformational selection and with inter-state exchange lifetimes ≥ 3 ms. Local conformational dynamics around residue 229 on TM6 was measured using Fluorescence Correlation Spectroscopy (FCS), which captures dynamic quenching due to photoinduced electron transfer (PET) between a covalently-attached dye and proximal aromatic residues. Global analysis of PET-FCS data revealedfast(150-350 ns),intermediate(50-60 μs) andslow(200-300 μs) conformational dynamics in A2AR, with lifetimes and amplitudes modulated by ligands and a G-protein mimetic (mini-Gs). Most notably, the agonist binding and the coupling to mini-Gsaccelerates and increases the relative contribution of the sub-microsecond phase. Molecular dynamics simulations identified three tyrosine residues (Y112, Y288, and Y290) as being responsible for the dynamic quenching observed by PET-FCS and revealed associated helical motions around residue 229 on TM6. This study provides a quantitative description of conformational dynamics in A2AR and supports the idea that ligands bias not only GPCR conformations but also the dynamics within and between distinct conformational states of the receptor.
Inhibitory synaptic vesicles have unique dynamics and exocytosis properties
Authors: Park Chungwon , Chen Xingxiang , Tian Chong-Li , Park Gyu Nam , Chenouard Nicolas , Lee Hunki , Yeo Xin Yi , Jung Sangyong , Bi Guoqiang , Tsien Richard W. , Park Hyokeun 
Published: September 2020

AbstractMaintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system, with inhibitory synaptic transmission playing an important role. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood. In particular, the dynamics and exocytosis of single inhibitory vesicles have not been investigated, due largely to both technical and practical limitations. Using a combination of quantum dots (QDs) conjugated to antibodies against the luminal domain of the vesicular GABA transporter (VGAT) to selectively label GABAergic (i.e., inhibitory) vesicles together with dual-focus imaging optics, we tracked the real-time three-dimensional position of single inhibitory vesicles up to the moment of exocytosis (i.e., fusion). Using three-dimensional trajectories, we found that inhibitory synaptic vesicles traveled a short distance prior to fusion and had a shorter time to fusion compared to synaptotagmin-1 (Syt1)-labeled vesicles, which were mostly from excitatory neurons. Moreover, our analysis revealed a close correlation between the release probability of inhibitory vesicles and both the proximity to their fusion site and the total travel length. Finally, we found that inhibitory vesicles have a higher prevalence of kiss-and-run fusion compared than Syt1-labeled vesicles. These results indicate that inhibitory synaptic vesicles have a unique set of dynamics and fusion properties to support rapid synaptic inhibition, thereby maintaining a tightly regulated balance between excitation and inhibition in the central nervous system.SignificanceDespite playing an important role in maintaining brain function, the dynamics of inhibitory synaptic vesicles are poorly understood. Here, we tracked the three-dimensional position of single inhibitory vesicles up to the moment of exocytosis in real time by loading single inhibitory vesicle with QDs-conjugated to antibodies against the luminal domain of the vesicular GABA transporter (VGAT). We found that inhibitory synaptic vesicles have a smaller total travel length before fusion, a shorter fusion time, and a higher prevalence of kiss-and-run than synaptotagmin-1-lableled vesicles. Our findings provide the first evidence that inhibitory vesicles have a unique set of dynamics and exocytosis properties to support rapid inhibitory synaptic transmission.
Interaction of replication factor Sld3 and histone acetyl transferase Esa1 alleviates gene silencing and promotes the activation of late and dormant replication origins
Authors: Tanaka Seiji 
Published: September 2020

SUMMARYDNA replication in eukaryotes is a multi-step process that consists of three main reactions: helicase loading (licensing), helicase activation (firing), and nascent DNA synthesis (elongation). Although the contributions of some chromatin regulatory factors in the licensing and elongation reaction have been determined, their functions in the firing reaction remain elusive. In the budding yeastSaccharomyces cerevisiae, Sld3, Sld7, and Cdc45 (3-7-45) are rate-limiting in the firing reaction and simultaneous overexpression of 3-7-45 causes untimely activation of late and dormant replication origins. Here we found that 3-7-45 overexpression not only activated dormant origins in the silenced locus,HMLα, but also exerted an anti-silencing effect at this locus. For these, interaction between Sld3 and Esa1, a conserved histone acetyltransferase, was responsible. Moreover, the Sld3–Esa1 interaction was required for untimely activation of late origins. These results reveal the Sld3–Esa1 interaction as a novel level of regulation in the firing reaction.
Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism
Authors: Bertoni Alessandra , Schaller Fabienne , Tyzio Roman , Gaillard Stephane , Santini Francesca , Xolin Marion , Diabira Diabé , Vaidyanathan Radhika , Matarazzo Valery , Medina Igor , Hammock Elizabeth , Zhang Jinwei , Chini Bice , Gaiarsa Jean-Luc , Muscatelli Françoise 
Published: September 2020

ABSTRACTOxytocin is a master regulator of the social brain. In some animal models of autism, notably inMagel2tm1.1Mus-deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms focusing on social memory performance.We showed thatMagel2tm1.1Mus-deficient mice present a deficit in social memory and studied the hippocampal circuits underlying this memory. We showed a co-expression ofMagel2andoxytocin-receptorin the dentate gyrus and CA2/CA3 hippocampal regions. Then, we demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin-receptors and of somatostatin interneurons. We also revealed a delay in the GABAergic development sequence inMagel2tm1.1Mus-deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring neuronal alterations and social memory.Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin-administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.
HRM as a catalyst for innovation in start‐ups
Authors: Jebali Dorra , Meschitti Viviana 
Published: September 2020

PurposeThe study seeks to reduce the blurriness remaining around the value that HRM can bring to innovation in the specific context of start‐ups, it advocates that the early adoption of appropriate HRM practices, can act as a catalyst for innovation because they constitute a powerful means to systematically promote and facilitate employees' innovative behaviours.Design/methodology/approachIn the aim of complementing the existing quantitative work, this paper employs a multiple case study approach to explore the role of HRM in fostering employees' innovative work behaviour in four Tunisian tech companies.FindingsThe study found substantial support for the importance of establishing a work environment for learning where employees can build their innovative capacities by upgrading their knowledge and skills through both formal and informal methods. Work autonomy and freedom are found to be essential parts of this environment. Workspace design that takes into account employees' comfort and the collaborative nature of their work, also stands out as a major contributor to innovative work behaviour.Originality/valueThe adopted qualitative approach enabled a grasp of the less apparent aspects underpinning the HRM and innovation relationship in start‐ups. “Ownership of space” is revealed as a key element of the innovation-supportive work environment. By having a feeling of control on the workspace, employees can develop a sense of ownership towards the organisation which enhances their eagerness to exert innovation efforts. It also demonstrated that developing an overly creative workforce can turn into a source of stagnation which can be mitigated by cultivating “an environment for idea ownership”.
Prevalence and association of discrimination and bullying and the impact on mental health in an occupational setting
Authors: Stratton Elizabeth , Player Michael J. , Dahlheimer Ariane , Choi Isabella , Glozier Nicholas 
Published: September 2020

PurposeDiscrimination and bullying contribute to mental ill-health in the workplace. At face value, they would seem linked but are often dealt with by different legislations. Workplace studies generally focus on bullying and population studies on discrimination. The authors aimed to evaluate the prevalence and relationship of discrimination and bullying in a male-dominated workforce, associated factors and relative impact on mental ill-health.Design/methodology/approachAn online cohort survey was conducted amongst employees of an Australian mining company, measuring discrimination, bullying, demographics and workplace and health factors over two months. Cross-sectional and prospective analyses assessed the prevalence of each, their association and their effects on depression and anxiety.FindingsA total of 580 employees (82% male) participated. There was no association between workplace bullying (n = 56, 9.7%) and discrimination (n = 160, 27.6%). Discrimination, but not bullying, was associated with higher depression, anxiety and suicidal ideation and lower well-being and resilience. After controlling for demographic, workplace and health and well-being factors, depression had the main effect on discrimination ß = 0.39, p = 0.003. Discrimination predicted an increase in depression scores at follow-up F (1, 129) = 4.88, p = 0.029.Originality/valueIn this male-dominated industry, discrimination was more prevalent than bullying. Discrimination, but not bullying, was associated with poorer mental health both cross sectionally and prospectively. Supporting the need to assess and manage discrimination and bullying in the workplace independently and the need for interventions to reduce a broader range of adverse interpersonal behaviours.