title: Dynamic bi-directional phosphorylation events associated with the reciprocal regulation of synapses during homeostatic up- and down-scaling.

abstract: Homeostatic synaptic scaling allows for bi-directional adjustment of the strength of synaptic connections in response to changes in their input. Protein phosphorylation modulates many neuronal and synaptic processes, but it has not been studied on a global, proteome-wide scale during synaptic scaling. To examine this, we used LC-MS/MS analyses to measure changes in the phosphoproteome in response to up- or down-scaling in cultured cortical neurons over minutes to 24 hours. Out of 45,000 phosphorylation events measured, ~3,300 (associated with 1,280 phospho-proteins) were regulated by homeostatic scaling. The activity-sensitive phosphoproteins were predominantly located at synapses and involved in cytoskeletal reorganization. We identified many early transient phosphorylation events which could serve as sensors for the activity offset as well as late and/or persistent phosphoregulation that could represent effector mechanisms driving the homeostatic response. Much of the persistent phosphorylation was reciprocally regulated by up- or down-scaling, suggesting that the mechanisms underlying these two poles of synaptic regulation make use of a common signaling axis.


title: Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

abstract:
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulate. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.

HighlightsO_LIPalmitoylation of mHTT is reduced in multiple transgenic HD mouse models
C_LIO_LIHTT palmitoylation decreases with increasing polyQ length in HD patient cells
C_LIO_LImHTT-lowering in mouse brains does not rescue aberrant palmitoylation
C_LIO_LImHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition
C_LIO_LIPromoting palmitoylation reduces mHTT aggregation and cytotoxicity in vitro
C_LI

category: neuroscience


title: Sensorimotor temporal recalibration: the contribution of motor-sensory and inter-sensory components

abstract: Adaptation to delays between actions and sensory feedback is important for efficiently interacting with our environment. Adaptation may rely on predictions of action-feedback pairing (motor-sensory component), or predictions of tactile-proprioceptive sensation from the action and sensory feedback of the action (inter-sensory component). Reliability of temporal information might differ across sensory feedback modalities (e.g. auditory or visual), influencing adaptation. Here, we investigated the role of motor-sensory and inter-sensory components on sensorimotor temporal recalibration for motor-auditory events (button press-tone) and motor-visual events (button press-Gabor patch). In the adaptation phase of the experiment, the motor action-feedback event pairs were presented with systematic temporal delays (0ms or 150ms). In the subsequent test phase, sensory feedback of the action were presented with variable delays. The participants were then asked whether this delay could be detected. To disentangle motor-sensory from inter-sensory component, we varied movements (active button press or passive depression of button) at adaptation and test. Our results suggest that motor-auditory recalibration is mainly driven by motor-sensory component, whereas motor-visual recalibration is mainly driven by inter-sensory component. Recalibration transferred from vision to audition, but not from audition to vision. These results indicate that motor-sensory and inter-sensory components of recalibration are weighted in a modality-dependent manner.


title: Continuity within somatosensory cortical map shapes the integration of optogenetic input

abstract:
The topographic organization of sensory cortices is a prominent feature, but its functional role remains unclear. Particularly, how activity is integrated within a cortical area depending on its topography is unknown. Here, we trained mice expressing channelrhodopsin in cortical excitatory neurons to track a bar photostimulation that rotated smoothly over the primary somatosensory cortex (S1). When photostimulation was aimed at vS1, the area which contains a contiguous representation of the whisker array at the periphery, mice could learn to discriminate angular positions of the bar to obtain a reward. In contrast, they could not learn the task when the photostimulation was aimed at the representation of the trunk and legs in S1, where neighboring zones represent distant peripheral body parts, introducing discontinuities. Mice demonstrated anticipation of reward availability, specifically when cortical topography enabled to predict future sensory activation. These results are particularly helpful for designing efficient cortical sensory neuroprostheses.

TeaserOptogenetic stimulation sweeping the cortical surface: A way to provide precise sensory information and guide behaviour.


title: mTORC2 contributes to murine lupus

abstract: The development of many systemic autoimmune diseases, including systemic lupus erythematosus, is associated with overactivation of the type I interferon (IFN) pathway, lymphopenia, and increased follicular helper T (Tfh) cell differentiation. However, the cellular and molecular mechanisms underlying these immunological perturbations remain incompletely understood. Here we show that the mechanistic target of rapamycin complex 2 (mTORC2) promotes Tfh differentiation and disrupts Treg homeostasis. Inactivation of mTORC2 in total T cells, but not in Tregs, greatly ameliorated the immunopathology in a systemic autoimmunity mouse model. This was associated with reduced Tfh differentiation, B cell activation, and reduced T cell glucose metabolism. Finally, we show that type I IFN can synergize with TCR ligation to activate mTORC2 in T cells, which partially contributes to T cell lymphopenia. These data indicate that mTORC2 may act as downstream of type I IFN, TCR, and costimulatory receptor ICOS, to promote glucose metabolism, Tfh differentiation, and T cell lymphopenia, but not to suppress Treg function in systemic autoimmunity. Our results suggest that mTORC2 might be a rational target for systemic autoimmunity treatment.

category: immunology


title: mTORC2 contributes to murine systemic autoimmunity


title: Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity

abstract: Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell type-specific deletion of Gpr35 in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.


title: A Chemical-Enhanced System for CRISPR-Based Nucleic Acid Detection

abstract: The CRISPR-based nucleic acid detection systems such as SHERLOCK, DETECTR and HOLMES have shown great potential for point-of-care testing of viral pathogens, especially in the context of COVID-19 pandemic. Here we optimize several key parameters of reaction chemistry and develop a Chemical Enhanced CRISPR Detection system for nucleic acid (termed CECRID). For the Cas12a/Cas13a-based signal detection phase, we determine buffer conditions and substrate range for optimal detection performance. By comparing several chemical additives, we find that addition of L-proline can secure or enhance Cas12a/Cas13a detection capability. For isothermal amplification phase with typical LAMP and RPA methods, inclusion of L-proline can also enhance specific target amplification as determined by CRISPR detection. Using SARS-CoV-2 pseudovirus, we demonstrate CECRID has enhanced detection sensitivity over chemical additive-null method with either fluorescence or lateral flow strip readout. Thus, CECRID provides an improved detection power and system robustness towards practical application of CRISPR-based diagnostics.

category: molecular biology


title: Every cog and wheel: Unraveling biocomplexity at the genomic and phenotypic level in a population complex of Chinook salmon.

abstract: Genomic diversity is the fundamental building block of biodiversity and the necessary ingredient for adaptation. Our rapidly increasing ability to quantify functional, compositional, and structural genomic diversity of populations forces the question of how to balance conservation goals - should the focus be on important functional diversity and key life history traits or on maximizing genomic diversity as a whole? Specifically, the intra-specific diversity (biocomplexity) comprised of phenotypic and genetic variation can determine the ability of a population to respond to changing environmental conditions. Here, we explore the biocomplexity of Californias Central Valley Chinook salmon (Oncorhynchus tshawytscha) population complex at the genomic level. Notably, despite apparent gene flow among individuals with the same migration (life history) phenotypes inhabiting different tributaries, each group is characterized by a surprising component of unique genomic diversity. Our results emphasize the importance of formulating conservation goals focused on maintaining biocomplexity at both the phenotypic and genotypic level. Doing so will maintain the species adaptive potential and increase the probability of persistence of the population complex despite changing environmental pressures.

category: ecology


title: Tracking the rates and mechanisms of canopy damage and recovery following Hurricane Maria using multitemporal lidar data

abstract:
Hurricane Maria (Category 4) snapped and uprooted canopy trees, removed large branches, and defoliated vegetation across Puerto Rico. The magnitude of forest damages and the rates and mechanisms of forest recovery following Maria provide important benchmarks for understanding the ecology of extreme events. We used airborne lidar data acquired before (2017) and after Maria (2018, 2020) to quantify landscape-scale changes in forest structure along a 439-ha elevational gradient (100 to 800 m) in the Luquillo Experimental Forest. Damages from Maria were widespread, with 73% of the study area losing [≥]1 m in canopy height (mean = -7.1 m). Taller forests at lower elevations suffered more damage than shorter forests above 600 m. Yet only 13% of the study area had canopy heights [≤]2 m in 2018, a typical threshold for forest gaps, highlighting the importance of damaged trees and advanced regeneration on post-storm forest structure. Heterogeneous patterns of regrowth and recruitment yielded shorter and more open forests by 2020. Nearly 45% of forests experienced initial height loss (<-1 m, 2017-2018) followed by rapid height gain (>1 m, 2018-2020), whereas 21.6% of forests with initial height losses showed little or no height gain, and 17.8% of forests exhibited no structural changes >|1| m in either period. Canopy layers <10 m accounted for most increases in canopy height and fractional cover between 2018-2020, with gains split evenly between height growth and lateral crown expansion by surviving individuals. These findings benchmark rates of gap formation, crown expansion, and canopy closure following hurricane damage.

MANUSCRIPT HIGHLIGHTSO_LIHurricane Maria gave forests a haircut by toppling trees and shearing branches.
C_LIO_LIRegrowth after Maria was patchy, with equal areas of height gain and no change.
C_LIO_LI3-D measures of forest recovery after hurricanes can improve ecosystem models.
C_LI


title: A distinct expression profile in the cerebellum and striatum for genes under selection within introgression deserts

abstract: Analyses of ancient DNA from extinct hominins have provided unique insights into the complex evolutionary history of Homo sapiens, intricately related to that of the Neanderthals and the Denisovans as revealed by several instances of admixture events. These analyses have also allowed the identification of introgression deserts: genomic regions in our species that are depleted of  archaic haplotypes. The presence of genes like FOXP2 in these deserts has been taken to be suggestive of brain-related functional differences between Homo species. Here, we seek a deeper characterization of these regions, taking into account signals of positive selection in our lineage. Analyzing publicly available transcriptomic data from the human brain at different developmental stages, we found that structures outside the cerebral neocortex, in particular the cerebellum, the striatum and the mediodorsal nucleus of the thalamus show the most divergent transcriptomic profiles when considering genes within large introgression deserts and under positive selection.

category: evolutionary biology


title: A distinct brain expression profile for genes within large introgression deserts and under positive selection in Homo sapiens


title: Sexual antagonism in haplodiploids

abstract: Females and males may face different selection pressures, such that alleles conferring a benefit in one sex may be deleterious in the other. Such sexual antagonism has received a great deal of theoretical and empirical attention, almost all of which has focused on diploids. However, a sizeable minority of animals display an alternative haplodiploid mode of inheritance, encompassing both arrhenotoky, whereby males develop from unfertilized eggs, and paternal genome elimination (PGE), whereby males receive but do not transmit a paternal genome. Alongside unusual genetics, haplodiploids often exhibit social ecologies that modulate the relative value of females and males. Here we develop a series of evolutionary-genetic models of sexual antagonism for haplodiploids, incorporating details of their molecular biology and social ecology. We find that: 1) PGE promotes female-beneficial alleles more than arrhenotoky, and to an extent determined by the timing of elimination - and degree of silencing of - the paternal genome; 2) sib-mating relatively promotes female-beneficial alleles, as do other forms of inbreeding, including limited male-dispersal, oedipal-mating, and the pseudo-hermaphroditism of Icerya purchasi; 3) resource competition between related females relatively inhibits female-beneficial alleles; and 4) sexual antagonism foments conflicts between parents and offspring, endosymbionts and hosts, and maternal-origin and paternal-origin genes.


title: Flow cytometry-based determination of ploidy from dried leaf specimens in genomically complex collections of the tropical forage grass Urochloa s. l.

abstract: We aimed to develop an optimized approach to determine ploidy for dried leaf material in a germplasm collection of a tropical forage grass group, including approaches to collect, dry and preserve plant samples for flow cytometry analysis. Urochloa (including Brachiaria, Megathyrus and some Panicum) tropical grasses are native to Africa and are now, after selection and breeding, planted worldwide, particularly in South America, as important forages with huge potential for further sustainable improvement and conservation of grasslands. The methods enable robust identification of ploidy levels (coefficient of variation, CV, typically <5%). Ploidy of some 353 forage grass accessions (ploidy range from 2 to 9), from international genetic resource collections, showing variation in basic chromosome numbers and reproduction modes (apomixis and sexual), were determined using our defined standard protocol. Two major Urochloa agamic complexes used in the current breeding programs at CIAT and EMBRAPA: the  brizantha and  humidicola agamic complexes are variable, with multiple ploidy levels and DNA content. U. brizantha has odd level of ploidy (x=5), and the relative differences in nuclear DNA content between adjacent cytotypes is reduced, thus more precise examination of this species is required. Ploidy measurement of U. humidicola revealed some aneuploidy.

category: genomics


title: Optimized hip-knee-ankle exoskeleton assistance at a range of walking speeds

abstract:
BackgroundEffective autonomous exoskeletons will need to be useful at a variety of walking speeds, but we do not know how optimal exoskeleton assistance should change with speed. Optimal exoskeleton assistance may increase with speed similar to biological torque changes or a well-tuned assistance profile may be effective at a variety of speeds.

MethodsWe optimized hip-knee-ankle exoskeleton assistance to reduce metabolic cost for three participants walking at 1.0 m/s, 1.25 m/s and 1.5 m/s. We measured metabolic cost, muscle activity, exoskeleton assistance and kinematics. We performed two tailed paired t-tests to determine significance.

ResultsExoskeleton assistance reduced the metabolic cost of walking compared to wearing the exoskeleton with no torque applied by 26%, 47% and 50% at 1.0, 1.25 and 1.5 m/s, respectively. For all three participants, optimized exoskeleton ankle torque was the smallest for slow walking, while hip and knee torque changed slightly with speed in ways that varied across participants. Total applied positive power increased with speed for all three participants, largely due to increased joint velocities, which consistently increased with speed.

ConclusionsExoskeleton assistance is effective at a range of speeds and is most effective at medium and fast walking speeds. Exoskeleton assistance was less effective for slow walking, which may explain the limited success in reducing metabolic cost for patient populations through exoskeleton assistance. Exoskeleton designers may have more success when targeting activities and groups with faster walking speeds. Speed-related changes in optimized exoskeleton assistance varied by participant, indicating either the benefit of participant-specific tuning or that a wide variety of torque profiles are similarly effective.

category: bioengineering


title: Continuous monitoring reveals protective effects of N-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

abstract: Microphysiological systems mimic the in-vivo cellular ensemble and microenvironment with the goal of providing more human-like models for biopharmaceutical research. We report the first such model of the blood-brain barrier (BBB-on-chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)-derived cells and continuous barrier integrity monitoring with <2-minute temporal resolution. We showcase its capabilities in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off-stoichiometry thiol-ene epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell-substrate endothelial resistance monitoring allows us to capture formation and breakdown of our blood-brain barrier model, consisting of co-cultured hiPSC-derived endothelial-like and astrocyte-like cells. We observe clear cellular disruption when exposing the BBB-on-chip to the nitrosative stressor linsidomine, and report on the barrier permeability and barrier-protective effects of the antioxidant N-acetylcysteine amide. Using metabolomic network analysis, we further find drug-induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like ours opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human-derived cells and providing high-resolution temporal readouts that can help in pharmacodynamic studies.


title: Building the Mega Single Cell Transcriptome Ocular Meta-Atlas

abstract: The development of highly scalable single cell transcriptome technology has resulted in the creation of thousands of datasets, over 30 in the retina alone. Analyzing the transcriptomes between different projects is highly desirable as this would allow for better assessment of which biological effects are consistent across independent studies. However it is difficult to compare and contrast data across different projects as there are substantial batch effects from computational processing, single cell technology utilized, and the natural biological variation. While many single cell transcriptome specific batch correction methods purport to remove the technical noise it is difficult to ascertain which method functions works best. We developed a lightweight R package (scPOP) that brings in batch integration methods and uses a simple heuristic to balance batch merging and celltype/cluster purity. We use this package along with a Snakefile based workflow system to demonstrate how to optimally merge 766,615 cells from 33 retina datsets and three species to create a massive ocular single cell transcriptome meta-atlas. This provides a model how to efficiently create meta-atlases for tissues and cells of interest.

category: bioinformatics


title: Profiles of expressed mutations in single cells reveal patterns of tumor evolution and therapeutic impact of intratumor heterogeneity

abstract: Advances in single-cell RNA sequencing (scRNAseq) technologies uncovered an unexpected complexity in tumors, underlining the relevance of intratumor heterogeneity to cancer progression and therapeutic resistance. Heterogeneity in the mutational composition of cancer cells is a result of distinct (sub)clonal expansions, each with a distinct metastatic potential and resistance to specific treatments. Unfortunately, due to their low read coverage per cell, scRNAseq datasets are too sparse and noisy to be used for detecting expressed mutations in single cells. Additionally, the large number of cells and mutations present in typical scRNAseq datasets are too large for available computational tools to, e.g., infer distinct subclones, lineages or trajectories in a tumor. Finally, there are no principled methods to assess distinct subclones inferred through single-cell sequencing data and the genomic alterations that seed and potentially cause them. Here we present Trisicell, a computational toolkit for scalable mutational intratumor heterogeneity inference and assessment from scRNAseq as well as single-cell genome or exome sequencing data. Trisicell allows reliable identification of distinct clonal lineages of a tumor, offering the ability to focus on the most important subclones and the genomic alterations that are associated with tumor proliferation. We comprehensively assessed Trisicell on a melanoma model by comparing distinct lineages and subclones it identifies on scRNAseq data, to those inferred using matching bulk whole exome (bWES) and transcriptome (bWTS) sequencing data from clonal sublines derived from single cells. Our results demonstrate that distinct lineages and subclones of a tumor can be reliably inferred and evaluated based on mutation calls from scRNAseq data through the use of Trisicell. Additionally, they reveal a strong correlation between aggressiveness and mutational composition, both across the inferred subclones, and among human melanomas. We also applied Trisicell to infer and evaluate distinct subclonal expansion patterns of the same mouse melanoma model after treatment with immune checkpoint blockade (ICB). After integratively analyzing our cell-specific mutation calls with their expression profiles, we observed that each subclone with a distinct set of novel somatic mutations is strongly associated with a specific developmental status. Moreover, each subclone had developed a unique ICB-resistance mechanism. These results demonstrate that Trisicell can robustly utilize scRNAseq data to delineate intratumor heterogeneity and help understand biological mechanisms underlying tumor progression and resistance to therapy.


title: Profiles of expressed mutations in single cells reveal subclonal expansion patterns and therapeutic impact of intratumor heterogeneity


title: ModPhred: an integrative toolkit for the analysis and storage of nanopore sequencing DNA and RNA modification data

abstract:
MotivationDNA and RNA modifications can now be identified using Nanopore sequencing. However, we currently lack a flexible software to efficiently encode, store, analyze and visualize DNA and RNA modification data.

ResultsHere we present ModPhred, a versatile toolkit that facilitates DNA and RNA modification analysis from nanopore sequencing reads in a user-friendly manner. ModPhred integrates probabilistic DNA and RNA modification information within the FASTQ and BAM file formats, can be used to encode multiple types of modifications simultaneously, and its output can be easily coupled to genomic track viewers, facilitating the visualization and analysis of DNA and RNA modification information in individual reads in a simple and computationally efficient manner.

Availability and ImplementationModPhred is available at https://github.com/novoalab/modPhred, is implemented in Python3, and is released under an MIT license.

Supplementary DataSupplementary Data are available at Bioinformatics online.


title: Gene Expression Variation in Arabidopsis Embryos at Single-Nucleus Resolution

abstract:
Soon after fertilization of egg and sperm, plant genomes become transcriptionally activated and drive a series of coordinated cell divisions to form the basic body plan during embryogenesis. Early embryonic cells rapidly diversify from each other, and investigation of the corresponding gene expression dynamics can help elucidate underlying cellular differentiation programs. However, current plant embryonic transcriptome datasets either lack cell-specific information or have RNA contamination from surrounding non-embryonic tissues. We have coupled fluorescence-activated nuclei sorting together with single-nucleus mRNA sequencing to construct a gene expression atlas of Arabidopsis thaliana early embryos at single-cell resolution. In addition to characterizing cell-specific transcriptomes, we found evidence that distinct epigenetic and transcriptional regulatory mechanisms operate across emerging embryonic cell types. These datasets and analyses, as well as the approach we devised, are expected to facilitate the discovery of molecular mechanisms underlying pattern formation in plant embryos.

Summary statementA transcriptome atlas of Arabidopsis embryos constructed from single nuclei reveals cell-specific epigenetic and transcriptional regulatory features.

category: plant biology


title: Uvariopsis ebo (Annonaceae) a new, Critically Endangered tree species from the Ebo Forest, Cameroon and a key to the Cameroonian species of Uvariopsis

abstract: A new species to science of evergreen forest tree, Uvariopsis ebo (Annonaceae) is described, illustrated, mapped, and compared morphologically with the other cauliflorous species of the genus. Restricted so far to a single site in evergreen lowland forest in the Ebo Forest, Yabassi, Littoral Region, Cameroon, this species is Critically Endangered using the IUCN 2012 standard, because the forest habitat of this species remains unprotected, and there exists threats of logging and conversion to plantations. This species adds to the growing list of threatened species resulting from anthropogenic pressure on Cameroon forests. Observations on the unusual corolla structure of the new species are made. A revised key to the 14 Cameroonian species of Uvariopsis is presented. Notes are given on other narrowly endemic and threatened species in the Ebo forest area, a highly threatened centre of diversity in Littoral Region, globally important for conservation.


title: The phosphate starvation response recruits the TOR pathway to regulate growth in Arabidopsis cell cultures

abstract: AO_SCPLOWBSTRACTC_SCPLOWIn eukaryotes, TOR (Target Of Rapamycin) is a conserved regulator of growth that integrates both endogenous and exogenous signals. These signals include the internal nutritional status, and in plants, TOR has been shown to be regulated by carbon, nitrogen and sulfur availability. In this study, we show that in Arabidopsis the TOR pathway also integrates phosphorus availability to actively modulate the cell cycle, which in turn regulates the intracellular content of amino acids and organic acids. We observed a substantial overlap between the phenotypic, metabolic and transcriptomic responses of TOR inactivation and phosphorus starvation in Arabidopsis cell culture. Although phosphorus availability modulates TOR activity, changes in the levels of TOR activity do not alter the expression of marker genes for phosphorus status. These data prompted us to place the sensing of phosphorus availability upstream of the modulation of TOR activity which, in turn, regulates the cell cycle and primary metabolism to adjust plant growth in plants.


title: The temperature-regulated DEAD-box RNA helicase CrhR interactome: Autoregulation and photosynthesis-related transcripts

abstract:
RNA helicases play crucial functions in RNA biology. In plants, RNA helicases are encoded by large gene families, performing roles in abiotic stress responses, development, the post-transcriptional regulation of gene expression as well as house-keeping functions. Several of these RNA helicases are targeted to the organelles, mitochondria and chloroplasts. Cyanobacteria are the direct evolutionary ancestors of plant chloroplasts. The cyanobacterium Synechocystis 6803 encodes a single DEAD-box RNA helicase, CrhR, that is induced by a range of abiotic stresses, including low temperature. Though the {Delta}crhR mutant exhibits a severe cold-sensitive phenotype, the physiological function(s) performed by CrhR have not been described. To identify transcripts interacting with CrhR, we performed RNA co-immunoprecipitation with extracts from a Synechocystis crhR deletion mutant expressing the FLAG-tagged native CrhR or a K57A mutated version with an anticipated enhanced RNA binding. The composition of the interactome was strikingly biased towards photosynthesis-associated and redox-controlled transcripts. A transcript highly enriched in all experiments was the crhR mRNA, suggesting an auto-regulatory molecular mechanism. The identified interactome explains the described physiological role of CrhR in response to the redox poise of the photosynthetic electron transport chain and characterizes CrhR as an enzyme with a diverse range of transcripts as molecular targets.

HighlightThe cyanobacterial DEAD-box RNA helicase CrhR binds mainly photosynthesis-associated and redox-controlled transcripts connecting its regulation, localization and phenotypes of mutants for the first time with a set of potential RNA targets.


title: Involvement of denervated midbrain-derived factors in the formation of ectopic cortico-mesencephalicprojection after hemispherectomy

abstract: Neuronal remodeling after brain injury is essential for functional recovery. After unilateral cortical lesion, axons from the intact cortex ectopically project to the denervated midbrain to compensate for the lost function, but the underlying molecular mechanisms remain largely unknown. To address this issue, we examined gene expression profiles in denervated and intact mouse midbrains after hemispherectomy at P6, when ectopic contralateral projection occurs robustly. The analysis showed that various axon growth-related genes were upregulated in the denervated midbrain, and most of these genes are reportedly expressed by astrocytes or microglia. To identify the underlying molecules, the receptors for candidate upregulated molecules were knocked out in layer 5 projection neurons in the intact cortex, using the CRISPR/Cas9-mediated method, and axonal projection from the knocked-out cortical neurons was examined after hemispherectomy. We found that the ectopic projection was significantly reduced when integrin subunit beta 3 (Itgb3) or neurotrophic receptor tyrosine kinase 2 (Ntrk2, also known as TrkB) was knocked out. Overall, the present study suggests that midbrain-derived glial factors whose expression is upregulated after hemispherectomy are involved in lesion-induced remodeling of the cortico-mesencephalic projection.


title: Axon guidance modalities in CNS regeneration revealed by quantitative proteomic analysis

abstract: Long-distance regeneration of the central nervous system (CNS) has been achieved from the eye to the brain through activation of neuronal molecular pathways or pharmacological approaches. Unexpectedly, most of the regenerative fibers display guidance defects, which prevents reinnervation and further functional recovery. Therefore, characterizing the mature neuronal environment is essential to understand the adult axonal guidance in order to complete the circuit reconstruction. To this end, we used mass spectrometry to characterize the proteomes of major nuclei of the adult visual system: suprachiasmatic nucleus (SCN), ventral and dorsal lateral geniculate nucleus (vLGN, dLGN) and superior colliculus (SCol)), as well as the optic chiasm. These analyses revealed the presence of guidance molecules and guidance-associated factors in the adult visual targets. Moreover, by performing bilateral optic nerve crush, we showed that the expression of some proteins was significantly modulated by the injury in the visual targets, even in the ones most distal to the lesion site. On another hand, we found that the expression of guidance molecules was not modified upon injury. This implies that these molecules may possibly interfere with the reinnervation of the brain targets. Together, our results provides an extensive characterization of the molecular environment in intact and injured conditions. These findings open new ways to correct regenerating axon guidance notably by manipulating the expression of the corresponding guidance receptors in the nervous system.


title: Paraburkholderia edwinii protects Aspergillus sp. from phenazines by acting as a toxin sponge

abstract: Many environmentally and clinically important fungi are sensitive to toxic, bacterially-produced, redox-active molecules called phenazines. Despite being vulnerable to phenazine-assault, fungi inhabit microbial communities that contain phenazine producers. Because many fungi cannot withstand phenazine challenge, but some bacterial species can, we hypothesized that bacterial partners may protect fungi in phenazine-replete environments. In the first soil sample we collected, we co-isolated several such physically associated pairings. We discovered the novel species Paraburkholderia edwinii and demonstrated it can protect a co-isolated Aspergillus species from phenazine-1-carboxylic acid (PCA) by sequestering it, acting as a toxin sponge; in turn, it also gains protection. When challenged with PCA, P. edwinii changes its morphology, forming aggregates within the growing fungal colony. Further, the fungal partner triggers P. edwinii to sequester PCA and maintains conditions that limit PCA toxicity by promoting an anoxic and highly reducing environment. A mutagenic screen revealed this program depends on the stress-inducible transcriptional repressor HrcA. We show that one relevant stressor in response to PCA challenge is fungal acidification and that acid stress causes P. edwinii to behave as though the fungus were present. Finally, we reveal this phenomenon as widespread among Paraburkholderia with moderate specificity among bacterial and fungal partners, including plant and human pathogens. Our discovery suggests a common mechanism by which fungi can gain access to phenazine-replete environments, and provides a tractable model system for its study. These results have implications for how rhizosphere microbial communities as well as plant and human infection sites are policed for fungal membership.

category: microbiology


title: Correction for sample overlap, winner's curse and weak instrument bias in two-sample Mendelian Randomization

abstract:
BackgroundInverse-variance weighted two-sample Mendelian randomization (IVW-MR) is the most widely used approach that utilizes genome-wide association studies (GWAS) summary statistics to infer the existence and the strength of the causal effect between an exposure and an outcome. Estimates from this approach can be subject to different biases due to the use of weak instruments and winners curse, which can change as a function of the overlap between the exposure and outcome samples.

MethodsWe developed a method (MRlap) that simultaneously considers weak instrument bias and winners curse, while accounting for potential sample overlap. Assuming spike-and-slab genomic architecture and leveraging LD-score regression and other techniques, we could analytically derive, reliably estimate, and hence correct for the bias of IVW-MR using association summary statistics only.

ResultsWe tested our approach using simulated data for a wide range of realistic settings. In all the explored scenarios, our correction reduced the bias, in some situations by as much as 30 folds. When applied to real data on obesity-related exposures, we observed significant differences between IVW-based and corrected effects, both for non-overlapping and fully overlapping samples. Additionally, our results are consistent with the fact that the strength of the biases will decrease as the sample size increases. Finally, we also showed that the overall bias is also dependent on the genetic architecture of the exposure, and traits with low heritability and/or high polygenicity are more strongly affected.

ConclusionsOur method not only reduces bias in causal effect estimation but also enables the use of much larger GWAS sample sizes, by allowing for potentially overlapping samples.

category: genetics


title: Bias correction for inverse variance weighting Mendelian randomization


title: Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by Supervised Molecular Dynamics simulation

abstract: Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing the SuMD method, we reconstructed the unbinding pathways of Indinavir from HIV and HTLV-1 proteases to compare and understand the mechanism of the unbinding and discover the reasons for the lack of inhibitory activity against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases. Also, we found that the mobility and fluctuations of the flap region are higher in the HTLV-1 protease, making the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98' and Phe67/Phe67' in the HTLV-1 protease could make strong {pi}-Stacking interactions with Indinavir, which are unfavorable for the stability of Indinavir in the active site. The details found in this study can make a reasonable explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can help design more effective and more selective inhibitors for the HTLV-1 protease.


title: Haplotype-aware pantranscriptome analyses using spliced pangenome graphs

abstract: Pangenomics is emerging as a powerful computational paradigm in bioinformatics. This field uses population-level genome reference structures, typically consisting of a sequence graph, to mitigate reference bias and facilitate analyses that were challenging with previous reference-based methods. In this work, we extend these methods into transcriptomics to analyze sequencing data using the pantranscriptome: a population-level transcriptomic reference. Our novel toolchain can construct spliced pangenome graphs, map RNA-seq data to these graphs, and perform haplotype-aware expression quantification of transcripts in a pantranscriptome. This workflow improves accuracy over state-of-the-art RNA-seq mapping methods, and it can efficiently quantify haplotype-specific transcript expression without needing to characterize a samples haplotypes beforehand.


title: Measuring hidden phenotype: Quantifying the shape of barley seeds using the Euler Characteristic Transform

abstract: Shape plays a fundamental role in biology. Traditional phenotypic analysis methods measure some features but fail to measure the information embedded in shape comprehensively. To extract, compare, and analyze this information embedded in a robust and concise way, we turn to Topological Data Analysis (TDA), specifically the Euler Characteristic Transform. TDA measures shape comprehensively using mathematical representations based on algebraic topology features. To study its use, we compute both traditional and topological shape descriptors to quantify the morphology of 3121 barley seeds scanned with X-ray Computed Tomography (CT) technology at 127 micron resolution. The Euler Characteristic Transform measures shape by analyzing topological features of an object at thresholds across a number of directional axes. A Kruskal-Wallis analysis of the information encoded by the topological signature reveals that the Euler Characteristic Transform picks up successfully the shape of the crease and bottom of the seeds. Moreover, while traditional shape descriptors can cluster the seeds based on their accession, topological shape descriptors can cluster them further based on their panicle. We then successfully train a support vector machine (SVM) to classify 28 different accessions of barley based exclusively on the shape of their grains. We observe that combining both traditional and topological descriptors classifies barley seeds better than using just traditional descriptors alone. This improvement suggests that TDA is thus a powerful complement to traditional morphometrics to comprehensively describe a multitude of "hidden" shape nuances which are otherwise not detected.


title: Orthogonal neural codes for phonetic features in the infant brain

abstract:
Creating invariant representations from an ever-changing speech signal is a major challenge for the human brain. Such an ability is particularly crucial for preverbal infants who must discover the phonological, lexical and syntactic regularities of an extremely inconsistent signal in order to acquire language. Within visual perception, an efficient neural solution to overcome signal variability consists in factorizing the input into orthogonal and relevant low-dimensional components. In this study we asked whether a similar neural strategy grounded on phonetic features is recruited in speech perception.

Using a 256-channel electroencephalographic system, we recorded the neural responses of 3-month-old infants to 120 natural consonant-vowel syllables with varying acoustic and phonetic profiles. To characterize the specificity and granularity of the elicited representations, we employed a hierarchical generalization approach based on multivariate pattern analyses. We identified two stages of processing. At first, the features of manner and place of articulation were decodable as stable and independent dimensions of neural responsivity. Subsequently, phonetic features were integrated into phoneme-identity (i.e. consonant) neural codes. The latter remained distinct from the representation of the vowel, accounting for the different weights attributed to consonants and vowels in lexical and syntactic computations.

This study reveals that, despite the paucity of articulatory motor plans and productive skills, the preverbal brain is already equipped with a structured phonetic space which provides a combinatorial code for speech analysis. The early availability of a stable and orthogonal neural code for phonetic features might account for the rapid pace of language acquisition during the first year.

SIGNIFICANCE STATEMENTFor adults to comprehend spoken language, and for infants to acquire their native tongue, it is fundamental to perceive speech as a sequence of stable and invariant segments despite its extreme acoustic variability. We show that the brain can achieve such a critical task thanks to a factorized representational system which breaks down the speech input into minimal and orthogonal components: the phonetic features. These elementary representations are robust to signal variability and are flexibly recombined into phoneme-identity percepts in a secondary processing phase. In contradiction with previous accounts questioning the availability of authentic phonetic representations in early infancy, we show that this neural strategy is implemented from the very first stages of language development.


title: Effects of sequence motifs in the yeast 3' untranslated region determined from massively-parallel assays of random sequences

abstract: The 3' untranslated region (UTR) plays critical roles in determining the level of gene expression, through effects on activities such as mRNA stability and translation. The underlying functional elements within this region have largely been identified through analyses of the limited number of native genes. To explore the effects of sequence elements when not present in biologically evolved sequence backgrounds, we analyzed hundreds of thousands of random 50-mers inserted into the 3' UTR of a reporter gene in the yeast Saccharomyces cerevisiae. We determined relative protein expression levels from the fitness of a library of transformants in a growth selection. We find that the consensus 3' UTR efficiency element significantly boosts expression, independent of sequence context; on the other hand, the consensus positioning element has only a small effect on expression. Some sequence motifs that are binding sites for Puf proteins substantially increase expression in this random library, despite these proteins generally being associated with post-transcriptional downregulation when bound to native mRNAs. Thus, the regulatory effects of 3' UTR sequence features like the positioning element and Puf binding sites appear to be strongly dependent on their context within native genes, where they exist alongside co-evolved sequence features. Our measurements also allowed a systematic examination of the effects of point mutations within efficiency element motifs across diverse sequence backgrounds. These mutational scans reveal the relative in vivo importance of individual bases in the efficiency element, which likely reflects their roles in binding the Hrp1 protein involved in cleavage and polyadenylation.


title: Energy Landscape of Ubiquitin is Weakly Multidimensional

abstract:
Single molecule pulling experiments report time-dependent changes in the extension (X) of a biomolecule as a function of the applied force (f). By fitting the data to one-dimensional analytical models of the energy landscape, the hopping rates between the folded and unfolded states in two-state folders, the height and the location of the transition state (TS) can be extracted. Although this approach is remarkably insightful, there are cases for which the energy landscape is multidimensional (catch bonds being the most prominent). To assess if the unfolding energy landscape in small single domain proteins could be one dimensional, we simulated force-induced unfolding of Ubiquitin (Ub) using the coarse-grained Self-Organized Polymer-Side Chain (SOP-SC) model. Brownian dynamics simulations using the SOP-SC model reveal that the Ub energy landscape is weakly multidimensional (WMD) governed predominantly by a single barrier. The unfolding pathway is confined to a narrow reaction pathway that could be described as diffusion in a quasi 1D X-dependent free energy profile. However, a granular analysis using the Pfold analysis, which does not assume any form for the reaction coordinate, shows that X alone does not account for the height, and more importantly, the location of the TS. The f-dependent TS location moves towards the folded state as f increases, in accord with the Hammond postulate. Our study shows that, in addition to analyzing the f-dependent hopping rates, the transition state ensemble must also be determined without resorting to X as a reaction coordinate in order to describe the unfolding energy landscapes of single domain proteins, especially if they are only WMD.

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category: biophysics


title: Transcription initiation at a consensus bacterial promoter proceeds via a "bind-unwind-load-and-lock" mechanism

abstract:
Transcription initiation starts with unwinding of promoter DNA by RNA polymerase (RNAP) to form a catalytically competent RNAP-promoter complex (RPO). Despite extensive study, the mechanism of promoter unwinding has remained unclear, in part due to the transient nature of intermediates on path to RPo. Here, using single-molecule unwinding-induced fluorescence enhancement to monitor promoter unwinding, and single-molecule fluorescence resonance energy transfer to monitor RNAP clamp conformation, we analyze RPo formation at a consensus bacterial core promoter. We find that the RNAP clamp is closed during promoter binding, remains closed during promoter unwinding, and then closes further, locking the unwound DNA in the RNAP active-centre cleft. Our work defines a new, "bind-unwind-load-and-lock," model for the series of conformational changes occurring during promoter unwinding at a consensus bacterial promoter and provides the tools needed to examine the process in other organisms and at other promoters.

Significance statementTranscription initiation, the first step and most important step in gene expression for all organisms, involves unwinding of promoter DNA by RNA polymerase (RNAP) to form an open complex (RPo); this step also underpins transcriptional regulation and serves as an antibiotic target. Despite decades of research, the mechanism of promoter DNA unwinding has remained unresolved. Here, we solve this puzzle by using single-molecule fluorescence to directly monitor conformational changes in the promoter DNA and RNAP in real time during RPo formation. We show that RPo forms via a "bind-unwind-load-and-lock" mechanism, where the promoter unwinds outside the RNAP cleft, the unwound template DNA loads into the cleft, and RNAP "locks" the template DNA in place by closing the RNAP clamp module.

category: biochemistry


title: Effects of short-term isolation on social animals' behavior: an experimental case study of Japanese macaque

abstract: One of the goals in animal socioecology is to understand the functions and dynamics of group living. While observations of free-ranging animals are a crucial source of information, an experimental investigation that manipulates the size or composition, or both, of animal groups in captivity can also bring complementary contributions to the research inquiry. When paired with an automatic data collection by biologging technology, experimental studies on captive animals also allow for big data analyses based on recent machine learning techniques. As an initial exploration of this research paradigm, the present study inquired to what extent isolation of captive Japanese macaques (Macaca fuscata) changed their movement patterns. Using three-dimensional location trajectories of the macaques that were systematically collected via Bluetooth Low Energy beacons and a deep neural network, we estimated the identifiability of whether a macaque was behaving in isolation or in group. We found that the neural network identified the isolation vs. in-group conditions with more than 90% accuracy from a five-minute location trajectory, suggesting that the isolation caused notable changes from the canonical group-living behaviors. In addition, the isolation made each individual more identifiable from one another based on their location trajectories.

category: animal behavior and cognition


title: Brain-wide neuronal activation and functional connectivity are modulated by prior exposure to repetitive learning episodes.

abstract: Memory storage and retrieval are shaped by past experiences. Prior learning and memory episodes have numerous impacts on brain structure from micro to macroscale. Previous experience with specific forms of learning increases the efficiency of future learning. It is less clear whether such practice effects on one type of memory might also have transferable effects to other forms of memory. Different forms of learning and memory rely on different brain-wide networks but there are many points of overlap in these networks. Enhanced structural or functional connectivity caused by one type of learning may be transferable to another type of learning due to overlap in underlying memory networks. Here, we investigated the impact of prior chronic spatial training on the task-specific functional connectivity related to subsequent contextual fear memory recall in mice. Our results show that mice exposed to prior spatial training exhibited decreased brain-wide activation compared to control mice during the retrieval of a context fear memory. With respect to functional connectivity, we observed changes in several network measures notably an increase in global efficiency. Interestingly, we also observed an increase in network resilience based on simulated targeted node deletion. Overall, this study suggests that chronic learning has transferable effects on the functional connectivity networks of other types of learning and memory. The generalized enhancements in network efficiency and resilience suggest that learning itself may protect brain networks against deterioration.


title: Comparative multi-tissue profiling reveals extensive tissue-specificity in transcriptome reprogramming upon cold exposure

abstract: Cold exposure is an extensively used intervention for enhancing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. The metabolic consequences of cold acclimation are not limited to the adipose tissues, however the impact on rest of the tissues in context of their gene expression profile remains unclear. Here we provide a systematic characterization of cold exposure-mediated effects in a comparative multi-tissue RNA sequencing approach using wide range of organs including spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, subcutaneous-, visceral- and brown adipose tissues. Our findings highlight that transcriptional responses to cold exposure exhibit high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, which is not directed by the basal gene expression pattern exhibited by the various organs. Our study places the cold adaptation of individual tissues in a whole-organism framework and provides an integrative transcriptional analysis necessary for understanding the cold exposure-mediated biological reprograming.

category: physiology


title: Histologic and Proteomic Remodeling of the Pulmonary Veins and Arteries in a Porcine Model of Chronic Pulmonary Venous Hypertension

abstract:
AIMIn heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling.

METHODSLarge PV were banded (PVH, n= 10) or not (Sham, n=9) in piglets. At sacrifice, PV and PA were perfusion labeled for vessel specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry.

RESULTSPulmonary vascular resistance (Wood Units; 8.6 versus 2.0) and PA (19.9 versus 10.3) and PV (14.2 versus 7.6) wall thickness/external diameter (%) were increased in PVH (p<0.01 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 versus 161), altered canonical pathways (17 versus 3) and predicted up-stream regulators (PUSR; 22 versus 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mTOR signaling with dysregulated growth. In PV, there was also activation of Rho/Rho kinase signaling with decreased actin cytoskeletal signaling and altered tight and adherens junctions, ephrin B, and caveolar mediated endocytosis signaling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (TGF-{beta}) indicated endothelial mesenchymal transition (EndoMT) in PV. Findings were confirmed in human autopsy specimens.

CONCLUSIONThese findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

TRANSLATIONAL PERSPECTIVEIn heart failure (HF) related (Group 2) PH, despite remodeling of pulmonary veins (PV) and arteries (PA), therapies targeting PA biology altered in Group 1 PH have not shown consistent benefit. In a porcine Group 2 PH model, microdissection allowed vessel specific (PV and PA) proteomics/bioinformatics. In PA and PV, the integrated stress response and mTOR signaling were activated with evidence of dysregulated growth. In PV, many more pathways were altered with broad evidence of disrupted endothelial barrier function and endothelial mesenchymal transition. Findings were confirmed in human specimens and provide new therapeutic targets in Group 2 PH.


title: Association of stress-related limbic activity and baseline interleukin-6 plasma levels in healthy adults

abstract: Several studies suggest a link between acute changes in inflammatory parameters due to an endotoxin or (psychological) stressor and the brains stress response. The extent to which basal circulating levels of inflammatory markers are associated with the brains stress response has been hardly investigated so far. In the present study, plasma levels of the cytokine interleukin (IL)-6 were obtained as a baseline measure of peripheral inflammatory processes and linked to neural markers of psychosocial stress using a modified version of the Montreal Imaging Stress Task in a sample of N=65 healthy subjects. Of three a-priori defined regions of interest - the amygdala, anterior insula, and anterior cingulate cortex - baseline IL-6 was significantly and negatively associated with stress-related neural activation in the right amygdala and left anterior insula. Our results suggest that baseline inflammatory physiology might be related to differences in the neural stress response and that this relationship could be inverse to that previously shown by studies on acutely induced inflammation.


title: Acute vagus nerve stimulation does not affect liking or wanting ratings of food in healthy participants

abstract: The vagus nerve plays a vital role in the regulation of food intake and vagal afferent signals may help regulate food cue reactivity by providing negative homeostatic feedback. Despite strong evidence from preclinical studies on vagal afferent "satiety" signals in guiding food intake, evidence from human studies is largely inconclusive to date. Here, we investigated the acute effects of left or right transcutaneous auricular vagus nerve stimulation (taVNS) on subjective ratings of wanting and liking of various food and non-food items in 82 healthy participants (46 women, MBMI = 23.1 kg/m2). In contrast to previous reports in patients with depression, we found moderate to anecdotal evidence supporting the absence of taVNS-induced changes in food ratings. To test whether the absence of taVNS effects on food ratings is due to heterogeneity in the sample, we conducted post hoc subgroup analyses by splitting the data according to stimulation side and sex (between-subject factors) as well as caloric density, perceived healthiness, and flavor (sweet vs. savory) of the food (within-subject factors). This multiverse analysis largely supported the absence of taVNS-induced changes since the strongest subgroup effects provided only anecdotal evidence in favor of taVNS-induced changes. We conclude that acute taVNS only has a marginal effect on subjective ratings of food, suggesting that it is an unlikely mechanism for the reported long-term effects of VNS on body weight. In light of an absence of acute taVNS effects on food craving, our results call for future research on the correspondence between acute and chronic effects of vagal afferent stimulation.


title: Identification of Blood Based biomarker for Huntington's disease using in-silico gene expression analysis

abstract: Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder with profound phenotypic characters. HD is at present incurable and there are several trials going on to find a cure. HD is caused when there is a mutation in the Huntingtin gene which is found to be associated with axonal transport. Diagnosis is based on the signs and symptoms of the patients but by that time the psychomotor problems have already reached the level from where reversing the disease is impossible. Blood based biomarkers can be used for the diagnosis of the disease at an early stage. In this study several gene expression study data were analyzed and there were 329 Differentially Expressed Genes (DEGs) in all the three chosen datasets. Protein protein interaction network was created using STRING and CytoHubba plug-in was used to identify top ten hub genes which are CXCL8, PSMC6, UBE2D1, UBE2D1, CD27, UBE2D3, SF3B1, CASP3, EIF4E, BIRC2 and PTEN. Online software Enrichr was used for Gene Ontology and KEGG pathway enrichment analysis to find out the biological process, molecular function, cellular component and the pathways that were enriched in HD. This study finds out that those genes which were present in all the three datasets namely FNDC3A, BCLAF1 and ALCAM were not the hub genes. So further studies are required for identifying a potential biomarker of HD.


title: Tactile spatial discrimination on the torso using vibrotactile and force stimulation

abstract: There is a steadily growing number of mobile communication systems that provide spatially encoded tactile information to the humans torso. However, the increased use of such hands-off displays is currently not matched with or supported by systematic perceptual characterization of tactile spatial discrimination on the torso. Furthermore, there are currently no data testing spatial discrimination for dynamic force stimuli applied to the torso. In the present study, we measured tactile point localization (PL) and tactile direction discrimination (DD) on the thoracic spine using two unisex torso-worn tactile vests realized with arrays of 3x3 vibrotactile or force feedback actuators. We aimed to, firstly, evaluate and compare the spatial discrimination of vibrotactile and force stimulations on the thoracic spine and, secondly, to investigate the relationship between the PL and DD results across stimulations. Thirty-four healthy participants performed both tasks with both vests. Tactile accuracies for vibrotactile and force stimulations were 60.7% and 54.6% for the PL task; 71.0% and 67.7% for the DD task, respectively. Performance correlated positively with both stimulations, although accuracies were higher for the vibrotactile than for the force stimulation across tasks, arguably due to specific properties of vibrotactile stimulations. We observed comparable directional anisotropies in the PL results for both stimulations; however, anisotropies in the DD task were only observed with vibrotactile stimulations. We discuss our findings with respect to tactile perception research as well as their implications for the design of high-resolution torso-mounted tactile displays for spatial cueing.


title: Data-driven speciation tree prior for better species divergence times in calibration-poor molecular phylogenies

abstract:
MotivationPrecise time calibrations needed to estimate ages of species divergence are not always available due to fossil records incompleteness. Consequently, clock calibrations available for Bayesian dating analyses can be few and diffused, i.e., phylogenies are calibration-poor, impeding reliable inference of the timetree of life. We examined the role of speciation birth-death tree prior on Bayesian node age estimates in calibration-poor phylogenies and tested the usefulness of an informative, data-driven tree prior to enhancing the accuracy and precision of estimated times.

ResultsWe present a simple method to estimate parameters of the birth-death tree prior from the molecular phylogeny for use in Bayesian dating analyses. The use of a data-driven birth-death (ddBD) tree prior leads to improvement in Bayesian node age estimates for calibration-poor phylogenies. We show that the ddBD tree prior, along with only a few well-constrained calibrations, can produce excellent node ages and credibility intervals, whereas the use of an uninformative, uniform (flat) tree prior may require more calibrations. Relaxed clock dating with ddBD tree prior also produced better results than a flat tree prior when using diffused node calibrations. We also suggest using ddBD tree priors to improve the detection of outliers and influential calibrations in cross-validation analyses.

ConclusionEmpirical Bayesian dating analyses with ddBD tree priors enable more accurate and precise node age estimates for calibration-poor phylogenies. Our results have practical applications because the ddBD tree prior reduces the number of well-constrained calibrations necessary to obtain reliable node age estimates. This would help address key impediments in building the grand timetree of life, revealing the process of speciation, and elucidating the dynamics of biological diversification.

AvailabilityAn R module for computing the ddBD tree prior, simulated datasets, and empirical datasets are available at https://github.com/cathyqqtao/ddBD-tree-prior.


title: iTaxoTools 0.1: Kickstarting a specimen-based software toolkit for taxonomists

abstract: While powerful and user-friendly software suites exist for phylogenetics, and an impressive cybertaxomic infrastructure of online species databases has been set up in the past two decades, software specifically targeted at facilitating alpha-taxonomic work, i.e., delimiting and diagnosing species, is still in its infancy. Here we present a project to develop a bioinformatic toolkit for taxonomy, based on open-source Python code, including tools focusing on species delimitation and diagnosis and centered around specimen identifiers. At the core of iTaxoTools is user-friendliness, with numerous autocorrect options for data files and with intuitive graphical user interfaces. Assembled standalone executables for all tools or a suite of tools with a launcher window will be distributed for Windows, Linux, and Mac OS systems, and in the future also implemented on a web server. The alpha version (iTaxoTools 0.1) distributed with this paper contains GUI versions of six species delimitation programs (ABGD, ASAP, DELINEATE, GMYC, PTP, tr2) and a simple threshold-clustering delimitation tool. There are also new Python implementations of existing algorithms, including tools to compute pairwise DNA distances, ultrametric time trees based on non-parametric rate smoothing, species-diagnostic nucleotide positions, and standard morphometric analyses. Other utilities convert among different formats of molecular sequences, geographical coordinates, and units; merge, split and prune sequence files and tables; and perform simple statistical tests. As a future perspective, we envisage iTaxoTools to become part of a bioinformatic pipeline for next-generation taxonomy that accelerates the inventory of life while maintaining high-quality species hypotheses.


title: MLG: Multilayer graph clustering for multi-condition scRNA-seq data

abstract: Single-cell transcriptome sequencing (scRNA-seq) enabled investigations of cellular heterogeneity at exceedingly higher resolutions. Identification of novel cell types or transient developmental stages across multiple experimental conditions is one of its key applications. Linear and non-linear dimensionality reduction for data integration became a foundational tool in inference from scRNA-seq data. We present Multi Layer Graph Clustering (MLG) as an integrative approach for combining multiple dimensionality reduction of multi-condition scRNA-seq data. MLG generates a multilayer shared nearest neighbor cell graph with higher signal-to-noise ratio and outperforms current best practices in terms of clustering accuracy across large-scale bench-marking experiments. Application of MLG to a wide variety of datasets from multiple conditions highlights how MLG boosts signal-to-noise ratio for fine-grained sub-population identification. MLG is widely applicable to settings with single cell data integration via dimension reduction.


title: Little evidence that Eurasian jays (Garrulus glandarius) protect their caches by responding to cues about a conspecific's desire and visual perspective

abstract: Corvids appear to be capable of adjusting their behaviour according to anothers perspective, knowledge and desire. For example, Eurasian jays have been found to employ a variety of cache protection strategies to minimise cache loss by responding to cues about the visual perspective or current desire of an observing conspecific. However, it is not known whether these jays (or any other corvid) can integrate multiple cues about different mental states and perform the optimal response accordingly. Across five experiments, we found little evidence that our Eurasian jays responded to either the visual perspective or current desire of another agent. In Experiments 1 and 2 we investigated whether Eurasian jays can limit the risk of cache loss by responding simultaneously to cues about the desire and perspective of a potential conspecific pilferer. Building on established paradigms, we used opaque and clear barriers to manipulate the observers visual access to cache locations, and specific satiety to manipulate the observers desire towards different types of food. Across both experiments the jays caching pattern provided no evidence that they could integrate information about the observers desire and perspective. Moreover, the results were also inconsistent with the previously reported effects that jays protect their caches by responding to either the visual access or specific satiety of the observer independently. To gain further insight into these unexpected results, we conducted three more experiments. In Experiments 3 and 4, we attempted to replicate the previous finding that Eurasian jays prefer to cache behind an opaque barrier over a clear barrier when observed by a conspecific than when caching in private. In Experiment 5, we further investigated the previous finding that jays preferentially cache a type of food that had been eaten to satiety by a conspecific over a food that had not been eaten by the conspecific. Experiments 3, 4 and 5 found no significant effects in the direction of the previously reported effects, questioning their robustness. We conclude by discussing the implications of our study for the field of corvid cognition and highlight several key issues that affect the reliability of comparative cognition research.


title: Discovery of signatures of fatal neonatal illness in vital signs using highly comparative time-series analysis

abstract:
ObjectiveTo seek new signatures of illness in heart rate and oxygen saturation vital signs from Neonatal Intensive Care Unit (NICU), we implemented highly comparative time-series analysis to discover features of all-cause mortality in the next 7 days.

DesignWe collected 0.5Hz heart rate and oxygen saturation vital signs of infants in the University of Virginia NICU from 2009 to 2019. We applied 4988 algorithmic operations from 11 mathematical families to random daily ten-minute segments. We clustered the results and selected a representative from each, and examined multivariable logistic regression models.

SettingNeonatal ICU

Patients5957 NICU infants; 205 died.

Measurements and main results3555 operations were usable; 20 cluster medoids held more than 81% of the information. A multivariable model had AUC 0.83. Five algorithms outperformed others: moving threshold, successive increases, surprise, and random walk. We computed provenance of the computations and constructed a software library with links to the data.

ConclusionsHighly comparative time-series analysis revealed new vital sign measures to identify NICU patients at the highest risk of death in the next week.


title: Interfacing Seurat with the R tidy universe

abstract:
MotivationSeurat is one of the most popular software suites for the analysis of single-cell RNA sequencing data. Considering the popularity of the tidyverse ecosystem, which offers a large set of data display, query, manipulation, integration and visualisation utilities, a great opportunity exists to interface the Seurat object with the tidyverse. This gives the large data science community of tidyverse users the possibility to operate with a familiar grammar.

ResultsIn order to provide Seurat with a tidyverse-oriented interface without compromising on efficiency, we developed tidyseurat, a light-weight adapter to the tidyverse. Cell information is automatically displayed as a tibble abstraction, which interfaces Seurat with dplyr, tidyr, ggplot2 and plotly packages powering efficient data manipulation, integration and visualisation. Iterative analyses on data subsets is enabled by interfacing with the popular nest-map framework.

Availability and implementationThe software is freely available at cran.r-project.org/web/packages/tidyseurat/ and github.com/stemangiola/tidyseurat

ContactStefano Mangiola (mangiola.s@wehi.edu.au) and Anthony T Papenfuss (papenfuss@wehi.edu.au).


title: SBGNview: Data Analysis, Integration and Visualization on All Pathways

abstract: Pathway analysis is widely used in genomics and omics research, but the data visualization has been highly limited in function, pathway coverage and data format. Here we develop SBGNview a comprehensive solution to address these needs. By adopting the standard SBGN format, SBGNview greatly extend the coverage of pathway based analysis and data visualization to essentially all major pathway databases beyond KEGG, including 5200 reference pathways and over 3000 species. In addition, SBGNview substantially extends current tools in both design and function, including standard coherent input/output formats, high quality graphics convenient for both computational and manual analysis, and flexible and open-end workflow. In addition to pathway analysis and data visualization, SBGNview provides essential infrastructure for SBGN data manipulation and processing. SBGNview is available online: https://github.com/datapplab/SBGNview.


title: RENANO: a REference-based compressor for NANOpore FASTQ files

abstract:
Nanopore sequencing technologies are rapidly gaining popularity, in part, due to the massive amounts of genomic data they produce in short periods of time (up to 8.5 TB of data in less than 72 hours). In order to reduce the costs of transmission and storage, efficient compression methods for this type of data are needed. Unlike short-read technologies, nanopore sequencing generates long noisy reads of variable length. In this note we introduce RENANO, a reference-based lossless FASTQ data compressor, specifically tailored to compress FASTQ files generated with nanopore sequencing technologies. RENANO builds on the recent compressor ENANO, which is the current state of the art. RENANO focuses on improving the compression of the base call sequence portion of the FASTQ file, leaving the other parts of ENANO intact. Two novel reference-based compression algorithms are introduced, contemplating different scenarios: in the first scenario, a reference genome is available without cost to both the compressor and the decompressor; in the second, the reference genome is available only on the compressor side, and a compacted version of the reference is transmitted to the decompressor as part of the compressed file. To evaluate the proposed algorithms, we compare RENANO against ENANO on several publicly available nanopore datasets. In the first scenario considered, RENANO improves the base call sequences compression of ENANO by 39.8%, on average, over all the datasets. As for total compression (including the other parts of the FASTQ file), the average improvement is 12.7%. In the second scenario considered, the base call compression improvements of RENANO over ENANO range from 15.2% to 49.0%, depending on the coverage of the compressed dataset, while in terms of total size, the improvements range from 5.1% to 16.5%.

Implementations of the proposed algorithms are freely available for download at https://github.com/guilledufort/RENANO.


title: Comparative in vitro antioxidant and antibacterial activities of leaf extract fractions of Crimson bottlebrush, Callistemon citrinus (Curtis.) Skeels

abstract:
ObjectivesThe present study aimed to analyze a comparative in vitro free radical scavenging and antibacterial potentials of leaf aqueous and the successive extract fractions of Callistemon citrinus.

MethodsFor in vitro antioxidant activity assessments, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, Fe3+ ion reducing antioxidant power (FRAP) assay, and total antioxidant capacity of the extracts were tested. Antibacterial potentials were tested through Agar well diffusion method using both gram-positive and gram-negative bacterial strains.

ResultsData indicate the polar successive aqueous fraction (AQF) possesses the highest free radicals scavenging capacity, with lowest EC50 (the required extract concentration to scavenge half of the free radicals) for DPPH and FRAP assays, and contains the highest total phenolics (308.2{+/-}5.9 {micro}g tannic acid equivalent/mg dry extract, DE), flavonoids (516.7{+/-}3.5 {micro}g quercetin equivalent/mg DE), total antioxidant capacity (441.48{+/-}12.8 {micro}g ascorbic acid equivalent/mg DE). Phenolics and flavonoids contents were positively correlated with the in vitro antioxidant activities. The antibacterial study indicates the petroleum ether and chloroform are suitable solvents for extracting antibacterial phytochemicals from C. citrinus leaves that are effective against both gram-positive and negative bacterial strains.

ConclusionThe most polar fraction i.e. the successive aqueous extract fraction of C. citrinus leaves exhibited the highest antioxidant activities while the most non-polar petroleum ether extract fraction showed the highest antibacterial potentials thus these extract fractions might have therapeutic importance.

category: pharmacology and toxicology


title: Paternal obesity results in placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolic function

abstract:
Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether paternal obesity-induced offspring metabolic dysfunction is associated with placental endoplasmic reticulum (ER) stress and impaired vascular development. We determined whether offspring glucose intolerance is fueled by ER stress-mediated changes in fetal hepatic development. Furthermore, we also determined whether paternal obesity may indirectly affect in utero development by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow diet (CON; 17% kcal fat) or high fat diet (PHF; 60% kcal fat) for 8-10 weeks were time-mated with control female mice to generate pregnancies and offspring. Glucose tolerance in pregnant females was evaluated at mid-gestation (embryonic day (E) 14.5) and term gestation (E18.5). At E14.5 and E18.5, fetal liver and placentae were collected, and markers of hypoxia, angiogenesis, endocrine function, and macronutrient transport, and unfolded protein response (UPR) regulators were evaluated to assess ER stress. Young adult offspring glucose tolerance and metabolic parameters were assessed at [~]60 days of age. Paternal obesity did not alter maternal glucose tolerance or placental lactogen in pregnancy but did induce placental hypoxia, ER stress, and altered placental angiogenesis. This effect was most pronounced in placentae associated with female fetuses. Consistent with this, paternal obesity also activated the ATF6 and PERK branches of the UPR in fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Adult offspring of obese fathers showed glucose intolerance and impaired whole-body energy metabolism, particularly in female offspring. Thus, paternal obesity programs sex-specific adverse placental structural and functional adaptations and alters fetal hepatic development via ER stress-induced pathways. These changes likely underpin metabolic deficits in adult offspring.

Summary SentencePaternal obesity alters placental vascular structures and is associated with sex-specific compromises in glucose tolerance and metabolism in young offspring


title: The link between static and dynamic brain functional network connectivity and genetic risk of Alzheimer's disease

abstract: Apolipoprotein E (APOE) polymorphic alleles are genetic factors associated with Alzheimers disease (AD) risk. Although previous studies have explored the link between AD genetic risk and static functional network connectivity (sFNC), to the best of our knowledge, no previous studies have evaluated the association between dynamic FNC (dFNC) and AD genetic risk. Here, we examined the link between sFNC, dFNC, and AD genetic risk with a reproducible, data-driven approach. We used rs-fMRI, demographic, and APOE data from cognitively normal individuals (N=894) between 42 to 95 years of age (mean = 70 years). We divided individuals into low, moderate, and high-risk groups. Using Pearson correlation, we calculated sFNC across seven brain networks. We also calculated dFNC with a sliding window and Pearson correlation. The dFNC windows were partitioned into three distinct states with k-means clustering. Next, we calculated the amount of time each subject spent in each state, called occupancy rate or OCR. We compared both sFNC and OCR, estimated from dFNC, across individuals with different genetic risk and found that both sFNC and dFNC are related to AD genetic risk. We found that higher AD risk reduces within-visual sensory network (VSN) sFNC and that individuals with higher AD risk spend more time in a state with lower within-VSN dFNC. Additionally, we found that AD genetic risk affects whole-brain sFNC and dFNC in women but not in men. In conclusion, we presented novel insights into the links between sFNC, dFNC, and AD genetic risk.


title: Resting-state based prediction of task-related activation in patients with disorders of consciousness

abstract:
BackgroundAssessment of the level of awareness of people with disorders of consciousness (DOC) is clinically challenging, motivating several studies to combine brain imaging with machine learning to improve this process. While this work has shown promise, it has limited clinical utility, as misdiagnosis of DOC patients is relatively high. As machine learning algorithms rely on accurately labelled data, any error in diagnosis will be learned by the algorithm, resulting in an equally limited diagnostic tool. The goal of the present study is to overcome this problem by stratifying patients, not by diagnosis, but by their capacity to perform volitional tasks during functional magnetic resonance imaging (fMRI) scanning.

MethodsA total of 71 patients were assessed for inclusion. They were excluded for the final analysis if they had large focal brain damage, excessive head motion during scanning, or suboptimal MRI preprocessing. Patients underwent both resting-state and task-based fMRI scanning. Univariate fMRI analysis was performed to determine if an individual patient had brain activity consistent with having retained volitional capacity (VC). Differences in resting brain network connectivity between patients with VC and patients without volitional capacity (non-VC) were measured. Connectivity data was then entered as input to a deep learning framework. We used a deep graph convolutional neural network (DGCNN) on connectivity data to identify a specific brain network that most significantly differentiates patients.

FindingsWe included 30 patients in our final analysis. Univariate analysis revealed that 13 patients displayed signs of VC, while 17 did not. We found that resting-state connectivity between frontoparietal control and salience network was significantly different between VC and non-VC patients (T(28) = 3.347, p = 0.0023, Bonferroni corrected p = 0.042). Furthermore, we found that using frontoparietal control network connectivity as input to the DGCNN resulted in the best classification performance (test accuracy = 0.85; ROC AUC = 0.92).

InterpretationWe found that the DGCNN performed best at discriminating between patients with VC when using only the frontoparietal control network as input to the model. The use of this deep learning method is a significant advance since its inherent flexibility permits the inclusion of both whole-brain and network-specific properties as input, allowing us to classify patients as either having or not having VC. This inclusion of multi-scale inputs (e.g. whole-brain and network-level) facilitates model interpretability and increases our understanding of the neurobiology of DOC. The results propose that the integrity of frontoparietal control network, a brain network well known to play a key role in executive functions and cognitive control, is essential for volitional capacity preservation in patients with DOC. The study also lays groundwork for development of a biomarker to aid in the diagnosis of DOC patients.

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSDisorders of consciousness (DOC) are a group of severe brain disorders characterised by damage to the neural systems underlying wakefulness and awareness. DOC are often caused by traumatic brain injury, hypoxia, or neurodegenerative diseases. The motor and cognitive impairments in DOC patients make providing an accurate diagnosis very challenging. Diagnosis is primarily made at the bedside by assessing a patients response to motor commands.


title: Neonatal 6-OHDA lesion of the SNc induces striatal compensatory sprouting from surviving SNc dopaminergic neurons without VTA contribution

abstract:
Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) are uniquely vulnerable to neurodegeneration in Parkinsons disease (PD). We hypothesize that their large axonal arbor is a key factor underlying their vulnerability, due to increased bioenergetic, proteostatic and oxidative stress. In keeping with this model, other DAergic populations with smaller axonal arbors are mostly spared during the course of PD and are more resistant to experimental lesions in animal models. Aiming to improve mouse PD models, we examined if neonatal partial SNc lesions could lead to adult mice with fewer SNc DA neurons that are endowed with larger axonal arbors because of compensatory mechanisms. We injected 6-hydroxydopamine (6-OHDA) unilaterally in the SNc at an early postnatal stage at a dose selected to induce loss of approximately 50% of SNc DA neurons. We find that at 10- and 90-days after the lesion, the axons of SNc DA neurons show massive compensatory sprouting, as revealed by the proportionally smaller decrease in tyrosine hydroxylase (TH) in the striatum compared to the loss of SNc DA neuron cell bodies. The extent and origin of this axonal sprouting was further investigated by AAV-mediated expression of eYFP in SNc or ventral tegmental area (VTA) DA neurons of adult mice. Our results reveal that SNc DA neurons have the capacity to substantially increase their axonal arbor size and suggest that mice designed to have reduced numbers of SNc DA neurons could potentially be used to develop better mouse models of PD, with elevated neuronal vulnerability.

Graphical abstract textO_LIWe describe a technique to induce the loss of approximately 50% of SNc DA neurons in neonate mice using unilateral intranigral 6-OHDA (left panel).
C_LIO_LICompensatory axonal sprouting was observed in the striatum as early as 10 days following the lesion (at P15), with effects lasting until adulthood (P90).
C_LIO_LIConditional AAV-mediated expression of eYFP (green) reveals SNc DA neurons, projecting to the dorsal striatum (middle panel), and not VTA DA neurons, projecting to the ventral striatum (right panel), as the main source of compensatory axonal sprouting.
C_LI

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/437271v1_ufig1.gif" ALT="Figure 1">
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title: Functional dynamics of brain networks associated with carry-over effects of negative events on subsequent resting state.

abstract:
Affective inertia represents the lasting impact of transient emotions at one time point on affective state at a subsequent time point. Here we describe the neural underpinnings of inertia following negative emotions elicited by sad events in movies. Using a co-activation pattern analysis of dynamic functional connectivity, we examined the temporal expression and reciprocal interactions among brain-wide networks during movies and subsequent resting periods. Our findings revealed distinctive spatiotemporal expression of visual (VIS), default mode (DMN), central executive (CEN), and frontoparietal control (FPCN) networks both in negative movies and in rest periods following these movies. We also identified different reciprocal relationships among these networks, in transitions from movie to rest. While FPCN and DMN expression increased during and after negative movies, respectively, FPCN occurrences during the movie predicted lower DMN and higher CEN expression during subsequent rest after neutral movies, but this relationship was reversed after the elicitation of negative emotions. Changes in FPCN and DMN activity correlated with more negative subjective affect. These findings provide new insights into the transient interactions of intrinsic brain networks underpinning the inertia of negative emotions. More specifically, they describe a major role of FPCN in emotion elicitation processes, with prolonged impact on DMN activity in subsequent rest, presumably involved in emotion regulation and restoration of homeostatic balance after negative events.

HighlightsO_LIModulations of dynamic functional brain connectivity are associated to the temporal inertia of negative emotions.
C_LIO_LIFunctional co-activations patterns (CAPs) during emotional episodes predict changes in spontaneous brain dynamics during subsequent resting state.
C_LIO_LIClassical "task-rest" anticorrelations in network activity are reversed by negative emotions.
C_LI


title: Dynamic functional brain networks underlying the temporal inertia of negative emotions


title: A projectome of the bumblebee central complex

abstract: Insects have evolved diverse and remarkable strategies for navigating in various ecologies all over the world. Regardless of species, insects share the presence of a group of morphologically conserved neuropils known collectively as the central complex (CX). The CX is a navigational hub, involved in sensory integration and coordinated motor activity. Despite the fact that our understanding of navigational behavior comes predominantly from ants and bees, most of what we know about the underlying neural circuitry of such behavior comes from work in fruit flies. Here we aim to close this gap, by providing the first comprehensive map of all major columnar neurons and their projection patterns in the CX of a bee. We find numerous components of the circuit that appear to be highly conserved between the fly and the bee, but also highlight several key differences which are likely to have important functional ramifications.


title: Stimulus presentation can enhance spiking irregularity across subcortical and cortical regions

abstract: Stimulus presentation is believed to quench neural response variability as measured by fano-factor (FF). However, the relative contribution of within trial spike irregularity (n{Psi}) and trial to trial rate variability (nRV) to FF reduction has remained elusive. Here, we introduce a principled approach for accurate estimation of variability components for a doubly stochastic point process which unlike previous methods allows for a time varying n{Psi} (aka {phi}). Notably, analysis across multiple subcortical and cortical areas showed across the board reduction in rate variability. However, unlike what was previously thought, spiking irregularity was not constant in time and was even enhanced in some regions abating the quench in the post-stimulus FF. Simulations confirmed plausibility of a time varying n{Psi} arising from within and between pool correlations of excitatory and inhibitory neural inputs. By accurate parsing of neural variability, our approach constrains candidate mechanisms that give rise to observed rate variability and spiking irregularity within brain regions.


title: Subthalamic-Cortical Network Reorganization during Parkinson's Tremor

abstract:
Tremor, a common and often primary symptom of Parkinsons disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from ten patients performing a naturalistic visual-motor task. From this task we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state.

SIGNIFICANCE STATEMENTTremor is a common symptom of Parkinsons disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functionally interact to produce tremor. In this manuscript, we analyzed intracranial recordings from the subthalamic nucleus and sensorimotor cortex in patients with PD undergoing deep brain stimulation (DBS) surgery. Using an intraoperative task, we examined tremor in two separate dynamic contexts: when tremor first emerged, and when tremor was sustained. We believe that these findings reconcile several models of Parkinsons tremor, while describing the short-timescale dynamics of subcortical-cortical interactions during tremor for the first time. These findings may describe a framework for developing proactive and responsive neurostimulation models for specifically treating tremor.