bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Nonequilibrium Mechanism of Noise Enhancer synergizing with Activator in HIV Latency Reactivation
Authors: Guo Xiaolu , Tang Tao , Duan Minxuan , Zhang Lei , Ge Hao 
Published: January 2020

SummaryReactivating HIV latency and then simultaneously eliminating it by antiretroviral therapy has become a leading strategy in curing HIV. Recently, single-cell screening experiments have shown the drug synergy between two categories of biomolecules, Activators (AC) and Noise Enhancers (NE): NE can amplify the reactivation of latent HIV induced by AC, although NE itself cannot reactivate HIV latency. Based on an established LTR-two-state effective model, we uncover two necessary conditions for this type of drug synergy: The decreasing of the turning-on rate of LTR induced by NE is highly inhibited when presented with AC; The timescale of LTR turning off without AC/NE presented should be no slower than the timescale of Tat transactivation. Then we propose a detailed LTR-four-state mechanistic model with both AC/NE regulation kinetics and Tat transactivation circuit. We show that, in order to achieve drug synergy, the system of HIV gene state transition must operate out of thermodynamic equilibrium, which is caused by energy input. The direction of energy input determines whether the inhibition of NE upon the reactivation rate of LTR-off states (unbinding of RNAP) can be successfully prevented in the presence of AC. The drug synergy can also be significantly enhanced if the energy input is appropriately distributed to more than one reaction. Our model reveals a generic nonequilibrium mechanism underpinning the noise enhanced drug synergy, which may apply to identify the same drug synergy on reactivating a diverse class of lentivirus latency.Significance StatementThe “kick and kill” strategy has become a promising way to cure HIV by eliminating latent HIV reservoirs, the main barrier to a clinical cure. Two categories of biomolecules, Activators (AC) and Noise Enhancers (NE), have been found to have synergy on reactivating latent HIV (kick strategy). We uncover the underlying non-equilibrium mechanism of such drug synergy by developing mathematical models based on genetic regulatory kinetics. We find that controlling the magnitude and direction of energy input into genetic regulatory kinetics can prevent NE from reducing the turn-on rate of the inactivated gene state in the presence of AC, which produces the synergy. This general nonequilibrium mechanism can be useful for identifying other drug synergies on lentivirus latency reactivation.
SETD7-mediated lysine monomethylation is abundant on non-hyperphosphorylated nuclear Tau
Authors: Bichmann Maria , Prat Oriol Nuria , Ercan-Herbst Ebru , Schöndorf David C. , Gomez Ramos Borja , Schwärzler Vera , Haberkant Per , Gasparini Laura , Ehrnhoefer Dagmar E. 
Published: January 2020

AbstractHuman tauopathies including Alzheimer’s disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, leading to the formation of insoluble aggregates, neuronal dysfunction and degeneration. Using a mass spectrometry approach, we identified multiple sites of lysine monomethylation on Tau isolated from a detergent-soluble fraction of human brain, some of which were increased in early AD samples. Brain tissues derived from a mouse model of tauopathy demonstrate an age-dependent increase in methylation at specific sites, with methylated Tau enriched in the soluble nuclear fraction and not associated with hyperphosphorylated, insoluble Tau species. Furthermore, we show that the protein lysine methyltransferase SETD7 methylates Tau at K132 and demonstrate an interaction with K130, an additional methylation site in close vicinity. These findings shed light on the function of a novel type of PTM on Tau that provide a potential signal for its translocation to different subcellular sites. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may furthermore provide insight into this disease-associated phenomenon.
Molecular signatures of local adaptation to light in Norway Spruce: role of lignin mediated immunity
Authors: Ranade Sonali Sachin , García-Gil María Rosario 
Published: January 2020

AbstractStudy of natural variation is an efficient method to elucidate how plants adapt to local climatic conditions, a key process for the evolution of a species. However, it is challenging to determine the genetic basis of adaptive variation especially in forest trees which have large and complex genomes. Norway spruce is a shade tolerant conifer in which the requirement of far-red light for growth increases latitudinally northwards. In the current work, hypocotyl-length followed a latitudinal cline in response to SHADE (low red:far-red ratio). RNA-sequencing revealed differential gene expression in response to SHADE, between a southern and a northern natural population in Sweden. Exome capture included analysis of uniquely large data set (1654 trees) that revealed missense variations in coding regions of nine differentially expressed candidate genes, which followed a latitudinal cline in allele and genotype frequencies. These genes included five transcription factors involved in vital processes like bud-set/bud-flush, lignin pathway and cold acclimation, and other genes that take part in cell-wall remodeling, secondary cell-wall thickening, response to starvation and immunity. Findings from this work primarily suggests that the northern populations of Norway spruce are better adapted towards disease resistance under shade by up-regulation of lignin pathway that is linked to immunity and it forms concrete basis for local adaptation to light quality in Norway spruce, one of the most economically important conifer tree species in Sweden.
Generalized calibration across LC-setups for generic prediction of small molecule retention times
Authors: Bouwmeester Robbin , Martens Lennart , Degroeve Sven 
Published: January 2020

AbstractMotivationAccurate prediction of liquid chromatographic retention times from small molecule structures is useful for reducing experimental measurements and for improved identification in targeted and untargeted MS. However, different experimental setups (e.g. differences in columns, gradients, solvents, or stationary phase) have given rise to a multitude of prediction models that only predict accurate retention times for a specific experimental setup. In practice this typically results in the fitting of a new predictive model for each specific type of setup, which is not only inefficient but also requires substantial prior data to be accumulated on each such setup.ResultsHere we introduce the concept of generalized calibration, which is capable of the straightforward mapping of retention time models between different experimental setups. This concept builds on the database-controlled calibration approach implemented in PredRet, and fits calibration curves on predicted retention times instead of only on observed retention times. We show that this approach results in significantly higher accuracy of elution peak prediction than is achieved by setup-specific models.
Informed dimension reduction of clinically-related genome-wide association summary data characterises cross-trait axes of genetic risk
Authors: Burren Oliver S , Reales Guillermo , Wong Limy , Bowes John , Lee James C , Barton Anne , Lyons Paul A , Smith Kenneth GC , Thomson Wendy , Kirk Paul DW , Wallace Chris 
Published: January 2020

AbstractIntegration of genome-wide association study (GWAS) data has been used to generate new hypotheses of biological mechanism, aetiological relationships between traits, or test causality of one factor for another. However, such approaches have typically been limited to pairwise comparisons of traits. We propose a generally applicable method, that exploits ideas from Bayesian genetic fine mapping to define a “lens” that focuses relevant variants before dimension reduction of a set of related GWAS summary statistics. We applied this technique to immune-mediated diseases, deriving 13 components which summarise the multidimensional patterns of genetic risk. Projection of independent datasets demonstrated the specificity and accuracy of our reduced dimension basis, enabled us to functionally characterise individual components, identify disease-discriminating components and suggest novel associations in rare diseases where classical GWAS approaches are challenging. Our approach summarises the genetic architectures underlying any range of aetiologically-related traits in fewer dimensions, facilitating more nuanced multidimensional comparative analyses.
Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons
Authors: Heppt Jana , Wittmann Marie-Theres , Zhang Jingzhong , Vogt-Weisenhorn Daniela , Prakash Nilima , Wurst Wolfgang , Taketo Makoto Mark , Lie D. Chichung 
Published: January 2020

AbstractIn adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/β-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing β-catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of β-catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of β-catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/β-catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.
Moderating Effect of Social Support on Role Conflict and Job Satisfaction among Nurses with Multiple Roles
Authors: Li Caifu , Song Rhayun , Fan Xing , Xu Lijuan 
Published: January 2020

AbstractRegistered nurses perform multiple roles in their lives at work, at home, and at school when they decide to pursue various types of advanced degrees. Work-family conflict was found to be negatively correlated with job satisfaction among nurses. This study aimed to determine the moderating effect of social support on the relationship between role conflicts and job satisfaction among registered nurses in mainland China. The study had a cross-sectional correlational design. Convenience sampling was applied to recruit 320 nurses with multiple roles from 8 nursing universities and 3 hospitals in China between January and August 2017. SPSS (version 20.0) software and PROCESS program was used to examine to moderating effect of social support between the relationship of role conflicts and job satisfaction. It was found that role conflicts were negatively correlated with job satisfaction. Support from work and support from family negatively moderated the relationship between role conflicts and job satisfaction. These findings suggest that support from family, coworkers and nursing administrators, and the implementation of school- and family-friendly policies would help nurses who are pursuing further nursing degrees to handle their multiple roles and improve their job satisfaction.
Evaluation of modulators of cAMP-response in terms of their impact on cell cycle and mitochondrial activity ofLeishmania donovani
Authors: Saha Amrita , Bhattacharjee Anindita , Vij Amit , Das Pijush K. , Bhattacharya Arijit , Biswas Arunima 
Published: January 2020

AbstractWith the identification of novel cAMP binding effecter molecules inTrypanosoma, role of cAMP in kinetopalstida parasites gained an intriguing break through. Despite earlier demonstrations of role of cAMP in survival ofLeishmaniaduring macrophage infection, there is essential need to specifically clarify involvement of cAMP in various cellular processes in the parasite. In this context, we sought to gain a comprehensive understanding of the effect of cAMPanalogs and cAMP-phosphodiesterase (PDE) inhibitors on proliferation of log phase parasites. Administration of both hydrolysable (8-pCPT-cAMP) and non-hydrolysable analogs (Sp-8-pCPT-cAMPS) of cAMP resulted in significant decrease ofLeishmaniaproliferation. Amongst the various PDE inhibitors, etazolate was found to be potently anti-proliferative. BrdU cell proliferation and K/N/F-enumeration microscopic study revealed that both cAMP analogues and selective PDE inhibitors resulted in significant cell cycle arrest at G1phase with reduced S-phase population. Furthermore, careful examination of the flagellar motility patterns revealed significantly reduced coordinated forward flagellar movement of the promastigotes with a concomitant decrease in cellular ATP levels. Alongside, 8-pCPT-cAMP and PDE inhibitors etazolate and trequinsin showed marked reduction in mitochondrial membrane potential. Treatment of etazolate at subcytotoxic concentration to infected macrophages significantly reduced parasite burden and administration of etazolate toLeishmania-infected BALB/c mice showed reduced liver and spleen parasite burden. Collectively, these results imply involvement of cAMP in various crucial processes paving the avenue for developing potent anti-leishmanial agent.Author SummaryLeishmania donovaniis the causative agent of fatal Visceral Leishmaniasis. The current available medications are toxic, expensive and require long term daily administrations. With an aim to develop improved therapeutic, components of cAMP homeostasis, particularly cAMP-phosphodiesteares, has been targeted forLeishmaniaand other kinetoplastid pathogens. cAMP plays diverse roles in functional processes involved in cell division, transition into different stages of the life cycle ofLeishmaniaand motility. In this study, the authors found administration of both hydrolysable and non-hydrolysable analogs of cAMP and certain PDE inhibitors resulted in remarkable decrease proliferation with considerable cytopathic impact on promastigotes. The mammalian phosphodiestearse inhibitor etazolate caused significant reduction in parasite load inL. donovaniinfected macrophages and demonstrated considerable reduction of liver and spleen parasite burden inin vivomouse infection model. The study suggested that etazolate, with its slightest impact on mammalian host, can be repurposed for developing effective anti-leishmanials.
Nobiletin Affects Circadian Rhythms and Oncogenic Characteristics in a Cell-Dependent Manner
Authors: Lellupitiyage Don Sujeewa S. , Robertson Kelly L. , Lin Hui-Hsien , Labriola Caroline , Harrington Mary E. , Taylor Stephanie R. , Farkas Michelle E. 
Published: January 2020

AbstractThe natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in models of cancer. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin’s anti-oncogenic effects are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cell culture models of cancer. In this study, we assessed nobiletin’s circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also vary in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin’s anti-cancer effects have been studied previously were evaluated here: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that both circadian and anti-cancer effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity, and substantially reduced oncogenic features. Based on these results and those previously described, we posit that a positive correlation exists between nobiletin’s circadian and therapeutic effects.
Roles of sarcoplasmic reticulum Ca2+ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model
Authors: Lee Yang , Chakraborty Sanjukta , Muthuchamy Mariappan 
Published: January 2020

AbstractThe intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum Ca2+ATPase (SERCA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SERCA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC20phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 increased phasic contractile frequency in the vessels from MetSyn, thereby, partially restored lymph flow. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.
The synergistic actions of hydrolytic genes reveal the mechanism ofTrichoderma harzianumfor cellulose degradation
Authors: Almeida Déborah Aires , Crivelente Horta Maria Augusta , Ferreira Filho Jaire Alves , Murad Natália Faraj , de Souza Anete Pereira 
Published: January 2020

AbstractBioprospecting genes and proteins related to plant biomass degradation is an attractive approach for the identification of target genes for biotechnological purposes, especially genes with potential applications in the biorefinery industry that can enhance second-generation ethanol production technology.Trichoderma harzianumis a potential candidate for cellulolytic enzyme prospection and production. Herein, the enzymatic activities, transcriptome, exoproteome, and coexpression networks of theT. harzianumstrain CBMAI-0179 were examined under biomass degradation conditions. We used RNA-Seq to identify differentially expressed genes (DEGs) and carbohydrate-active enzyme (CAZyme) genes related to plant biomass degradation and compared them with the genes of strains from congeneric species (T. harzianumIOC-3844 andT. atrovirideCBMAI-0020).T. harzianumCBMAI-0179 harbors strain- and treatment-specific CAZyme genes and transcription factors. We detected important proteins related to biomass degradation, including β-glucosidases, endoglucanases, cellobiohydrolases, lytic polysaccharide monooxygenases, endo-1,4-β-xylanases and β-mannanases, in the exoproteome under cellulose growth conditions. Coexpression networks were constructed to explore the relationships among the genes and corresponding secreted proteins that act synergistically for cellulose degradation. An enriched cluster with degradative enzymes was described, and the subnetwork of CAZymes revealed strong correlations among the secreted proteins (AA9, GH6, GH10, GH11 and CBM1) and differentially expressed CAZyme genes (GH45, GH7, AA7 and GH1). Our results provide valuable information for future studies on the genetic regulation of plant cell wall-degrading enzymes. This knowledge can be exploited for the improvement of enzymatic reactions in biomass degradation for bioethanol production.Key pointsDifferent biotechnological approaches were used to understand the mechanism of cellulose degradation ofTrichodermaspp.T. harzianumCBMAI-0179 is a potential candidate for the production of cellulolytic enzymes.Coexpression networks revealed genes and proteins acting synergistically for cellulose hydrolysis.
Early metazoan origin and multiple losses of a novel clade of RIM pre-synaptic calcium channel scaffolding protein homologues
Authors: Piekut Thomas , Wong Yuen Yan , Walker Sarah E. , Smith Carolyn L. , Gauberg Julia , Harracksingh Alicia N. , Lowden Christopher , Mary Cheng Hai-Ying , Spencer Gaynor E. , Senatore Adriano 
Published: January 2020

AbstractThe precise localization of CaV2 voltage-gated calcium channels at the synapse active zone requires various interacting proteins, of which,Rab3 interactingmolecule or RIM is considered particularly important. In vertebrates, RIM interacts with CaV2 channelsin vitrovia a PDZ domain that binds to the extreme C-termini of the channels at acidic ligand motifs of D/E-D/E/H-WC-COOH, and knockout of RIM in vertebrates and invertebrates disrupts CaV2 channel synaptic localization and synapse function. Here, we describe a previously uncharacterized clade of RIM proteins bearing homologous domain architectures as known RIM homologues, but some notable differences including key amino acids associated with PDZ domain ligand specificity. This novel RIM emerged near the stem lineage of metazoans and underwent extensive losses, but is retained in select animals including the early-diverging placozoanTrichoplax adhaerens, and molluscs. RNA expression and localization studies inTrichoplaxand the mollusc snailLymnaea stagnalisindicate differential regional/tissue type expression, but overlapping expression in single isolated neurons fromLymnaea. Ctenophores, the most early-diverging animals with synapses, are unique among animals with nervous systems in that they lack the canonical RIM, bearing only the newly identified homologue. Through phylogenetic analysis, we find that CaV2 channel D/E-D/E/H-WC-COOHlike PDZ ligand motifs were present in the common ancestor of cnidarians and bilaterians, and delineate some deeply conserved C-terminal structures that distinguish CaV1 from CaV2 channels, and CaV1/CaV2 from CaV3 channels.