bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addressing the Embeddability Problem in Transition Rate Estimation
Authors: Goolsby Curtis , Losey James , Xu Yuchen , Düker Marie-Christine , Sherman Mila Getmansky , Matteson David S. , Moradi Mahmoud 
Published: August 2019

AbstractMarkov State Models (MSM) and related techniques have gained significant traction as a tool for analyzing and guiding molecular dynamics (MD) simulations due to their ability to extract structural, thermodynamic, and kinetic information on proteins using computationally feasible MD simulations. The MSM analysis often relies on spectral decomposition of empirically generated transition matrices. Here, we discuss an alternative approach for extracting the thermodynamic and kinetic information from the so-called rate/generator matrix rather than the transition matrix. Although the rate matrix itself is built from the empirical transition matrix, it provides an alternative approach for estimating both thermodynamic and kinetic quantities, particularly in diffusive processes. We particularly discuss a fundamental issue with this approach, known as the embeddability problem and offer ways to address this issue. We describe eight different methods to overcome the embeddability problem, including a novel approach developed for this work. The algorithms were tested on data from a one-dimensional toy model to show the workings of these methods and discuss the robustness of each method in terms of its dependence in lag time and trajectory length.
LARP1 facilitates translational recovery after amino acid refeeding by preserving long poly(A)-tailed TOP mRNAs
Authors: Ogami Koichi , Oishi Yuka , Nogimori Takuto , Sakamoto Kentaro , Hoshino Shin-ichi 
Published: August 2019

ABSTRACTOccasionally, cells must adapt to an inimical growth conditions like amino acid starvation (AAS) by downregulating protein synthesis. A class of transcripts containing 5’terminal oligopyrimidine (5’TOP) motif encodes translation-related proteins such as ribosomal proteins (RPs) and elongation factors, and therefore, their translation is severely repressed during AAS to conserve energy1. The RNA-binding protein LARP1 transduces amino acid signaling to TOP gene expression by controlling translation and stability of TOP mRNAs2-6. When released from AAS, translation machineries in turn have to be restored, however, the underlying mechanism of such re-adaptation is largely unknown. Here we show that LARP1 preserves TOP mRNAs in a long polyadenylated state during long-term AAS. We found that TOP mRNAs become highly polyadenylated when cells are in AAS or treated with the mTOR (mechanistic target of rapamycin) inhibitor Torin1. Importantly, depletion of LARP1 completely abrogated the polyadenylation of TOP mRNAs. Comprehensive analysis of poly(A) tail length using the Nanopore direct RNA sequencing revealed that TOP mRNAs are selectively polyadenylated under mTOR inhibition. Since a long poly(A) tail confers increased stability and polysome formation of TOP mRNAs, we predict that LARP1-dependent preservation of TOP mRNAs enables rapid translational resumption after the release from AAS.
Saccadic adaptation in the presence of artificial central scotomas
Authors: Song Youngmin , Ouchene Lydia , Khan Aarlenne Z. 
Published: August 2019

AbstractSaccadic adaptation can occur over a short period of time through a constant adjustment of the saccade target during the saccade, resulting in saccadic re-referencing which directs the saccade to a location different from the target that elicited the saccade. Saccade re-referencing could be used to help patients with age-related macular degeneration (AMD) to optimally use their residual visual function. However, it remains unknown whether saccade adaptation can take place in the presence of central scotomas (i.e., without central vision).We tested participants in two experiments in a conventional double-step paradigm with a central gaze-contingent artificial scotoma. Experiment 1 (N= 12) comprised a backward adaptation paradigm with a visible and an invisible 3° diameter scotomas. Experiment 2 (N= 13) comprised a forward adaptation paradigm with invisible 2° and 4° diameter scotomas.In Experiment 1, we observed significant adaptation in both the visible and invisible scotoma conditions comparable to the control condition with no scotoma. This was the case even when the saccade landed such that the target was occluded by the scotoma. We observed that adaptation occurred based on peripheral viewing of the stepped target during the deceleration period.In Experiment 2, we found that both scotoma conditions showed adaptation again comparable to the control condition with no scotoma. We conclude that saccadic adaptation can occur with central scotomas, showing that it does not require central vision and is driven primarily by peripheral retinal error.
Bee visitation and fruit quality in berries under protected cropping vary along the length of polytunnels
Authors: Hall Mark , Jones Jeremy , Rocchetti Maurizio , Wright Derek , Rader Romina 
Published: August 2019

AbstractWild and managed bees provide effective crop pollination services worldwide. Protected cropping conditions are thought to alter the ambient environmental conditions in which pollinators forage for flowers, yet few studies have compared conditions at the edges and centre of growing tunnels. We measured environmental variables (temperature, relative humidity, wind speed, white light and UV light) and surveyed the activity of managed honeybeesApis mellifera, wild stingless beesTetragonula carbonariaand sweat beesHomalictus urbanusalong the length of 32 multiple open-ended polyethylene growing tunnels. These were spaced across 12 blocks at two commercial berry farms, in Coffs Harbour, New South Wales and Walkamin, North Queensland, Australia. Berry yield, fresh weight and other quality metrics were recorded at discrete increments along the length of the tunnels. We found a higher abundance and greater number of flower visits by stingless bees and honeybees at the end of tunnels, and less frequent visits to flowers toward the middle of tunnels. The centre of tunnels experienced higher temperatures and reduced wind speed. In raspberry, fruit shape was improved with greater pollinator abundance and was susceptible to higher temperatures. In blueberry, per plant yield and mean berry weight were positively associated with pollinator abundance and were lower at the centre of tunnels than at the edge. Fruit quality (crumbliness) in raspberries was improved with a greater number of visits by sweat bees, who were not as susceptible to climatic conditions within tunnels. Understanding bee foraging behaviour and changes to yield under protected cropping conditions is critical to inform the appropriate design of polytunnels and aid pollinator management within them.
Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ
Authors: Del Rosario John Smith , Yudin Yevgen , Su Songxue , Hartle Cassandra , Mirshahi Tooraj , Rohacs Tibor 
Published: August 2019

SUMMARYDysregulation of mechanosensitive Piezo2 channels is a hallmark of mechanical allodynia, yet the cellular mechanisms that sensitize mechanoreceptors are still poorly understood. Activation of Gi-coupled receptors sensitizes Piezo2 currents, but whether Gi-coupled receptors regulate the activity of Piezo2 channels is not known. Here, we found that activation of Gi-coupled receptors potentiates Piezo2 currents in dorsal root ganglion (DRG) neurons and in heterologous systems, but inhibits Piezo1 currents in heterologous systems. The potentiation, or inhibition of Piezo currents is abolished when blocking Gβγ with the c-terminal domain of the beta-adrenergic kinase (βARKct). Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), also abolished the potentiation of Piezo2 currents. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents after activation of Gi-coupled receptors.
Temporal dynamics of nitrogen cycle gene diversity in a hyporheic microbiome
Authors: Nelson William C. , Graham Emily B. , Crump Alex R. , Fansler Sarah J. , Arntzen Evan V. , Kennedy David W. , Stegen James C. 
Published: August 2019

ABSTRACTBiodiversity is thought to prevent decline in community function in response to changing environmental conditions through replacement of organisms with similar functional capacity but different optimal growth characteristics. We examined how this concept translates to the within-gene level by exploring seasonal dynamics of within-gene diversity for genes involved in nitrogen cycling in hyporheic zone communities. Nitrification genes displayed low richness— defined as the number of unique within-gene phylotypes—across seasons. Conversely, denitrification genes varied in both richness and the degree to which phylotypes were recruited or lost. These results demonstrate that there is not a universal mechanism for maintaining community functional potential for nitrogen cycling activities, even across seasonal environmental shifts to which communities would be expected to be well adapted. As such, extreme environmental changes could have very different effects on the stability of the different nitrogen cycle activities. These outcomes suggest a need to modify existing conceptual models that link biodiversity to microbiome function to incorporate within-gene diversity. Specifically, we suggest an expanded conceptualization that (1) recognizes component steps (genes) with low diversity as potential bottlenecks influencing pathway-level function, and (2) includes variation in both the number of entities (e.g.species, phylotypes) that can contribute to a given process and the turnover of those entities in response to shifting conditions. Building these concepts into process-based ecosystem models represents an exciting opportunity to connect within-gene-scale ecological dynamics to ecosystem-scale services.
Glucocorticoids Induce the Expansion of an Immature Human CFU-E Population
Authors: Ashley Ryan , Yan Hongxia , Wang Nan , Hale John , Dulmovits Brian M. , Papoin Julien , Olive Meagan , Udeshi Namrata D. , Carr Steven A. , Vlachos Adrianna , Lipton Jeffrey M. , Da Costa Lydie , Hillyer Christopher , Kinet Sandrina , Taylor Naomi , Mohandas Narla , Narla Anupama , Blanc Lionel 
Published: August 2019

AbstractDespite effective clinical use, the mechanistic bases for the regulation of human erythropoiesis by glucocorticoids remain poorly understood. Here, we employed an erythroid culture system to differentiate primary human CD34+cells isolated from control peripheral blood, cord blood and patients with Diamond Blackfan anemia (DBA), as model of an erythropoietic disorder treated with glucocorticoids. We found that the response to Dexamethasone is dependent on the developmental origin of the source of CD34+cells, specifically increasing the expansion of CD34+cells from peripheral blood but not cord blood. We also demonstrated that Dex treatment leads to the expansion of a novel immature colony-forming unit-erythroid (CFU-E) population in peripheral blood which is uniquely responsible for the proliferative effects observed during human adult erythropoiesis. Dex treatment of peripheral blood CFU-E cells also induced p57Kip2expression while patients with DBA resistant to steroids had altered p57Kip2expression that did not increase with Dex. Furthermore, shRNA knockdown of p57Kip2reduced proliferation and abrogated the effects of Dex. Finally, proteomics of Dex-treated CFU-E from peripheral blood and cord blood additionally revealed novel Dex targets in the erythroid system. Altogether, these results provide novel insights into the regulation of human erythropoiesis by glucocorticoids.Graphical Abstract
Yeast Bax Inhibitor (Bxi1p/Ybh3p) is a Calcium Channel inE. coli
Authors: Mullin James , Kalhorn John , Mello Nicholas , Raffa Amanda , Strakosha Alexander , Austriaco O.P. Nicanor 
Published: August 2019

AbstractHuman Bax Inhibitor-1 (HsBI-1/TMBIM6) is the founding member of the evolutionary conserved TMBIM superfamily of proteins that share sequence homology within the transmembrane Bax inhibitor-containing motif (TMBIM). Mechanistically, BI-1/TMBIM6 and all the other mammalian TMBIM proteins appear to be involved in the maintenance of calcium homeostasis, and the crystal structure of a bacterial TMBIM protein, BsYetJ, suggests that the protein is a pH-sensitive calcium leak. The budding yeast,Saccharomyces cerevisiae, has a single TMBIM family member (YNL305C) named Bxi1p/Ybh3p. To determine the function of Bxi1p/Ybh3p, we overexpressed Bxi1p-EGFP inE. colito determine if it is a calcium channel. We show that bacterial cells expressing Bxi1p-EGFP are more permeable to calcium than controls. Thus, our data suggests that yeast Bax inhibitor (Bxi1p) is a calcium channel inE. coli, lending support to our proposal that Bxi1p is abona fidemember of the TMBIM family of proteins. Further, we use our bacterial system to show that gadolinium is an inhibitor of Bxi1pin vivo, suggesting a path forward to identifying other small-molecular inhibitors of this clinically-important and highly conserved superfamily of proteins. Finally, parallel experiments revealed that the human Bax Inhibitor-1 (HsBI-1/TMBIM6) is also a calcium channel in bacteria that can be inhibited by gadolinium.
Single-cell RNA-seq highlights heterogeneity in human primary Wharton’s Jelly mesenchymal stem/stromal cells cultured in vitro
Authors: Sun Changbin , Wang Lei , Wang Hailun , Huang Tingrun , Zhang Xi 
Published: August 2019

SUMMARYMesenchymal Stem/Stromal cells (MSCs) are multipotent cells with promising application potential in regenerative medicine and immunomodulation. However, MSCs cultured in vitro exhibit functional heterogeneity. The underlying molecular mechanisms that define MSC heterogeneity remain unclear. Here, we investigated gene-expression heterogeneity of human primary Wharton’s Jelly-derived MSCs (WJMSCs) cultured in vitro via single-cell RNA-seq. At the single-cell level, highly variable genes (HVGs) are associated with functional characteristics of classic MSCs. Differentially expressed genes analysis revealed the existence of several distinct subpopulations exhibit different functional characteristics associated with proliferation, development, and inflammation response. By comparing our WJMSCs data with a public available adipose-derived MSCs (ADMSCs) single cell transcriptomic data, we found that HVGs from these two studies are largely overlapped and have similar functional enrichment. Taken together, these results suggested that these HVGs hold the potential to be used as candidate markers for further potency association studies.
Altering Mammalian Transcription Networking with Adaadi: An Inhibitor of Atp-Dependent Chromatin Remodeling
Authors: Rakesh Radhakrishnan , Hussain Saddam , Goel Kaveri , Sharma Soni , Bisht Deepa , Chanana Upasana Bedi , Hockensmith Joel W. , Muthuswami Rohini 
Published: August 2019

ABSTRACTTranscriptional control has been earnestly pursued for the regulation of cellular proliferation associated with cancer progression. The foundational paradigm of targeting transcription factors has yielded exquisite specificity, but many factors cannot yet be targeted. In contrast, targeting epigenetic factors to control chromatin structure and consequential gene expression generally yields more global effects on transcription. Our working paradigm targets neither specific transcription factors nor global epigenetic factors but ATP-dependent chromatin remodeling factors that regulate expression of a limited set of genes. Active DNA-dependent ATPase A Domain inhibitor (ADAADi) synthesized by aminoglycoside phosphotransferases is the first-in-class inhibitor of ATP-dependent chromatin remodeling proteins that targets the ATPase domain of these proteins. Mammalian cells are sensitive to ADAADi but cell lines are variable in their individual responses to the inhibitor. The ADAADi product can be generated from a variety of aminoglycoside substrates with cells showing differential responses to ADAADi depending on the starting aminoglycoside. RNA seq analysis demonstrated that targeting the chromatin remodeling by treatment with a sub-lethal concentration of ADAADi yields alterations to the transcriptional network of the cell. Predominantly, the tumor-promoting genes were repressed while pro-apoptotic and tumor suppressors genes were upregulated on treatment with ADAADi, leading to apoptotic-type cell death. Treatment with ADAADi reversed the EMT process as well as inhibited migration of cells and their colony forming ability. In conjunction with the previous report that treatment with ADAADi regresses tumors in mouse model, this chromatin remodeling inhibitor shows promising anti-tumor properties by targeting the main hallmarks of cancer.
Usp14 is required for spermatogenesis and ubiquitin stress responses in Drosophila melanogaster
Authors: Kovács Levente , Nagy Ágota , Pál Margit , Deák Peter 
Published: August 2019

ABSTRACTDeubiquitinating (DUB) enzymes free covalently linked ubiquitins from ubiquitin-ubiquitin and ubiquitin-protein conjugates, and thereby maintain the equilibrium between free and conjugated ubiquitins and regulate ubiquitin-mediated cellular processes. The present genetic analyses of mutant phenotypes demonstrate that loss of Usp14 function results in male sterility, with defects in spermatid individualization and reduced testicular free monoubiquitin levels. These phenotypes were rescued by germline specific overexpression of wild type Usp14. Synergistic genetic interactions with Ubi-p63E and cycloheximide sensitivity suggest that ubiquitin shortage is a primary cause of male sterility. In addition, Usp14 is predominantly expressed in testes in Drosophila, and differential expression patterns may be causative of testis-specific loss of function Usp14 phenotypes. Collectively, these results suggest a major role of Usp14 in maintaining normal steady state free monoubiquitin levels during the later stages of Drosophila spermatogenesis.
NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina
Authors: Palazzo Isabella , Deistler Kyle , Hoang Thanh V. , Blackshaw Seth , Fischer Andy J. 
Published: August 2019

AbstractNeuronal regeneration in the retina is a robust, effective process in some cold-blooded vertebrates, but this process is ineffective in warm-blooded vertebrates. Understanding the mechanisms and cell-signaling pathways that restrict the reprogramming of Müller glia into proliferating neurogenic progenitors is key to harnessing the regenerative potential of the retina. Inflammation and reactive microglia are known to influence the formation of Müller glia-derived progenitor cells (MGPCs), but the mechanisms underlying this response are unknown. Using the chick retinain vivoas a model system, we investigate the role of the Nuclear Factor kappa B (NF-κB) signaling, a critical regulator of inflammation. We find that components of the NF-κB pathway are expressed by Müller glia and are dynamically regulated after neuronal damage or treatment with growth factors. Inhibition of NF-κB enhances, whereas activation suppresses the formation of proliferating MGPCs. Additionally, activation of NF-κB promotes glial differentiation from MGPCs in damaged retinas. With microglia ablated, the effects of NF-κB-agonists/antagonists on MGPC formation are reversed, suggesting that the context and timing of signals provided by reactive microglia influence how NF-κB-signaling impacts the reprogramming of Müller glia. We propose that NF-κB-signaling is an important signaling “hub” that suppresses the reprogramming of Müller glia into proliferating MGPCs and this “hub” coordinates signals provided by reactive microglia.
Whole integration of neural connectomics, dynamics and bio-mechanics for identification of behavioral sensorimotor pathways in Caenorhabditis elegans
Authors: Kim Jimin , Santos Julia A. , Alkema Mark J. , Shlizerman Eli 
Published: August 2019

AbstractThe ability to fully discern how the brain orchestrates behavior requires the development of successful computational approaches to integrate and inform in-vivo investigations of the nervous system. To effectively assist with such investigations, computational approaches must be generic, scalable and unbiased. We propose such a comprehensive framework to investigate the interaction between the nervous system and the body for the nematode Caenorhabditis elegans (C. elegans). Specifically, we introduce a model that computationally emulates the activity of the complete somatic nervous system and its response to stimuli. The model builds upon the full anatomical wiring diagram, the connectome, and integrates it with additional layers including intra-cellular and extra-cellular bio-physically relevant neural dynamics, layers translating neural activity to muscle forces and muscle impulses to body postures. In addition, it implements inverse integration which modulates neural dynamics according to external forces on the body. We validate the model by in-silico injection of currents into sensory- and inter-neurons known to play a role in locomotion behaviors (e.g. posterior/anterior touch) and by applying external forces on the body. We are able to generate characteristic baseline locomotion behaviors (forward and backward movements). Inclusion of proprioceptive feedback, implemented through inverse integration, shows that feedback can entrain and sustain movements initiated by neural or mechanical triggers. We further apply neural stimuli, experimentally known to modulate locomotion, and show that our model supports natural behavioral responses such as turns, reversals and avoidance. The proposed model can be utilized to infer neural circuits involved in sensorimotor behavior. For this purpose, we develop large-scale computational ablation approaches such as (i) ablation survey and (ii) conditional ablation. Our results show how an ablation survey can identify neurons required for a ventral turning behavior. We also show how conditional ablation can identify alternative novel neural pathways, e.g. propose neurons which facilitate steering behavior towards olfactory attractants. The outcomes of our study show that the framework can be utilized to identify neural circuits, which control, mediate and generate natural behavior.
Landscape scale terrestrial factors are also vital in shaping Odonata diversity of watercourses
Authors: Nagy H. Beáta , László Zoltán , Szabó Flóra , Szőcs Lilla , Dévai György , Tóthmérész Béla 
Published: August 2019

ABSTRACTHabitat loss and fragmentation causes decline of insect populations. Odonata (both dragonflies and damselflies) are especially threatened, because they are notably influenced by both aquatic and terrestrial environment. We explored the relative importance of local and landscape variables for Odonata assemblages (species richness, assemblage composition, population abundance) revealing differences in the sensitivity of Zygoptera and Anisoptera on the selected variables. Our study took two years and was placed along 11 lowland watercourses. We sampled the specimens using 500 m long transects from May to September. Landscape variables (length of watercourses, forest patch proportion, and farmland patch size) were calculated at three scales to better account for fragmentation. Our findings show that local variables influence damselflies, but dragonflies are more sensitive to landscape variables. Damselfly’s diversity decreased with the increasing macrovegetation cover, while dragonfly’s diversity decreased with the increasing degree of land use intensification, but increased with the length of watercourses. Our findings, both on local and landscape scales demonstrated the importance of terrestrial environment on Odonata. Based on our findings we stress the importance of partial watercourse clearing, and maintenance of traditional farm management based on small parcel farming near watercourses to maintain diverse and healthy Odonata assemblages.