bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statistics of eigenvalue dispersion indices: quantifying the magnitude of phenotypic integration
Authors: Watanabe Junya 
Published: June 2021

AbstractQuantification of the magnitude of trait covariation plays a pivotal role in the study of phenotypic evolution, for which statistics based on dispersion of eigenvalues of a covariance or correlation matrix—eigenvalue dispersion indices—are commonly used. This study remedies major issues over the use of these statistics, namely, a lack of clear understandings on their statistical justifications and sampling properties. The relative eigenvalue variance of a covariance matrix is known in the statistical literature a test statistic for sphericity, thus is an appropriate measure of eccentricity of variation. The same of a correlation matrix is equal to the average squared correlation, which has a straightforward interpretation as a measure of integration. Expressions for the mean and variance of these statistics are analytically derived under multivariate normality, clarifying the effects of sample sizeN, number of variablesp, and parameters on sampling bias and error. Simulations confirmed that approximations involved are reasonably accurate with a moderate sample size (N≥ 16–64). Importantly, sampling properties of these indices are not adversely affected by a highp:Nratio, promising their utility in high-dimensional phenotypic analyses. They can furthermore be applied to shape variables and phylogenetically structured data with appropriate modifications.
Long-term molecular turnover of actin stress fibers revealed by advection-reaction analysis in fluorescence recovery after photobleaching
Authors: Saito Takumi , Matsunaga Daiki , Matsui Tsubasa S. , Deguchi Shinji 
Published: June 2021

AbstractFluorescence recovery after photobleaching (FRAP) is a versatile technique to evaluate the intracellular molecular exchange called turnover. Physicochemical models of FRAP typically consider the molecular diffusion and chemical reaction that simultaneously occur on a time scale of seconds to minutes. Particularly for long-term measurements, however, an advection effect can no longer be ignored, which transports the proteins in specific directions within the cells and accordingly shifts the spatial distribution of the local chemical equilibrium. Nevertheless, existing FRAP models have not considered the spatial shift, and as such, the turnover rate is often analyzed without considering the spatiotemporally updated chemical equilibrium. Here we develop a new FRAP model aimed at long-term measurements to quantitatively determine the two distinct effects of the advection and chemical reaction, i.e., the different major sources of the change in fluorescence intensity. To validate this approach, we carried out FRAP experiments on actin in stress fibers over a time period of more than 900 s, and the advection rate was shown to be comparable in magnitude to the chemical dissociation rate. We further found that the actin–myosin interaction and actin polymerization differently affect the advection and chemical dissociation. Our results thus suggest that the distinction between the two effects is indispensable to extract the intrinsic chemical properties of the actin cytoskeleton from the observations of complicated turnover in cells.
Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling
Authors: Liu Xin , Bae Chilman , Liu Bolong , Zhang Yongmei , Zhou Xiangfu , Zhang Donghang , Zhou Cheng , DiBua Adriana , Schutz Livia , Kaczocha Martin , Puopolo Michelino , Yamaguchi Terry P. , Chung Jin Mo , Tang Shao-Jun 
Published: June 2021

ABSTRACTOpioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic ablation of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.
Visual stimulation induces distinct forms of sensitization of On-Off direction-selective ganglion cell responses in the dorsal and ventral retina
Authors: Huang Xiaolin , Kim Alan Jaehyun , Ledesma Héctor Acarón , Ding Jennifer , Smith Robert G. , Wei Wei 
Published: June 2021

AbstractExperience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (On-Off DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that the On-Off DSGC can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral DSGCs that receive visual inputs from lower and upper visual fields respectively. Although responses of both dorsal and ventral DSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of dorsal DSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the DSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support direct electrotonic propagation between On and Off dendritic layers. By contrast, ventral DSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral On-Off DSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.
Nutrient-sensitive reinforcement learning in monkeys
Authors: Huang Fei-Yang , Grabenhorst Fabian 
Published: June 2021

ABSTRACTAnimals make adaptive food choices to acquire nutrients that are essential for survival. In reinforcement learning (RL), animals choose by assigning values to options and update these values with new experiences. This framework has been instrumental for identifying fundamental learning and decision variables, and their neural substrates. However, canonical RL models do not explain how learning depends on biologically critical intrinsic reward components, such as nutrients, and related homeostatic regulation. Here, we investigated this question in monkeys making choices for nutrient-defined food rewards under varying reward probabilities. We found that the nutrient composition of rewards strongly influenced monkeys’ choices and learning. The animals preferred rewards high in nutrient content and showed individual preferences for specific nutrients (sugar, fat). These nutrient preferences affected how the animals adapted to changing reward probabilities: the monkeys learned faster from preferred nutrient rewards and chose them frequently even when they were associated with lower reward probability. Although more recently experienced rewards generally had a stronger influence on monkeys’ choices, the impact of reward history depended on the rewards’ specific nutrient composition. A nutrient-sensitive RL model captured these processes. It updated the value of individual sugar and fat components of expected rewards from experience and integrated them into scalar values that explained the monkeys’ choices. Our findings indicate that nutrients constitute important reward components that influence subjective valuation, learning and choice. Incorporating nutrient-value functions into RL models may enhance their biological validity and help reveal unrecognized nutrient-specific learning and decision computations.
Resting-state functional connectivity relates to interindividual variations in positive memory
Authors: Isato Ayako , Suhara Tetsuya , Yamada Makiko 
Published: June 2021

AbstractIndividual differences in positive memory recollection are of interest in mental health, as positive memories can help protect people against stress and depression. However, it is unclear how individual differences in positive memory recollection are reflected in brain activity in the resting state. Here, we investigate the resting-state functional connectivity (FC) associated with interindividual variations in positive memory by employing cluster-level inferences based on randomization/permutation region of interest (ROI)-to-ROI analyses. We identified a cluster of FCs that was positively associated with positive memory performance, including the frontal operculum, central operculum, parietal operculum, Heschl’s gyrus, and planum temporale. The current results suggest that positive memory is innervated by frontotemporal network connectivity, which may have implications for future investigations of vulnerability to stress and depression.
Functional network motifs defined through integration of protein-protein and genetic interactions
Authors: Sahoo Amruta , Pechmann Sebastian 
Published: June 2021

ABSTRACTCells are enticingly complex systems. The identification of feedback regulation is critically important for understanding this complexity. Network motifs defined as small graphlets that occur more frequently than expected by chance have revolutionized our understanding of feed-back circuits in cellular networks. However, with their definition solely based on statistical over-representation, network motifs often lack biological context, which limits their usefulness. Here, we define functional network motifs (FNMs) through the systematic integration of genetic interaction data that directly informs on functional relationships between genes and encoded proteins. Occurring two orders of magnitude less frequently than conventional network motifs, we found FNMs significantly enriched in genes known to be functionally related. Moreover, our comprehensive analyses of FNMs in yeast showed that they are powerful at capturing both known and putative novel regulatory interactions, thus suggesting a promising strategy towards the systematic identification of feedback regulation in biological networks. Many FNMs appeared as excellent candidates for the prioritization of follow-up biochemical characterization, which is a recurring bottleneck in the targeting of complex diseases. More generally, our work highlights a fruitful avenue for integrating and harnessing genomic network data.
Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal cancer
Authors: Kal Satadeepa , Chakraborty Shrabastee , Karmakar Subhajit , Ghosh Mrinal K 
Published: June 2021

AbstractThe differential expression pattern of Carboxy terminus of Hsc70 Interacting Protein (CHIP, alias STIP1 Homology and U–box Containing Protein 1 or STUB1) in cancers is associated with ubiquitination mediated degradation of its client proteins. Emerging evidences suggest its abundant expression of CHIP in colorectal cancer compared to normal tissues, but the mechanistic detail of this augmented expression pattern is unclear. The signature driver of canonical Wnt pathway, β-catenin, and its co-activator RNA helicase p68, are also overexpressed in colorectal cancer. In this study, we describe a novel mechanism of Wnt/β-catenin and p68 mediated transcriptional activation of CHIP gene leading to enhanced proliferation of colorectal cancer cells. Wnt3A treatment and pharmacological activation of canonical Wnt signaling pathway resulted in increased nuclear translocation of β-catenin and elevated expression of CHIP. Likewise, overexpression and knockdown of β-catenin and p68 upregulated and downregulated CHIP expression, respectively, at both mRNA and protein levels. After cloning CHIP promoter, the increased and decreased promoter activities of CHIP induced by overexpression and knockdown of either β-catenin or p68 further confirmed transcriptional regulation of CHIP gene by Wnt/β-catenin signaling cascade. p68 along with β-catenin were found to occupy Transcription Factor 4 (TCF4) binding sites on endogenous CHIP promoter and regulate its transcription. Finally, enhanced cellular propagation and migration of colorectal cancer cells induced by ‘Wnt/β-catenin-p68–CHIP’ axis established the significance of this pathway in oncogenesis. To the best of our knowledge, this is the first report elucidating the mechanistic details of transcriptional regulation of CHIP (STUB1) gene expression.
A Novel Membrane Protein in the Rhodobacter sphaeroides LH1-RC Photocomplex
Authors: Tani K. , Nagashima K. V. P. , Kanno R. , Kawamura S. , Kikuchi R. , Hall M. , Yu L.-J. , Kimura Y. , Madigan M. T. , Mizoguchi A. , Humbel B. M. , Wang-Otomo Z.-Y. 
Published: June 2021

AbstractWe present a cryo-EM structure of the monomeric light-harvesting-reaction center (LH1-RC) core complex from photosynthetic purple bacterium Rhodobacter (Rba.) sphaeroides at 2.9 Å resolution. The LH1 complex forms a C-shaped structure composed of 14 αβ-polypeptides around the RC with a large ring opening. From the cryo-EM density map, a previously unrecognized integral membrane protein, referred to as protein-U, was identified. Protein-U has a U-shaped conformation near the LH1-ring opening and was annotated as a hypothetical protein in the Rba. sphaeroides genome. Deletion of protein-U resulted in a mutant strain that expressed a much-reduced amount of the dimeric LH1-RC, indicating an important role for protein-U in dimerization of the LH1-RC complex. PufX was located opposite protein-U on the LH1-ring opening, and both its position and conformation differed from that of previous reports of dimeric LH1-RC structures obtained at low-resolution. Twenty-six molecules of the carotenoid spheroidene arranged in two distinct configurations were resolved in the Rba. sphaeroides LH1 and were positioned within the complex to block its pores. Our findings offer a new view of the core photocomplex of Rba. sphaeroides and the connections between structure and function in bacterial photocomplexes in general.
Pan-Cancer Analysis of DNA Methylation Identifies Genes and Biological Functions Associated with Overall Survival
Authors: Cavet Romola , Yue Peng , Cavet Guy 
Published: June 2021

AbstractDNA methylation influences gene expression and is altered in many cancers, but the relationship between DNA methylation and cancer outcomes is not yet fully understood. If methylation of specific genes is associated with better or worse outcomes, it could implicate genes in driving cancer and suggest therapeutic strategies. To advance our understanding of DNA methylation in cancer biology, we conducted a pan-cancer analysis of the relationship between methylation and overall survival. Using data on 28 tumor types from The Cancer Genome Atlas (TCGA), we identified genes and genomic regions whose methylation was recurrently associated with survival across multiple cancer types. While global DNA methylation levels are associated with outcome in some cancers, we found that the gene-specific associations were largely independent of these global effects. Genes with recurrent associations across cancer types were enriched for certain biological functions, such as immunity and cell-cell adhesion. While these recurrently associated genes were found throughout the genome, they were enriched in certain genomic regions, which may further implicate certain gene families and gene clusters in affecting survival. By finding common features across cancer types, our results link DNA methylation to patient outcomes, identify biological mechanisms that could explain survival differences, and support the potential value of treatments that modulate the methylation of tumor DNA.
Unigems: plasmids and parts to facilitate teaching on assembly, gene expression control and logic in E. coli
Authors: Siddall Alex , Williams Abbie Ann , Sanders Jason , Denton Jai A. , Madden Dean , Schollar John , Bryk Jarosław 
Published: June 2021

AbstractSynthetic biology is as an excellent vehicle for education, as it enables creative combination of engineering and molecular biology approaches for quantitative characterisations of the assembled constructs. However, there is a limited number of resources available for such applications in the educational context, where straightforward setup, easily measurable phenotypes and extensibility are of particular importance. To expand the availability of education-friendly resources to teach synthetic biology and genetic engineering, we developed Unigems, a set of 10 plasmids that enable out-of-the-box investigations of principles of gene expression control, as well as more complex designs a biological logic gate. The system uses a common high-copy plasmid backbone and a common set of primers to enable Gibson-assembly of PCR-generated or synthesised parts into a target vector. It currently has two reporter genes with either two constitutive (high- or low-level) or two inducible (lactose- or arabinose-) promoters, as well as a single-plasmid implementation of an AND logic gate. The Unigems system has already been employed in undergraduate teaching settings, during outreach events and for training of iGEM teams. All plasmids have been deposited in Addgene.
Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice
Authors: Ivanova Deyana , Li Xiao-Feng , McIntyre Caitlin , Liu Yali , Kong Lingsi , O’Byrne Kevin T 
Published: June 2021

AbstractExposure to psychosocial stress disrupts reproductive function and interferes with pulsatile luteinising hormone (LH) secretion in mammals. The posterodorsal sub-nucleus of the medial amygdala (MePD) is part of the limbic brain and is an upstream modulator of the reproductive axis as well as stress and anxiety states. Corticotropin releasing factor type-2 receptors (CRFR2) are activated in the presence of psychosocial stress together with an increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress exposure on LH pulsatility. Firstly, we administered Ucn3 into the MePD and monitored the effect on pulsatile LH secretion in ovariectomised mice. Next, we delivered Astressin2B, a highly selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-Trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected ovariectomised Ucn3-cre-tdTomato mice with inhibitory DREADDs targeting the MePD Ucn3 neurons while exposing the mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone (CORT) release. Administration of Ucn3 into the MePD dose-dependently inhibited pulsatile LH secretion and intra-MePD administration of Astressin2B blocked the suppressive effect TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses as well as CORT release in the presence of TMT. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and psychosocial stress-induced CORT secretion. Ucn3 signalling in the MePD plays a fundamental role in modulating the hypothalamic-pituitary-ganadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal centre in the crosstalk between the reproductive and stress axes.
Autogenous and anautogenousCulex pipiensbioforms exhibit insulin-like peptide signaling pathway gene expression differences that are not dependent upon larval nutrition
Authors: Cheatle Jarvela Alys M. , Bell Katherine L. , Noreuil Anna , Fritz Megan L. 
Published: June 2021

AbstractCulex pipiensformpipiensandCx. pipiensformmolestusdiffer in their ability to produce eggs without a bloodmeal. Autogenous mosquitoes, such as themolestusbioform ofCx. pipiens, depend on nutrition acquired as larvae instead of a bloodmeal to fuel the energy intensive process of vitellogenesis, which requires abundant production of yolk proteins. In anautogenous mosquito systems, ovary ecdysteroidogenic hormone (OEH) and insulin-like peptides (ILPs) transduce nutritional signals and trigger egg maturation in response to a bloodmeal. It is unclear to what extent the process is conserved in autogenous mosquitoes and how the bloodmeal trigger has been replaced by teneral reserves. Here, we measured the effects of a series of nutritional regimens on autogeny, time to pupation, and survival inCx. pipiensformmolestusand formpipiens. We find that abundant nutrients never result in autogenous formpipiensand extremely poor food availability rarely eliminates autogeny from formmolestus. However, the number of autogenous eggs generated increases with nutrient availability. Similarly, using qPCR to quantify gene expression, we find several differences in the expression levels ofilpsbetween bioforms that are reduced and delayed by poor nutrition, but not extinguished. Changes inOEHexpression do not explain bioform-specific differences in autogeny. Surprisingly, the source of most of the gene expression differences correlated with autogeny is the abdomen, not the brain. Overall, our results suggest that autogeny is modulated by nutritional availability, but the trait is encoded by genetic differences between forms and these impact the expression of ILPs.
Improvement of association between confidence and accuracy after integration of separate evidence over time
Authors: Azizi Zahra , Zabbah Sajjad , Jahanitabesh Azra , Ebrahimpour Reza 
Published: June 2021

AbstractWhen making decisions in real-life, we may receive discrete evidence during a time period. Although participants can integrate information from separate cues to improve their accuracy, it is still debatable how confidence changes after receiving discrete information. Nevertheless, based on the strong positive relationship between accuracy and confidence, we predicted that similar to what is observed in accuracy, confidence would improve following the integration of separate pieces of information. We used a Random-dot-motion discrimination task in which one or two brief stimuli (i.e., pulse[s]) were presented, and participants had to indicate the predominant direction of dot motions by saccadic eye movement. Two pulses intervals (up to 1s) were randomly selected, where color-coded targets facilitated indicating confidence simultaneously. Using behavioral data, computational models, pupillometry, and EEG methodology, our data revealed that compared to single-pulse trials, in double-pulse trials, participants improve their confidence resolution rather than reporting higher confidence and that the EEG signal (centro-parietal-positivity) and pupil dynamics appear to follow confidence levels but only in double-pulse trials. Overall, our findings suggest that evidence integration helps to improve the associations between confidence and accuracy.