bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of cytosine modifications on DNA flexibility and nucleosome mechanical stability
Authors: Ngo Thuy T. M. , Yoo Jejoong , Dai Qing , Zhang Qiucen , He Chuan , Aksimentiev Aleksei , Ha Taekjip 
Published: February 2016

AbstractCytosine can undergo modifications, forming 5-methylcytosine (5-mC) and its oxidized products 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). Despite their importance as epigenetic markers and as central players in cellular processes, it is not well understood how these modifications influence physical properties of DNA and chromatin. Here we report a comprehensive survey of the effect of cytosine modifications on DNA flexibility. We find that even a single copy of 5-fC increases DNA flexibility markedly. 5-mC reduces and 5-hmC enhances flexibility, and 5-caC does not have a measurable effect. Molecular dynamics simulations show that these modifications promote or dampen structural fluctuations, likely through competing effects of base polarity and steric hindrance, without changing the average structure. The increase in DNA flexibility increases the mechanical stability of the nucleosome and vice versa, suggesting a gene regulation mechanism where cytosine modifications change the accessibility of nucleosomal DNA through their effects on DNA flexibility.
The role of kinetic context in apparent biased agonism at GPCRs
Authors: Klein Herenbrink Carmen , Sykes David A. , Donthamsetti Prashant , Canals Meritxell , Coudrat Thomas , Shonberg Jeremy , Scammells Peter J. , Capuano Ben , Sexton Patrick M. , Charlton Steven J. , Javitch Jonathan A. , Christopoulos Arthur , Lane J. Robert 
Published: February 2016

AbstractBiased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.
Subnanometre enzyme mechanics probed by single-molecule force spectroscopy
Authors: Pelz Benjamin , Žoldák Gabriel , Zeller Fabian , Zacharias Martin , Rief Matthias 
Published: February 2016

AbstractEnzymes are molecular machines that bind substrates specifically, provide an adequate chemical environment for catalysis and exchange products rapidly, to ensure fast turnover rates. Direct information about the energetics that drive conformational changes is difficult to obtain. We used subnanometre single-molecule force spectroscopy to study the energetic drive of substrate-dependent lid closing in the enzyme adenylate kinase. Here we show that in the presence of the bisubstrate inhibitor diadenosine pentaphosphate (AP5A), closing and opening of both lids is cooperative and tightly coupled to inhibitor binding. Surprisingly, binding of the substrates ADP and ATP exhibits a much smaller energetic drive towards the fully closed state. Instead, we observe a new dominant energetic minimum with both lids half closed. Our results, combining experiment and molecular dynamics simulations, give detailed mechanical insights into how an enzyme can cope with the seemingly contradictory requirements of rapid substrate exchange and tight closing, to ensure efficient catalysis.
Differences in the Pulsatile Component of the Skin Hemodynamic Response to Verbal Fluency Tasks in the Forehead and the Fingertip
Authors: Takahashi Toshimitsu , Takikawa Yoriko , Kawagoe Reiko 
Published: February 2016

AbstractSeveral studies have claimed that hemodynamic signals measured by near-infrared spectroscopy (NIRS) on the forehead exhibit different patterns during a verbal fluency task (VFT) in various psychiatric disorders, whereas many studies have noted that NIRS signals can reflect task-related changes in skin blood flow. If such a task-related skin hemodynamic response is also observed in the fingertip, a simpler biomarker may be developed. Furthermore, determining the difference in the response pattern may provide physiological insights into the condition. We found that the magnitude of the pulsatile component in skin hemodynamic signals increased on the forehead (p < 0.001 for N = 50, p = 0.073 for N = 8) but decreased on the fingertip (p < 0.001, N = 8) during the VFT, whereas the rate in both areas increased (p < 0.02, N = 8). We also did not find a repetition effect in both the rate and the magnitude on the fingertip, whereas the effect was present in the magnitude (p < 0.02, N = 8) but not in the rate on the forehead. These results suggest that the skin vasomotor system in the forehead could have a different vessel mechanism to psychological tasks compared to the fingertip.
Camphor-mediated synthesis of carbon nanoparticles, graphitic shell encapsulated carbon nanocubes and carbon dots for bioimaging
Authors: Oza Goldie , Ravichandran M. , Merupo Victor-Ishrayelu , Shinde Sachin , Mewada Ashmi , Ramirez Jose Tapia , Velumani S. , Sharon Madhuri , Sharon Maheshwar 
Published: February 2016

AbstractA green method for an efficient synthesis of water-soluble carbon nanoparticles (CNPs), graphitic shell encapsulated carbon nanocubes (CNCs), Carbon dots (CDs) using Camphor (Cinnamomum camphora) is demonstrated. Here, we describe a competent molecular fusion and fission route for step-wise synthesis of CDs. Camphor on acidification and carbonization forms CNPs, which on alkaline hydrolysis form CNCs that are encapsulated by thick graphitic layers and on further reduction by sodium borohydride yielded CDs. Though excitation wavelength dependent photoluminescence is observed in all the three carbon nanostructures, CDs possess enhanced photoluminescent properties due to more defective carbonaceous structures. The surface hydroxyl and carboxyl functional groups make them water soluble in nature. They possess excellent photostability, higher quantum yield, increased absorption, decreased cytotoxicity and hence can be utilized as a proficient bio imaging agent.
Stiffening hydrogels for investigating the dynamics of hepatic stellate cell mechanotransduction during myofibroblast activation
Authors: Caliari Steven R. , Perepelyuk Maryna , Cosgrove Brian D. , Tsai Shannon J. , Lee Gi Yun , Mauck Robert L. , Wells Rebecca G. , Burdick Jason A. 
Published: February 2016

AbstractTissue fibrosis contributes to nearly half of all deaths in the developed world and is characterized by progressive matrix stiffening. Despite this, nearly all in vitro disease models are mechanically static. Here, we used visible light-mediated stiffening hydrogels to investigate cell mechanotransduction in a disease-relevant system. Primary hepatic stellate cell-seeded hydrogels stiffened in situ at later time points (following a recovery phase post-isolation) displayed accelerated signaling kinetics of both early (Yes-associated protein/Transcriptional coactivator with PDZ-binding motif, YAP/TAZ) and late (alpha-smooth muscle actin, α-SMA) markers of myofibroblast differentiation, resulting in a time course similar to observed in vivo activation dynamics. We further validated this system by showing that α-SMA inhibition following substrate stiffening resulted in attenuated stellate cell activation, with reduced YAP/TAZ nuclear shuttling and traction force generation. Together, these data suggest that stiffening hydrogels may be more faithful models for studying myofibroblast activation than static substrates and could inform the development of disease therapeutics.
A Novel Method to Simulate the Progression of Collagen Degeneration of Cartilage in the Knee: Data from the Osteoarthritis Initiative
Authors: Mononen Mika E. , Tanska Petri , Isaksson Hanna , Korhonen Rami K. 
Published: February 2016

AbstractWe present a novel algorithm combined with computational modeling to simulate the development of knee osteoarthritis. The degeneration algorithm was based on excessive and cumulatively accumulated stresses within knee joint cartilage during physiological gait loading. In the algorithm, the collagen network stiffness of cartilage was reduced iteratively if excessive maximum principal stresses were observed. The developed algorithm was tested and validated against experimental baseline and 4-year follow-up Kellgren-Lawrence grades, indicating different levels of cartilage degeneration at the tibiofemoral contact region. Test groups consisted of normal weight and obese subjects with the same gender and similar age and height without osteoarthritic changes. The algorithm accurately simulated cartilage degeneration as compared to the Kellgren-Lawrence findings in the subject group with excess weight, while the healthy subject group’s joint remained intact. Furthermore, the developed algorithm followed the experimentally found trend of cartilage degeneration in the obese group (R2 = 0.95, p < 0.05; experiments vs. model), in which the rapid degeneration immediately after initiation of osteoarthritis (0–2 years, p < 0.001) was followed by a slow or negligible degeneration (2–4 years, p > 0.05). The proposed algorithm revealed a great potential to objectively simulate the progression of knee osteoarthritis.
Different pollinator assemblages ensure reproductive success of Cleisostoma linearilobatum (Orchidaceae) in fragmented holy hill forest and traditional tea garden
Authors: Zhou Xiang , Liu Qiang , Han Jessie Yc , Gao JiangYun 
Published: February 2016

AbstractOrchids are generally recognized to have specialist pollination systems and low fruit set is often thought to be characteristic of the family. In this study, we investigated the reproductive ecology of Cleisostoma linearilobatum, an epiphytic tropical orchid, in a holy hill forest fragment and a traditional tea garden in SW China using comparable methods. C. linearilobatum is self-compatible and dependent on insects for pollination. Fruit production in natural conditions was both pollinator- and resource-limited. However, the natural fruit set remained stable over multiple years at both sites. Pollination observations showed that C. linearilobatum has a generalized pollination system and seven insect species were observed as legitimate pollinators. Although the visit frequencies of different pollinators were different in the two sites, the pollinator assemblages ensured reproductive success of C. linearilobatum in both study sites over multiple years. The results partly explain why C. linearilobatum is so successful in the area and also suggest that holy hill forest fragments and traditional tea gardens in Xishuangbanna are important in preserving orchids, especially those with generalist pollination.
Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification
Authors: Liu Ling , Liu Xu , Ren Xudong , Tian Yue , Chen Zhenyu , Xu Xiangjie , Du Yanhua , Jiang Cizhong , Fang Yujiang , Liu Zhongliang , Fan Beibei , Zhang Quanbin , Jin Guohua , Yang Xiao , Zhang Xiaoqing 
Published: February 2016

AbstractThe transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events.
The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression
Authors: de Bruin Ruben G. , van der Veer Eric P. , Prins Jurriën , Lee Dae Hyun , Dane Martijn J. C. , Zhang Huayu , Roeten Marko K. , Bijkerk Roel , de Boer Hetty C. , Rabelink Ton J. , van Zonneveld Anton Jan , van Gils Janine M. 
Published: February 2016

AbstractProper regulation of endothelial cell-cell contacts is essential for physiological functioning of the endothelium. Interendothelial junctions are actively involved in the control of vascular leakage, leukocyte diapedesis and the initiation and progression of angiogenesis. We found that the RNA-binding protein quaking is highly expressed by endothelial cells and that its expression was augmented by prolonged culture under laminar flow and the transcription factor KLF2 binding to the promoter. Moreover, we demonstrated that quaking directly binds to the mRNA of VE-cadherin and β-catenin and can induce mRNA translation mediated by the 3′UTR of these genes. Reduced quaking levels attenuated VE-cadherin and β-catenin expression and endothelial barrier function in vitro and resulted in increased bradykinin-induced vascular leakage in vivo. Taken together, we report that quaking is essential in maintaining endothelial barrier function. Our results provide novel insight into the importance of post-transcriptional regulation in controlling vascular integrity.
The uncoupled ATPase activity of the ABC transporter BtuC2D2 leads to a hysteretic conformational change, conformational memory and improved activity
Authors: Livnat-Levanon Nurit , I. Gilson Amy , Ben-Tal Nir , Lewinson Oded 
Published: February 2016

AbstractABC transporters comprise a large and ubiquitous family of proteins. From bacteria to man they translocate solutes at the expense of ATP hydrolysis. Unlike other enzymes that use ATP as an energy source, ABC transporters are notorious for having high levels of basal ATPase activity: they hydrolyze ATP also in the absence of their substrate. It is unknown what are the effects of such prolonged and constant activity on the stability and function of ABC transporters or any other enzyme. Here we report that prolonged ATP hydrolysis is beneficial to the ABC transporter BtuC2D2. Using ATPase assays, surface plasmon resonance interaction experiments and transport assays we observe that the constantly active transporter remains stable and functional for much longer than the idle one. Remarkably, during extended activity the transporter undergoes a slow conformational change (hysteresis) and gradually attains a hyperactive state in which it is more active than it was to begin with. This phenomenon is different from stabilization of enzymes by ligand binding: the hyperactive state is only reached through ATP hydrolysis and not ATP binding. BtuC2D2 displays a strong conformational memory for this excited state and takes hours to return to its basal state after catalysis terminates.
Carbonate-based Janus micromotors moving in ultra-light acidic environment generated by HeLa cells in situ
Authors: Guix Maria , Meyer Anne K. , Koch Britta , Schmidt Oliver G. 
Published: February 2016

AbstractNovel approaches to develop naturally-induced drug delivery in tumor environments in a deterministic and controlled manner have become of growing interest in recent years. Different polymeric-based microstructures and other biocompatible substances have been studied taking advantage of lactic acidosis phenomena in tumor cells, which decrease the tumor extracellular pH down to 6.8. Micromotors have recently demonstrated a high performance in living systems, revealing autonomous movement in the acidic environment of the stomach or moving inside living cells by using acoustic waves, opening the doors for implementation of such smart microengines into living entities. The need to develop biocompatible motors which are driven by natural fuel sources inherently created in biological systems has thus become of crucial importance. As a proof of principle, we here demonstrate calcium carbonate Janus particles moving in extremely light acidic environments (pH 6.5), whose motion is induced in conditioned acidic medium generated by HeLa cells in situ. Our system not only obviates the need for an external fuel, but also presents a selective activation of the micromotors which promotes their motion and consequent dissolution in presence of a quickly propagating cell source (i.e. tumor cells), therefore inspiring new micromotor configurations for potential drug delivery systems.
Unique Loss of the PYHIN Gene Family in Bats Amongst Mammals: Implications for Inflammasome Sensing
Authors: Ahn Matae , Cui Jie , Irving Aaron T. , Wang Lin-Fa 
Published: February 2016

AbstractRecent genomic analysis of two bat species (Pteropus alecto and Myotis davidii) revealed the absence of the PYHIN gene family. This family is recognized as important immune sensors of intracellular self and foreign DNA and activators of the inflammasome and/or interferon pathways. Further assessment of a wider range of bat genomes was necessary to determine if this is a universal pattern for this large mammalian group. Here we expanded genomic analysis of this gene family to include ten bat species. We confirmed the complete loss of this gene family, with only a truncated AIM2 remaining in one species (Pteronotus parnellii). Divergence of the PYHIN gene loci between the bat lineages infers different loss-of-function histories during bat evolution. While all other major groups of placental mammals have at least one gene member, only bats have lost the entire family. This removal of inflammasome DNA sensors may indicate an important adaptation that is flight-induced and related, at least in part, to pathogen-host co-existence.
Picosecond optical vortex pulse illumination forms a monocrystalline silicon needle
Authors: Takahashi Fuyuto , Miyamoto Katsuhiko , Hidai Hirofumi , Yamane Keisaku , Morita Ryuji , Omatsu Takashige 
Published: February 2016

AbstractThe formation of a monocrystalline silicon needle by picosecond optical vortex pulse illumination was demonstrated for the first time in this study. The dynamics of this silicon needle formation was further revealed by employing an ultrahigh-speed camera. The melted silicon was collected through picosecond pulse deposition to the dark core of the optical vortex, forming the silicon needle on a submicrosecond time scale. The needle was composed of monocrystalline silicon with the same lattice index (100) as that of the silicon substrate and had a height of approximately 14 μm and a thickness of approximately 3 μm. Overlaid vortex pulses allowed the needle to be shaped with a height of approximately 40 μm without any changes to the crystalline properties. Such a monocrystalline silicon needle can be applied to devices in many fields, such as core–shell structures for silicon photonics and photovoltaic devices as well as nano- or microelectromechanical systems.
Spin-communication channels between Ln(III) bis-phthalocyanines molecular nanomagnets and a magnetic substrate
Authors: Candini A. , Klar D. , Marocchi S. , Corradini V. , Biagi R. , De Renzi V. , del Pennino U. , Troiani F. , Bellini V. , Klyatskaya S. , Ruben M. , Kummer K. , Brookes N. B. , Huang H. , Soncini A. , Wende H. , Affronte M. 
Published: February 2016

AbstractLearning the art of exploiting the interplay between different units at the atomic scale is a fundamental step in the realization of functional nano-architectures and interfaces. In this context, understanding and controlling the magnetic coupling between molecular centers and their environment is still a challenging task. Here we present a combined experimental-theoretical work on the prototypical case of the bis(phthalocyaninato)-lanthanide(III) (LnPc2) molecular nanomagnets magnetically coupled to a Ni substrate. By means of X-ray magnetic circular dichroism we show how the coupling strength can be tuned by changing the Ln ion. The microscopic parameters of the system are determined by ab-initio calculations and then used in a spin Hamiltonian approach to interpret the experimental data. By this combined approach we identify the features of the spin communication channel: the spin path is first realized by the mediation of the external (5d) electrons of the Ln ion, keeping the characteristic features of the inner 4 f orbitals unaffected, then through the organic ligand, acting as a bridge to the external world.
Expression of the innate immune receptor LILRB5 on monocytes is associated with mycobacteria exposure
Authors: Hogan Louise E. , Jones Des C. , Allen Rachel L. 
Published: February 2016

AbstractAntigen presenting cells (APC) are critical components of innate immunity and consequently shape the adaptive response. Leukocyte Ig Like Receptors (LILR) are innate immune receptors predominantly expressed on myeloid cells. LILR can influence the antigen presenting phenotype of monocytic cells to determine the nature of T cell responses in infections including Mycobaterium leprae. We therefore investigated the relevance of LILR in the context of Mycobacterium tuberculosis. Real-time PCR studies indicated that the transcriptional profile of the orphan receptor LILRB5 was significantly up-regulated following exposure to mycobacteria. Furthermore, LILRA1 and LILRB5 were able to trigger signalling through direct engagement of mycobacteria using tranfectant cells incorporating a reporter system. We describe for the first time the expression of this receptor on T cells, and highlight the potential relevance to mycobacterial recognition. Furthermore, we demonstrate that crosslinking of this receptor on T cells increases proliferation of cytotoxic, but not helper, T cells.