bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and evaluation of a novel step in the flavonoid biosynthesis pathway regulated by F3H gene using a yeast expression system
Authors: Jan Rahmatullah , Asaf Sajjad , Paudel Sanjita , Lee Sangkyu , Kim Kyung-Min
Published: September 2019

Kaempferol and quercetin are the essential plant secondary metabolites that confer huge biological functions in the plant defense system. These metabolites are produced in low quantities in plants, therefore engineering microbial factory is a favorable strategy for the production of these metabolites. In this study, biosynthetic pathways for kaempferol and quercetin were constructed in Saccharomyces cerevisiae using naringenin as a substrate. The results elucidated a novel step for the first time in kaempferol and quercetin biosynthesis directly from naringenin catalyzed by flavonol 3-hydroxylase (F3H). F3H gene from rice was cloned into pRS42K yeast episomal plasmid (YEP) vector using BamH1 and Xho1 restriction enzymes. We analyzed our target gene activity in engineered and in empty strains. The results were confirmed through TLC followed by Western blotting, nuclear magnetic resonance (NMR), and LC-MS. TLC showed positive results on comparing both compounds extracted from the engineered strain with the standard reference. Western blotting confirmed lack of Oryza sativa flavonol 3-hydroxylase (OsF3H) activity in empty strains while high OsF3H expression in engineered strains. NMR spectroscopy confirmed only quercetin, while LCMS-MS results revealed that F3H is responsible for naringenin conversion to both kaempferol and quercetin. These results concluded that rice F3H catalyzes naringenin metabolism via hydroxylation and synthesizes kaempferol and quercetin.

Highlights

Current study is a discovery of a novel step in flavonoid biosynthesis pathway of rice plant.

In this study F3H gene from rice plant was functionally expressed in yeast expression system.

Results confirmed that, F3H gene is responsible for the canalization of naringenin and converted into kaempferol and quercetin.

The results were confirmed through, western blotting, TLC, HPLC and NMR analysis.
Type-specific dendritic integration in mouse retinal ganglion cells
Authors: Ran Yanli , Huang Ziwei , Baden Tom , Baayen Harald , Berens Philipp , Franke Katrin , Euler Thomas
Published: September 2019

Neural computation relies on the integration of synaptic inputs across a neuron’s dendritic arbour. However, the fundamental rules that govern dendritic integration are far from understood. In particular, it is still unclear how cell type-specific differences in dendritic integration arise from general features of neural morphology and membrane properties. Here, retinal ganglion cells (RGCs), which relay the visual system’s first computations to the brain, represent an exquisite model. They are functionally and morphologically diverse yet defined, and they allow studying dendritic integration in a functionally relevant context. Here, we show how four morphologically distinct types of mouse RGC with shared excitatory synaptic input (transient Off alpha, transient Off mini, sustained Off, and F-miniOff) exhibit distinct dendritic integration rules. Using two-photon imaging of dendritic calcium signals and biophysical modelling, we demonstrate that these RGC types strongly differ in their spatio-temporal dendritic integration: In transient Off alpha cells, dendritic receptive fields displayed little spatial overlap, indicative of a dendritic arbour that is partitioned in largely isolated regions. In contrast, dendritic receptive fields in the other three RGCs overlapped greatly and were offset to the soma, suggesting strong synchronization of dendritic signals likely due to backpropagation of somatic signals. Also temporal correlation of dendritic signals varied extensively among these types, with transient Off mini cells displaying the highest correlation across their dendritic arbour. Modelling suggests that morphology alone cannot explain these differences in dendritic integration, but instead specific combinations of dendritic morphology and ion channel densities are required. Together, our results reveal how neurons exhibit distinct dendritic integration profiles tuned towards their type-specific computations in their circuits, with the interplay between morphology and ion channel complement as a key contributor.
Contextual extinction of drug-associated discriminative stimuli fails to attenuate drug-vs-food choice in rhesus monkeys
Authors: Banks Matthew L , Hutsell Blake A. , Negus S Stevens
Published: September 2019

Relapse within the context of a substance use disorder can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug-taking behavior. Extinction procedures can weaken this association between drug-associated cues and drug-taking behavior and may reduce the probability of relapse. This study evaluated a regimen of extinction training on cocaine and heroin self-administration in rhesus monkeys under a drug-vs.-food choice procedure. Behavior was initially maintained under a concurrent schedule of food (1-g food pellets; fixed-ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection; fixed-ratio 10) (n=4 males) or heroin injections (0-0.01 mg/kg/injection; fixed-ratio 10) (n=3 females and 1 male) during daily 2-h choice sessions. Subsequently, choice sessions were supplemented by daily 20-h extinction sessions for 14 consecutive days. During extinction sessions, drug-associated discriminative stimuli were presented, but responding produced saline injections. Drug continued to be available during choice sessions. Prior to extinction, both cocaine- and heroin-maintained dose-dependent increases in drug-vs.-food choice. Exposure to 14 extinction sessions failed to significantly decrease drug choice and increase food choice. These preclinical results do not support the effectiveness of extinguishing drug-associated discriminative stimuli as a non-pharmacological treatment strategy for reducing drug choice.
Effects of Repeated Treatment with Monoamine-Transporter-Inhibitor Antidepressants on Pain-Related Depression of Intracranial Self-Stimulation in Rats
Authors: Legakis LP , Karim-Nejad L , Negus SS
Published: September 2019

Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into the presynaptic terminal via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat pain, and emergence of analgesic effects by these compounds often requires repeated treatment for days or weeks. The present study compared antinociceptive effects produced by repeated treatment with monoamine transporter inhibitors in a preclinical assay of pain-related depression of positively reinforced operant responding. Adult male Sprague-Dawley rats equipped with microelectrodes targeting a brain-reward area responded for pulses of electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus that repeatedly depressed ICSS and also produced weight loss during 7 days of repeated acid administration. Both acid-induced ICSS depression and weight loss were blocked by repeated pretreatment with the nonsteroidal anti-inflammatory drug ketorolac (a positive control) but not by the kappa opioid receptor agonist U69,593 (a negative control). Like ketorolac, the DAT/NET inhibitor bupropion fully blocked acid-induced ICSS depression and weight loss throughout all 7 days of treatment. Conversely, the NET-selective inhibitor nortriptyline and SERT-selective inhibitor citalopram produced antinociception only after several days of repeated treatment, and weight loss was attenuated by citalopram but not by nortriptyline. These results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce a more gradual onset of antinociception during repeated treatment.
Divergent Cl− and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
Authors: Leisle Lilia , Xu Yanyan , Fortea Eva , Galpin Jason , Vien Malvin , Ahern Christopher A. , Accardi Alessio , Bernèche Simon
Published: September 2019

The CLC family of anion transporting proteins is comprised of secondary active H+-coupled exchangers and of Cl− channels. Both functional subtypes play key roles in human physiology, and mutations causing their dysfunction lead to numerous genetic disorders. Current models suggest that the CLC exchangers do not utilize a classical ‘ping-pong’ mechanism of antiport, where the transporter sequentially interacts with one substrate at a time. Rather, in the CLC exchangers both substrates bind and translocate simultaneously while moving through partially congruent pathways. How ions of opposite electrical charge bypass each other while moving in opposite directions through a shared permeation pathway remains unknown. Here, we use MD simulations in combination with biochemical and electrophysiological measurements to identify a pair of highly conserved phenylalanine residues that form an aromatic pathway, separate from the Cl− pore, whose dynamic rearrangements enable H+ movement. Mutations of these aromatic residues impair H+ transport and voltage-dependent gating in the CLC exchangers. Remarkably, the role of the aromatic pathway is evolutionarily conserved in CLC channels. Using atomic-scale mutagenesis we show that the electrostatic properties and conformational flexibility of these aromatic residues are essential determinants of channel gating. Our results suggest that Cl− and H+ move through physically distinct and evolutionarily conserved routes through the CLC channels and transporters. We propose a unifying mechanism that describes the gating mechanism of CLC exchangers and channels.
Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors
Authors: Parikh Bijal A. , Bern Michael D. , Piersma Sytse J. , Yang Liping , Beckman Diana L. , Poursine-Laurent Jennifer , Douglas Beatrice Plougastel , Yokoyama Wayne M.
Published: September 2019

Viruses have evolved strategies that highlight critical, intertwined host immune mechanisms. As postulated by the missing-self hypothesis, natural killer (NK) cells and major histocompatibility complex class I (MHC-I)-restricted cytotoxic T lymphocytes (CTLs) have opposing requirements for ubiquitously expressed MHC-I molecules. Since NK cell MHC-I-specific Ly49 inhibitory receptors prevent killing of cells with normal MHC-I, viruses evading CTLs by down-regulating MHC-I should be vulnerable to NK cells. However, definitive integratedin vivoevidence for this interplay has been lacking, in part due to receptor polymorphism and a proposed second function of Ly49 receptors in licensing NK cells via self-MHC-I. Here we generated mice lacking specific Ly49 inhibitory receptors to show their essential role in licensing and controlling murine cytomegalovirus (MCMV) infectionin vivoin an MHC-restricted manner. When MCMV cannot down-regulate MHC-I, NK cells cannot control infection that instead is mediated by CTLs, as predicted by the missing-self hypothesis.
EnClaSC: A novel ensemble approach for accurate and robust cell-type classification of single-cell transcriptomes
Authors: Chen Xiaoyang , Chen Shengquan , Jiang Rui
Published: September 2019

Background

In recent years, the rapid development of single-cell RNA-sequencing (scRNA-seq) techniques enables the quantitative characterization of cell types at a single-cell resolution. With the explosive growth of the number of cells profiled in individual scRNA-seq experiments, there is a demand for novel computational methods for classifying newly-generated scRNA-seq data onto annotated labels. Although several methods have recently been proposed for the cell-type classification of single-cell transcriptomic data, such limitations as inadequate accuracy, inferior robustness, and low stability greatly limit their wide applications.

Results

We propose a novel ensemble approach, named EnClaSC, for accurate and robust cell-type classification of single-cell transcriptomic data. Through comprehensive validation experiments, we demonstrate that EnClaSC can not only be applied to the self-projection within a specific dataset and the cell-type classification across different datasets, but also scale up well to various data dimensionality and different data sparsity. We further illustrate the ability of EnClaSC to effectively make cross-species classification, which may shed light on the studies in correlation of different species. EnClaSC is freely available at https://github.com/xy-chen16/EnClaSC.

Conclusions

EnClaSC enables highly accurate and robust cell-type classification of single-cell transcriptomic data via an ensemble learning method. We expect to see wide applications of our method to not only transcriptome studies, but also the classification of more general data.
A rare opportunist,Morganella morganii, decreases severity of polymicrobial catheter-associated urinary tract infection
Authors: Learman Brian S. , Brauer Aimee L. , Eaton Kathryn A. , Armbruster Chelsie E.
Published: September 2019

Catheter-associated urinary tract infections (CAUTIs) are common hospital-acquired infections and frequently polymicrobial, which complicates effective treatment. However, few studies experimentally address the consequences of polymicrobial interactions within the urinary tract, and the clinical significance of polymicrobial bacteriuria is not fully understood.Proteus mirabilisis one of the most common causes of monomicrobial and polymicrobial CAUTI, and frequently co-colonizes withEnterococcus faecalis, Escherichia coli, Providencia stuartii, andMorganella morganii. P. mirabilisinfections are particularly challenging due to its potent urease enzyme, which facilitates formations of struvite crystals, catheter encrustation, blockage, and formation of urinary stones. We previously determined that interactions betweenP. mirabilisand other uropathogens can enhanceP. mirabilisurease activity, resulting in greater disease severity during experimental polymicrobial infection. Our present work reveals thatM. morganiiacts onP. mirabilisin a contact-independent manner to decrease urease activity. Furthermore,M. morganiiactively prevents urease enhancement byE. faecalis, P. stuartii, andE. coli.Importantly, these interactions translate to modulation of disease severity during experimental CAUTI, predominantly through a urease-dependent mechanism. Thus, products secreted by multiple bacterial species in the milieu of the catheterized urinary tract can directly impact prognosis.
Apical length governs computational diversity of L5 pyramidal neurons
Authors: Galloni Alessandro R. , Laffere Aeron , Rancz Ede
Published: September 2019

Anatomical similarity across the neocortex has led to the common assumption that the circuitry is modular and performs stereotyped computations. Layer 5 pyramidal neurons (L5PNs) in particular are thought to be central to cortical computation because of their extensive arborisation and nonlinear dendritic operations. Here, we demonstrate that computations associated with dendritic Ca2+ plateaus in L5PNs vary substantially between the primary and secondary visual cortices. L5PNs in the secondary visual cortex show reduced dendritic excitability and smaller propensity for burst firing. This reduced excitability is correlated with shorter apical dendrites. Using numerical modelling, we uncover a universal principle underlying the influence of apical length on dendritic backpropagation and excitability, based on a Na+ channel-dependent broadening of backpropagating action potentials. In summary, we provide new insights into the modulation of dendritic excitability by apical dendrite length and show that the operational repertoire of L5 neurons is not universal throughout the brain.
Toward a dynamic threshold for quality-score distortion in reference-based alignment
Authors: Hernandez-Lopez Ana A. , Alberti Claudio , Mattavelli Marco
Published: September 2019

The intrinsic high entropy sequence metadata, known as quality scores, are largely the cause of the substantial size of sequence data files. Yet, there is no consensus on a viable reduction of the resolution of the quality score scale, arguably because of collateral side effects. In this paper we leverage on the penalty functions of HISAT2 aligner to rebin the quality score scale in such a way as to avoid any impact on sequence alignment, identifying alongside a distortion threshold for “safe” quality score representation. We tested our findings on whole-genome and RNA-seq data, and contrasted the results with three methods for lossy compression of the quality scores.
Frequency-dependent organization of the brain’s functional network through delayed-interactions
Authors: Ziaeemehr Abolfazl , Zarei Mina , Valizadeh Alireza , Mirasso Claudio R.
Published: September 2019

The structure of the brain network shows modularity at multiple spatial scales. The effect of the modular structure on the brain dynamics has been the focus of several studies in recent years but many aspects remain to be explored. For example, it is not well-known how the delays in the transmission of signals between the neurons and the brain regions, interact with the modular structure to determine the brain dynamics. In this paper, we show an important impact of the delays on the collective dynamics of the brain network with modular structure; that is, the degree of the synchrony between different brain regions is dependent on the frequency. In particular, we show that increasing the frequency the network transits from a global synchrony state to an asynchronous state, through a transition region over which the local synchrony inside the modules is stronger than the global synchrony. When the delays are dependent on the distance between the nodes, the modular structure of different spatial scales appears in the correlation matrix over different specific frequency bands, so that, finer spatial modular structure reveal in higher frequency bands. The results are justified by a simple theoretical argument and elaborated by simulations on several simplified modular networks and the connectome with different spatial resolutions.
Signals of anticipation of reward and of mean reward rates in the human brain
Authors: Viviani Roberto , Dommes Lisa , Bosch Julia , Steffens Michael , Paul Anna , Schneider Katharina L. , Stingl Julia C. , Beschoner Petra
Published: September 2019

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.
Effects of enriched housing on the neuronal morphology of mice that lack zinc transporter 3 (ZnT3) and vesicular zinc
Authors: McAllister Brendan B. , Thackray Sarah E. , de la Orta Brenda Karina Garciá , Gosse Elise , Tak Purnoor , Chipak Colten , Rehal Sukhjinder , Rascón Abril Valverde , Dyck Richard H.
Published: September 2019

In the central nervous system, certain neurons store zinc within the synaptic vesicles of their axon terminals. This vesicular zinc can then be released in an activity-dependent fashion as an intercellular signal. The functions of vesicular zinc are not entirely understood, but evidence suggests that it is important for some forms of experience-dependent plasticity in the brain. The ability of neurons to store and release vesicular zinc is dependent on expression of the vesicular zinc transporter, ZnT3. Here, we examined the neuronal morphology of mice that lack ZnT3. Brains were collected from mice housed under standard laboratory conditions and from mice housed in enriched environments – large, multilevel enclosures with running wheels, numerous objects and tunnels, and a greater number of cage mates. Golgi-Cox staining was used to visualize neurons for analysis of dendritic length and dendritic spine density. Neurons were analyzed from the barrel cortex, striatum, basolateral amygdala, and hippocampus (CA1). ZnT3 knockout mice, relative to wild type mice, exhibited increased basal dendritic length in the layer 2/3 pyramidal neurons of barrel cortex, independently of housing condition. Environmental enrichment decreased apical dendritic length in these same neurons and increased dendritic spine density on striatal medium spiny neurons. Elimination of ZnT3 did not modulate any of the effects of enrichment. Our results provide no evidence that vesicular zinc is required for the experience-dependent changes that occur in response to environmental enrichment. They are consistent, however, with recent reports suggesting increased cortical volume in ZnT3 knockout mice.
DecipheringLegionellaeffector delivery by Icm/Dot secretion system reveals a new role for c-diGMP signaling
Authors: Allombert J. , Jaboulay C. , Michard C. , Andréa C. , Charpentier X. , Vianney A. , Doublet P.
Published: September 2019

Secretion of bacterial effector proteins into host cells plays a key role in bacterial virulence. Yet, the dynamics of the secretion systems activity remains poorly understood, especially when machineries deal with the export of numerous effectors. We address the question of multi-effector secretion by focusing on theLegionella pneumophilaIcm/Dot T4SS that translocates a record number of 300 effectors. We set up a kinetic translocation assay, based on theβ-lactamase translocation reporter system combined with the effect of the protonophore CCCP. When used for translocation analysis of Icm/Dot substrates constitutively produced byL. pneumophila,this assay allows a fine monitoring of the secretion activity of the T4SS, independently of the expression control of the effectors. We observed that effectors are translocated with a specific timing, suggesting a control of their docking/translocation by the T4SS. Their delivery is accurately organized to allow effective manipulation of the host cell, as exemplified by the sequential translocation of effectors targeting Rab1, namely SidM/DrrA, LidA, LepB. Remarkably, the timed delivery of effectors does not depend only on their interaction with chaperone proteins but implies cyclic-di-GMP signaling, as the diguanylate cyclase Lpl0780/Lpp0809, contributes to the timing of translocation.

Graphical abstract

Highlights

The dynamics of multi-effector secretion is addressed in the paradigmLegionellaIcm/Dot T4SS

A kinetic translocation assay allowing a fine monitoring of the T4SS activity is set up

Specific secretion patterns consistent with sequential functions in the host are reported

T4SS-dependent translocation is promoted by a diguanylate cyclase

Unreported control of Type 4 secretion by the second messenger c-di-GMP signaling is revealed
Full-annual demography and seasonal cycles in a resident vertebrate
Authors: Guimarães Murilo , Correa Décio , Gaiarsa Marília Palumbo , Kéry Marc
Published: September 2019

Demography is usually studied at a single point in time within a year when species, mostly long-distance migrants, are more active and easier to find. However, this provides only a low-resolution glimpse into demographic temporal patterns, compromising a complete understanding of species’ population dynamics over full annual cycles. The full annual cycle is often influenced by environmental seasonality, which induces a cyclic behavior in many species. However, cycles have rarely been explicitly included in models for demographic parameters, and most information on full annual cycle demography is restricted to migratory species. Here we used a high-resolution capture-recapture study of a resident tropical lizard to assess the full intra-annual demography and within-year periodicity in survival, temporary emigration and recapture probabilities. We found important variation over the annual cycle and up to 92% of the total monthly variation explained by cycles. Fine-scale demographic studies and assessments on the importance of cycles within parameters are fundamental to understand population persistence over time.
Humanin vitromodel of material-driven vascular regeneration reveals how cyclic stretch and shear stress differentially modulate inflammation and tissue formation
Authors: van Haaften Eline E. , Wissing Tamar B. , Kurniawan Nicholas A. , Smits Anthal I.P.M. , Bouten Carlijn V.C.
Published: September 2019

1

Resorbable synthetic scaffolds designed to regenerate living tissues and organs inside the body emerge as a clinically attractive technology to replace diseased blood vessels. However, mismatches between scaffold design andin vivohemodynamic loading (i.e., cyclic stretch and shear stress) can result in aberrant inflammation and adverse tissue remodeling, leading to premature graft failure. Yet, the underlying mechanisms remain elusive. Here, a humanin vitromodel is presented that mimics the transient local inflammatory and biomechanical environments that drive scaffold-guided tissue regeneration. The model is based on the co-culture of human (myo)fibroblasts and macrophages in a bioreactor platform that decouples cyclic stretch and shear stress. Using a resorbable supramolecular elastomer as the scaffold material, it is revealed that cyclic stretch initially reduces pro-inflammatory cytokine secretion and, especially when combined with shear stress, stimulates IL-10 secretion. Moreover, cyclic stretch stimulates downstream (myo)fibroblast proliferation and neotissue formation. In turn, shear stress attenuates cyclic-stretch-induced tissue growth by enhancing MMP-1/TIMP-1-mediated collagen remodeling, and synergistically alters (myo)fibroblast phenotype when combined with cyclic stretch. The findings suggest that shear stress acts as a stabilizing factor in cyclic stretch-induced tissue formation and highlight the distinct roles of hemodynamic loads in the design of resorbable vascular grafts.
Engineering recombination between diverged yeast species reveals genetic incompatibilities
Authors: Bozdag G. Ozan , Ono Jasmine , Denton Jai A. , Karakoc Emre , Hunter Neil , Leu Jun-Yi , Greig Duncan
Published: September 2019

The major cause of the sterility of F1 hybrids formed betweenSaccharomyces cerevisiaeandSaccharomyces paradoxusis anti-recombination. The failure of homologous chromosomes from the different species to recombine causes them to mis-segregate, resulting in aneuploid gametes, most of which are inviable. These effects of anti-recombination have previously impeded the search for other forms of incompatibility, such as negative genetic interactions (Bateson-Dobzhoansky-Muller incompatibilities). By suppressing the meiotic expression ofMSH2andSGS1, we could increase recombination and improve hybrid fertility seventy-fold. This allowed us to recover meiotic tetrads in which all four gametes were viable, ensuring that segregation had occurred properly to produce perfectly haploid, not aneuploid, recombinant hybrid gametes. We sequenced the genomes of 84 such tetrads, and discovered that some combinations of alleles from different species were significantly under-represented, indicating that there are incompatible genes contributing to reproductive isolation.
Dispersal ability predicts evolutionary success among mammalian carnivores
Authors: Faurby S. , Werdelin L. , Antonelli A.
Published: September 2019

Understanding why some clades contain more species than others is a major challenge in evolutionary biology, and variation in dispersal ability and its connection to diversification rate may be part of the explanation. Several studies have suggested a negative relationship between dispersal capacity and diversification rate among living mammals. However, this pattern may differ when also considering extinct species, given known extinction biases. The colonization of new areas by various lineages may be associated with both diversity increases in those colonising lineages and declines in the lineages already present. Past diversity declines are, however, effectively impossible to infer based on phylogenies of extant taxa, and the underlying process may, therefore, be difficult to determine. Here we produce a novel species-level phylogeny of all known extant and extinct species of the order Carnivora and related extinct groups (1,723 species in total) to show that there is instead a positive relationship between dispersal rate and diversification rate when all extinct species are included. Species that disperse between continents leave more descendant species than non-dispersers, and dispersing species belong to lineages that at the time of dispersal were diversifying faster than the average non-disperser. Our study showcases the importance of combining fossils and phylogenies to better understand evolutionary and biogeographic patterns.
Rapid Reconstruction of Time-varying Gene Regulatory Networks with Limited Main Memory
Authors: Pyne Saptarshi , Anand Ashish
Published: September 2019

Reconstruction of time-varying gene regulatory networks underlying a time-series gene expression data is a fundamental challenge in the computational systems biology. The challenge increases multi-fold if the target networks need to be constructed for hundreds to thousands of genes. There have been constant efforts to design an algorithm that can perform the reconstruction task correctly as well as can scale efficiently (with respect to both time and memory) to such a large number of genes. However, the existing algorithms either do not offer time-efficiency, or they offer it at other costs – memory-inefficiency or imposition of a constraint, known as the ‘smoothly time-varying assumption’. In this paper, two novel algorithms – ‘an algorithm for reconstructing Time-varying Gene regulatory networks with Shortlisted candidate regulators - which is Light on memory’ (TGS-Lite) and ‘TGS-Lite Plus’ (TGS-Lite+) – are proposed that are time-efficient, memory-efficient and do not impose the smoothly time-varying assumption. Additionally, they offer state-of-the-art reconstruction correctness as demonstrated with three benchmark datasets.

Source Code

https://github.com/sap01/TGS-Lite-supplem/tree/master/sourcecode
Task-generic and task-specific connectivity modulations in the ADHD brain: An integrated analysis across multiple tasks
Authors: Chauvin Roselyne J. , Buitelaar Jan K. , Sprooten Emma , Oldehinkel Marianne , Franke Barbara , Hartman Catharina , Heslenfeld Dirk J. , Hoekstra Pieter J. , Oosterlaan Jaap , Beckmann Christian F. , Mennes Maarten
Published: September 2019

Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with altered functioning in multiple cognitive domains and neural networks. This paper offers an overarching biological perspective across these. We applied a novel strategy that extracts functional connectivity modulations in the brain across one (Psingle), two (Pmix) or three (Pall) cognitive tasks and compared the pattern of modulations between participants with ADHD (n-89), unaffected siblings (n=93) and controls (n=84; total N=266; age range=8-27 years).

Participants with ADHD had significantly fewer Pallconnections (modulated regardless of task), but significantly more task-specific (Psingle) connectivity modulations than the other groups. The amplitude of these Psinglemodulations was significantly higher in ADHD. Unaffected siblings showed a similar degree of Pallconnectivity modulation as controls but a similar degree of Psingleconnectivity modulation as ADHD probands. Pallconnections were strongly reproducible at the individual level in controls, but showed marked heterogeneity in both participants with ADHD and unaffected siblings.

The pattern of reduced task-generic and increased task-specific connectivity modulations in ADHD may be interpreted as reflecting a less efficient functional brain architecture due to a reduction in the ability to generalise processing pathways across multiple cognitive domains. The higher amplitude of unique task-specific connectivity modulations in ADHD may index a more “effortful” coping strategy. Unaffected siblings displayed a task connectivity profile in between that of controls and ADHD probands, supporting an endophenotype view. Our approach provides a new perspective on the core neural underpinnings of ADHD.
A framework for quantifying deviations from dynamic equilibrium theory
Authors: Kalyuzhny Michael , Flather Curtis H. , Shnerb Nadav M. , Kadmon Ronen
Published: September 2019

Community assembly is governed by colonization and extinction processes, and the simplest model describing it is Dynamic Equilibrium (DE) theory, which assumes that communities are shaped solely by stochastic colonization and extinction events. Despite its potential to serve as a null model for community dynamics, there is currently no accepted methodology for measuring deviations from the theory and testing it. Here we propose a novel and easily applicable methodology for quantifying deviations from the predictions and assumptions of DE by comparing observed community time-series to a randomization-based null model. We show that this methodology has good statistical properties on simulated data, and it can detect deviations from both the assumptions and predictions of DE in the classical Florida Keys experiment. We discuss alternative methods and present guidelines for practical use of the methodology, hoping it will enhance the applicability of DE as a reference for studying changes in ecological communities.
Sex-specific molecular specialization and activity rhythm dependent gene expression changes in honey bee antennae
Authors: Jain Rikesh , Brockmann Axel
Published: September 2019

Eusocial insects, like honey bees, which show an elaborate division of labor involving morphologically and physiologically specialized phenotypes provide a unique toolkit to study molecular underpinnings of behavior as well as neural processing. In this study, we performed an extensive RNA-seq based comparison of gene expression levels in the antennae of honey bee drones and foragers collected at different time of days and activity states to identify molecules involved in peripheral olfactory processing and provide insights into distinct strategies in sensory processing. First, honey bee drone and worker antennae differ in the number of olfactory receptor genes (ORs) showing a biased expression pattern. Only 19 Ors were higher expressed in drone antennae, whereas 54 Ors were higher expressed in workers. Second, drone antennae showed predominant higher expression of genes involved in energy metabolism, and worker antennae showed a higher expression of genes involved in neuronal communication. Third, drones and afternoon-trained foragers showed similar daily changes in the expression of major clock genes, per and cry2. Most of the other genes showing changes with the onset of daily activity were specific to drones and foragers suggesting sex-specific circadian changes in antennae. Drone antennae are specialized to detect small amounts of queen’s pheromone and quickly respond to changes in pheromone concentration involving energetically costly action potentials, whereas forager antennae are predominantly involved in behavioral context dependent detection and discrimination of complex odor mixtures which requires mechanisms of sensory filtering and neural plasticity.
The basolateral nucleus of the amygdala regulates both the predictive and incentive motivational properties of reward cues
Authors: Servonnet Alice , Hernandez Giovanni , Hage Cynthia El , Rompré Pierre-Paul , Samaha Anne-Noël
Published: September 2019

Reward-associated stimuli can acquire both predictive and incentive motivational properties. These conditioned stimuli (CS) can then guide reward-seeking behaviour in adaptive (e.g., locating food) and maladaptive (e.g., binge eating) ways. The basolateral amygdala (BLA) contributes to learning of the predictive value of CS, but less is known about BLA contributions to the incentive motivational properties of appetitive CS. Here we studied the influence of BLA neuron activity on both the predictive and incentive motivational effects of CS. Water-restricted male rats learned to associate a light-tone cue (CS) with water delivery into a port. We assessed the predictive value to the CS by measuring CS-evoked port entries during Pavlovian conditioning. We assessed CS-evoked incentive motivation by measuring lever-pressing for the CS during instrumental responding sessions. During Pavlovian conditioning, we paired CS presentations with photo-stimulation of channelrhodopsin-2 (ChR2)-expressing BLA neurons. This potentiated CS-evoked port entries during conditioning, but suppressed subsequent lever-pressing for the CS. This indicates increased conditioned responding to the CS, but an apparent decrease in incentive motivation for that CS. However, in rats previously naïve to photo-stimulation, pairing BLA-ChR2 stimulations during lever-pressing for the CS intensified responding, indicating enhanced motivation for the CS. Rats did not self-administer BLA-ChR2 stimulations, suggesting that BLA activation does not carry a primary reward signal. Lastly, intra-BLA infusions of d-amphetamine also intensified lever-pressing for the CS. These converging findings suggest that BLA mediated-activity enhances both the predictive and incentive motivational properties of CS, allowing BLA-dependent circuits to guide behaviour in the presence of reward-associated cues.

SIGNIFICANCE STATEMENT

Cues paired with rewards can guide animals to valuable resources such as food. Cues can also promote dysfunctional reward-seeking behaviour, as in over-eating. Reward-paired cues influence reward seeking through two major mechanisms. First, reward-paired cues are predictive and thus evoke anticipation of future rewards. Second, reward-paired cues are powerful motivators and they can evoke pursuit in their own right. Here we show that increasing neural activity in the basolateral amygdala enhances both the predictive and motivational effects of reward-paired cues. The basolateral amygdala therefore facilitates cue-induced control over behaviour by both increasing anticipation for impending rewards and making reward cues more attractive.
Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney
Authors: Wang Xiaoxin X. , Myakala Komuraiah , Libby Andrew E. , Panov Julia , Ranjit Suman , Takahashi Shogo , Jones Bryce A. , Bhasin Kanchan , Qi Yue , Krausz Kristopher W. , Zerfas Patricia M. , Velenosi Thomas J. , Patel Daxesh P. , Daneshpajouhnejad Parnaz , Titievsky Avi , Sharov Vadim , Ostretsov Boris , Billon Cyrielle , Chatterjee Arindam , Walker John K. , Kopp Jeffrey B. , Rosenberg Avi Z. , Gonzalez Frank J. , Guha Udayan , Brodsky Leonid , Burris Thomas P. , Levi Moshe
Published: September 2019

Background

A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR).

Methods

A pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. In addition, 21-month-old mice were treated with a STING inhibitor for 3 weeks.

Results

Remarkably, only an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression.

Conclusions

Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.

Significance Statement

There is an increasing need for prevention and treatment strategies for age-related kidney disease. The hallmarks of aging kidneys are decreased mitochondrial function and increased inflammation. The expression of the nuclear hormone receptors estrogen-related receptors (ERRs) are decreased in aging human and mouse kidneys. This paper investigates the role of ERRs in the aging kidney. Treatment of aging mice with a pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING signaling pathways. Treatment of aging mice with a STING inhibitor decreased inflammation and increased mitochondrial gene expression. These findings identify ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.
Epitope containing short peptides capture distinct IgG serodynamics that enable DIVA for live-attenuated vaccines
Authors: Xue Qinghong , Xu Hongke , Liu Huaidong , Pan Jiaojiao , Yang Jiao , Sun Miao , Chen Yanfei , Xu Wenwen , Cai Xuepeng , Ma Hongwei
Published: September 2019

Differentiating infected from vaccinated animals (DIVA) strategies have been central enabling techniques in several successful viral disease elimination programs. However, owing to their long and uncertain development process, no DIVA-compatible vaccines are available for many important diseases. We report herein a new DIVA strategy based on hybrid protein-peptide microarrays which can theoretically work with any vaccine. Leading from our findings from Peste des petits ruminants (PPR), we found 4 epitope containing short peptides (ECSPs) which have distinct IgG serodynamics: anti-ECSP IgGs only exist for 10-60 days post vaccination (dpv), while anti-protein IgGs remained at high levels for >1000 dpv. These data enabled design of a DIVA diagnostic microarray containing 4 ECSPs and 3 proteins, which unlike cELISA and VNT, enables ongoing monitoring of serological differences between vaccinated individuals and individuals exposed to the pathogen. For 50 samples after 60 dpv, 20 animals were detected with positive anti-ECSP IgGs, indicating recent infections in vaccinated goat/sheep herds. These DIVA diagnostic microarrays will almost certainly facilitate eradication programs for (re-)emerging pathogens and zoonoses.
Interleukin 11 expression causes murine inflammatory bowel disease
Authors: Lim Wei-Wen , Ng Benjamin , Widjaja Anissa , Xie Chen , Su Liping , Ko Nicole , Lim Sze-Yun , Kwek Xiu-Yi , Lim Stella , Cook Stuart A , Schafer Sebastian
Published: September 2019

Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11SMC). Within days of transgene activation, Il11SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11Fib mouse. This additional model largely phenocopied the Il11SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn’s disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.
Anthropogenic marine debris and its dynamics across peri-urban and urban mangroves on Penang Island, Malaysia
Authors: Yin Chee Su , Chai Yee Jean , Carey Danielle , Yusup Yusri , Gallagher John Barry
Published: September 2019

Mangroves act as sinks to a variety of anthropogenic marine debris (AMD) forms. However, knowledge of their distribution and accumulation dynamics is limited. To address this shortfall, abundance, sorting, and diversity parameters of AMD were evaluated across the canopy of Penang’s urban and peri-urban mangroves. Two urban and two peri-urban mangroves were sampled at different periods over 2 months, with differences constrained by possible changes in their wind fields, and neap-spring tidal development. Debris were counted and classified across transects parallel to the coastline at progressively higher water marks. Plastics made up most of the AMD across all sites. More AMD was retained in the urban sites, consistent with their larger resident population density. Diversity of debris forms were consistent with the type of land use and population livelihood in each area. The greatest differences in abundance, diversity, and evenness were recorded between the lower tidal zones and the remaining inner transects consistent with sorting towards the coastal edge in favour of plastic items. Overall, differences across transects and sites suggested: 1) the canopy and root structure within the main body of the mangrove efficiently retained debris with little sorting; and 2) debris deposited closer to the edge is increasingly sorted and lost to the water body in favour of smaller plastic items, for a constant wind field and irrespective of neap-spring phases. The findings show that mangrove areas are vulnerable to a constant build of potentially harmful debris with selective leakage and sorting of materials back to the water body closer to their coastal edges. For Penang Island, the study highlights the areas in need of attention and prioritization, lists the types of debris needing proper management, and will aid in the future monitoring, mitigation and/or rehabilitation of these sensitive ecosystems.