title: Dissection of function and recognition mechanism of M. tuberculosis ESX-1 secreted virulence factor EspC

abstract: Mycobacterium tuberculosis uses the ESAT-6 system-1/type VII (ESX-1) system for secretion of virulence proteins into the host cell, however the mechanism of virulence proteins secretion, molecular components and regulation of ESX-1 system are only partly understood. In the current study, we have analyzed the biological function and recognition mechanism between ESX-1 virulence EspC and EccA1 ATPase proteins. The EspC enters into A549 human lung carcinoma cells and exhibited cytotoxicity, as observed in MTT Assay. To understand the recognition mechanism between EspC and EccA1 ATPase, the EspC and EccA1 mutants were generated based on EspC~EccA1 interactions, as observed in molecular modeling. Binding analysis shows that EspC export arm interacts specifically to the {beta}-hairpin insertion motif of the TPR domain of EccA1 ATPase. Mutations in these epitopes lead to significant decrease/or abolish the binding between EspC and EccA1 ATPase. Our study provides insight into biological function and recognition mechanism between EspC and EccA1 ATPase, which can be used as target to prevent EspC secretion/ or in general virulence factor secretion by mycobacterial ESX-1 system.

category: biophysics


title: Computational study on Strontium ion modified Fibronectin-Hydroxyapatite interaction

abstract:
Protein adsorption is the first key step in cell-material interaction. The initial phase of such adsorption process can only be probed using modelling approaches like molecular dynamics (MD) simulation. Despite a large number of studies on the adsorption behaviour of proteins on different biomaterials including hydroxyapatite (HA); little attention has been paid towards quantitative assessment of the effects of various physicochemical influencers like surface modification, pH, and ionic strength. Among these factors, surface modification through isomorphic substitution of foreign ions inside the apatite structure is of particular interest in the context of protein-HA interaction as it is widely used to tailor the biological response of HA. Given this background, we present here the molecular-level understanding of fibronectin (FN) adsorption mechanism and kinetics on Sr2+-doped HA (001) surface, at 300K by means of all-atom molecular dynamics simulation. Electrostatic interaction involved in adsorption of FN on HA was found to be significantly modified in presence of Sr2+ doping in apatite lattice. In harmony with the published experimental observations, the Sr-doped surface was found to better support FN adhesion compared to pure HA, with 10 mol% Sr-doped HA exhibiting best FN adsorption. Sr2+ ions also influence the stability of the secondary structure of FN, as observed from the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis. The presence of Sr2+ enhances the flexibility of specific residues (residue no. 20-44, 74-88) of the FN module. Rupture forces to disentangle FN from the biomaterials surface, obtained from steered molecular dynamics (SMD) simulations, were found to corroborate well with the results of equilibrium MD simulations. One particular observation is that, the availability of RGD motif for the interaction with cell surface receptor integrin is not significantly influenced by Sr2+ substitution. Summarizing, the present work establishes a quantitative foundation towards the molecular basis of the earlier experimentally validated better cytocompatibility of Sr-doped HA.

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title: Influence of high energy diet and polygenic predisposition for obesity on postpartum health in rat dams

abstract: It is estimated that 30% of pregnant women worldwide are overweight or obese, which leads to adverse health effects for both the mother and child. Women with obesity during pregnancy are at higher risk for developing both metabolic and mental disorders, such as diabetes and depression. Numerous studies have used rodent models of maternal obesity to understand its consequences on the offspring, yet characterization of changes in the dams is rare, and most rodent models rely solely on a high fat diet to induce maternal obesity, without regarding genetic propensity for obesity. Here we present the influence of both peripartum high energy diet (HE) and obesity-proneness on maternal health using selectively-bred diet-resistant (DR) and diet-induced obese (DIO) rat dams. Outbred Sprague-Dawley rats were selected and bred according to their propensity to gain weight. From F1 onward, dams consuming a HE diet displayed higher body weight gain during pregnancy, and HE diet had a strong effect on meal patterns. Sensitivity to the hormone amylin was preserved during pregnancy, regardless of diet. After several rounds of selective breeding, dams from generation F3 were assessed for their postpartum physiology and behaviors. We observed strong diet and phenotype effects on gestational weight gain, with DIO-HE dams gaining 119% more weight than DR-chow. A high-resolution analysis of maternal behaviors on postpartum day 2 (P2) did not detect main effects of diet or phenotype, but a subset of DIO dams showed decreased pup-related behaviors. During a sucrose preference test (SPT) on P14, all DR dams consumed at least 70% sucrose, while a subset of DIO dams preferred water. In generation F6/F7 dams, effects on gestational weight gain persisted, and we observed a main effect of phenotype of SPT, with DIO-chow dams showing the lowest sucrose preference. Both DIO and DR dams consuming HE diet had severe postpartum liver lipidosis and exhibited reduced leptin sensitivity in the arcuate nucleus at the time of pup-weaning. These data demonstrate that both diet and genetic obesity-proneness have consequences on maternal health.

category: physiology


title: Sieve tube structural variation in Austrobaileya scandens and its significance for lianescence

abstract:
Lianas are characterized by large leaf areas and slender stems, a combination of features that require an efficient vascular system. The only extant member of the Austrobaileyaceae, is an endemic twining liana of the tropical Australian forests with well-known xylem hydraulic traits. However, the vascular phloem continuum through aerial organs remains understudied.

We analyzed the structure of phloem conduits across leaf veins and stems of A. scandens, combining topological data obtained through light and electron microscopy, with current models of phloem transport.

Leaves displayed a low xylem to phloem ratio compared with leaves of other angiosperms, with vascular elements invariant in diameter along the midrib, but tapered across vein hierarchies. Sieve plate pore radii were extremely small: 0.08 {micro}m in minor veins, increasing to 0.12{micro}m in the petiole and only to 0.20{micro}m at the base of the stem, tens of meters away. Searcher branches contained tube shaped phloem conduits with a pectin-rich wall, whereas twining stems displayed sieve elements with tangential connections that displayed a greater fraction of the tubes populated with an astonishing number of sieve plates.

Hydraulic segmentation of the leaves in Austrobaileyaceae correlate with vesseless leaves that benefit photoassimilate export through volumetric scaling of the sieve tube elements. Yet, compared with canopy dominant trees, the geometrical properties of the sieve tube in twining stems, restrict considerably energy distribution in the sub-canopy layers, potentially favoring the allocation of assimilates toward the elongating branches. Thus, the conductive xylem of twining stems contrasts with a poorly conductive phloem that meets the mechanical constraints of lianescence.

category: plant biology


title: DcPAR1 Is Required For Development And Carotenoid Synthesis In The Dark-Grown Carrot Taproot

abstract:
Light stimulates carotenoid synthesis in plants during photomorphogenesis through the expression of PHYTOENE SYNTHASE (PSY), a key gene in carotenoid biosynthesis. The orange Daucus carota (carrot) synthesizes and accumulates high amounts of carotenoids in the taproot that grows underground. Contrary to other organs, light impairs carrot taproot development and represses the expression of carotenogenic genes such as DcPSY1 and DcPSY2 reducing carotenoid accumulation. By means of an RNA-seq, in previous analysis we observed that carrot PHYTOCHROME RAPIDLY REGULATED 1 (DcPAR1) is more expressed in the underground grown taproot respect to those grown in light. PAR1 is a transcriptional cofactor with a negative role in the shade avoidance syndrome regulation in Arabidopsis thaliana through the dimerization with PHYTOCHROME INTERACTING FACTORs (PIFs), allowing a moderate synthesis of carotenoids. Here we show that overexpressing AtPAR1 in carrot produces an increment of carotenoids in taproots grown underground as well as higher DcPSY1 expression. The high identity of AtPAR1 and DcPAR1 let us to suggest a functional role of DcPAR1 that was verified through the in vivo binding to AtPIF7 and the overexpression in Arabidopsis, where it increments AtPSY expression and carotenoid accumulation together with a photomorphogenic phenotype. Finally, DcPAR1 antisense carrot lines presented a dramatic decrease in carotenoids levels and in the relative expression of key carotenogenic genes as well as impairment in taproot development. These results let us to propose that DcPAR1 is a key factor for secondary root development, plastid differentiation and carotenoid synthesis in carrot taproot grown underground.

One-sentence summaryDcPAR1 is a key factor for secondary root development, plastid differentiation and carotenoid synthesis in carrot taproot grown underground.


title: Algorithmic Reconstruction of GBM Network Complexity

abstract: Glioblastoma (GBM) is a complex disease that is difficult to treat. Establishing the complex genetic interactions regulating cell fate decisions in GBM can help to shed light on disease aggressivity and improved treatments. Networks and data science offer alternative approaches to classical bioinformatics pipelines to study gene expression patterns from single-cell datasets, helping to distinguish genes associated with control of differentiation and thus aggressivity. Here, we applied a host of data theoretic techniques, including clustering algorithms, Waddington landscape reconstruction, trajectory inference algorithms, and network approaches, to compare gene expression patterns between pediatric and adult GBM, and those of adult glioma-derived stem cells (GSCs) to identify the key molecular regulators of the complex networks driving GBM/GSC and predict their cell fate dynamics. Using these tools, we identified critical genes and transcription factors coordinating cell state transitions from stem-like to mature GBM phenotypes, including eight transcription factors (OLIG1/2, TAZ, GATA2, FOXG1, SOX6, SATB2, YY1) and four signaling genes (ATL3, MTSS1, EMP1, and TPT1) as clinically targetable novel putative function interactions differentiating pediatric and adult GBMs from adult GSCs. Our study provides strong evidence of the applicability of complex systems approaches for reverse-engineering gene networks from patient-derived single-cell datasets and inferring their complex dynamics, bolstering the search for new clinically relevant targets in GBM.

category: systems biology


title: Integrative analysis allows a global and precise identification of functional miRNA target genes in mESCs

abstract: MicroRNA (miRNA) loaded Argonaute (AGO) complexes regulate gene expression via direct base pairing with their mRNA targets. Current prediction approaches identified that between 20 to 60% of mammalian transcriptomes are regulated by miRNAs, but it remains largely unknown which fraction of these interactions are functional in a specific cellular context. Here, we integrated transcriptome data from a set of miRNA-depleted mouse embryonic stem cell (mESC) lines with published miRNA interaction predictions and AGO-binding profiles. This integrative approach, combined with molecular validation data, identified that only 6% of expressed genes are functionally and directly regulated by miRNAs in mESCs. In addition, analyses of the stem cell-specific miR-290-295 cluster target genes identified TFAP4 as an important transcription factor for early development. The extensive datasets developed in this study will support the development of improved predictive models for miRNA-mRNA functional interactions.


title: Compositional phylogenomic modelling resolves the 'Zoraptera problem': Zoraptera are sister to all other polyneopteran insects

abstract: The evolution of wings propelled insects to their present mega-diversity. However, interordinal relationships of early-diverging winged insects and the timescale of their evolution are difficult to resolve, in part due to uncertainties in the placement of the enigmatic and species-poor order Zoraptera. The  Zoraptera problem has remained a contentious issue in insect evolution since its discovery more than a century ago. This is a key issue because different placements of Zoraptera imply dramatically different scenarios of diversification and character evolution among polyneopteran. Here, we investigate the systematic placement of Zoraptera using the largest protein-coding gene dataset available to date, deploying methods to mitigate common sources of error in phylogenomic inference, and testing historically proposed hypotheses of zorapteran evolution. We recover Zoraptera as the earliest-diverging polyneopteran order, while earwigs (Dermaptera) and stoneflies (Plecoptera) form a monophyletic clade (Dermoplectopterida) sister to the remainder of Polyneoptera. The morphology and palaeobiology of stem-zorapterans are informed by Mesozoic fossils. The gut content and mouthparts of a male specimen of Zorotypus nascimbenei from Kachin amber (Cretaceous) reveal a fungivorous diet of Mesozoic zorapterans, akin to extant species. Based on a set of 42 justified fossil and stratigraphic calibrations, we recover a Devonian origin of winged insects and Polyneoptera, suggesting that these groups coincided with the rise of arborescence during the diversification of early terrestrial plants, fungi, and animals. Our results provide a robust framework for understanding the pattern and timescale of early winged insect diversification.

category: zoology


title: Arterial vasodilation drives convective fluid flow in the brain: a poroelastic model

abstract: The movement of fluid into, through, and out of the brain plays an important role in clearing metabolic waste. However, there is controversy regarding the mechanisms driving fluid movement, and whether the movement metabolic waste is primarily driven by diffusion or convection. The dilation of penetrating arterioles in the brain in response to increases in neural activity (neurovascular coupling) is an attractive candidate for driving fluid circulation, as it drives deformation of the brain tissue and of the paravascular space around arteries, resulting in fluid movement. We simulated the effects of vasodilation on fluid movement into and out of the brain using a novel poroelastic model of brain tissue. We found that arteriolar dilations could drive convective flow through the brain radially outward from the arteriole, and that this flow is sensitive to the dynamics of the dilation. Simulations of sleep-like conditions, with larger vasodilations and increased extracellular volume in the brain showed enhanced movement of fluid from the paravascular space into the brain. Our simulations suggest that both sensory-evoked and sleep-related arteriolar dilations can drive convective flow of cerebrospinal fluid from the paravascular space into the brain tissue around arterioles.

category: neuroscience


title: Pathological and metabolic underpinnings of energetic inefficiency in temporal lobe epilepsy

abstract: The human brain consumes a disproportionate amount of energy to generate neural dynamics. Yet precisely how energetic processes are altered in neurological disorders remains far from understood. Here, we use network control theory to profile the brains energy landscape, describing the rich dynamical repertoire supported by the structural connectome. This approach allows us to estimate the energy required to activate a circuit, and determine which regions most support that activation. Focusing on temporal lobe epilepsy (TLE), we show that patients require more control energy to activate the limbic network than healthy volunteers, especially ipsilateral to the seizure focus. Further, greater energetic costs are largely localized to the ipsilateral temporo-limbic regions. Importantly, the energetic imbalance between ipsilateral and contralateral temporo-limbic regions is tracked by asymmetric metabolic patterns, which in turn are explained by asymmetric gray matter volume loss. In TLE, failure to meet the extra energy demands may lead to suboptimal brain dynamics and inadequate activation. Broadly, our investigation provides a theoretical framework unifying gray matter integrity, local metabolism, and energetic generation of neural dynamics.


title: The impact of phosphorylated Pten at threonine 366 on cortical connectivity and behaviour

abstract: The lipid phosphatase Pten (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. Pten mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. Pten enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here we specifically focussed on the role of Pten T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A/T366A). We identify that phosphorylation of Pten at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellular overgrowth of cortical neurons in PtenT366A/T366A brains, linked to increases in both dendritic arborization and soma size. In a combinatorial approach of anterograde and retrograde monosynaptic tracing using rabies virus, we characterize differences in connectivity to the primary somatosensory cortex of PtenT366A/T366A brains, with imbalances in long-range cortico-cortical input to neurons. We conclude that phosphorylation of Pten at T366 controls neuron size and connectivity of brain circuits involved in sensory processing and propose that PTEN T366 signalling may account for a subset of autism-related functions of Pten.


title: Not all that is gold glitters: PV-IRES-Cre mouse line shows low efficiency of labeling of parvalbumin interneurons in the perirhinal cortex

abstract: The wide diversity of cortical inhibitory neuron types populating the cortex allows the assembly of diverse microcircuits and endows these circuits with different computational properties. Thus, characterizing neuronal diversity is fundamental to describe the building blocks of cortical microcircuits and probe their function. To this purpose, the mouse has emerged as a powerful tool to genetically label and manipulate specific inhibitory cell-types in the mammalian brain. Among these cell-types, the parvalbumin-expressing interneuron type (PV-INs) is perhaps the most characterized. Several mouse lines have been generated to target PV-INs. Among these mouse lines, the PV-IRES-Cre lines is the most widely used and demonstrated a high specificity and efficiency in targeting PV-INs in different cortical areas. However, a characterization of the performance across cortical regions is still missing. Here we show that the PV-IRES-Cre mouse line labels only a fraction of parvalbumin immunoreactive neurons in perirhinal cortex and other association areas. Our results point to a yet uncharacterized diversity within the PV-INs and emphasize the need to characterize these tools in specific cortical areas.


title: Characterization of Cervical-Cranial Muscle Network in Correlation with Vocal Features

abstract: Objective evaluation of physiological responses using non-invasive methods has attracted great interest regarding the assessment of vocal performance and disorders. This paper, for the first time, demonstrates that the topographical features of the cervical-cranial intermuscular coherence network generated using surface electromyography (sEMG) have a strong potential for detecting subtle changes in vocal performance. For this purpose, in this paper, 12 sEMG signals were collected from six cervical and cranial muscles bilaterally. Data were collected from four subjects without a history of a voice disorder performing a series of vocal tasks. The vocal tasks were varied phonation (an /a/ sustained for the maximal duration with combinations of two levels of loudness and two levels of pitch), a pitch glide from low to high, singing a familiar song, spontaneous speech, and reading with different loudness levels. The varied phonation tasks showed the median degree, and weighted clustering coefficient of the coherence-based intermuscular network ascends monotonically, with a high effect size (|rrb| = 0.52). The set of tasks, including pitch glide, singing, and speech, was significantly distinguishable using the network features as both degree and weighted clustering coefficient had a very high effect size (|rrb| > 0.83) across these tasks. Also, pitch glide has the highest degree and weighted clustering coefficient among all tasks (degree > 0.6, weighted clustering coefficient > 0.6). Spectrotemporal features performed far less effective than the proposed functional muscle network metrics to differentiate the vocal tasks. The highest effect size for spectrotemporal features was only |rrb| = 0.19. In this paper, for the first time, the power of a cervical-cranial muscle network has been demonstrated as a neurophysiological window to vocal performance. The results also shed light on the tasks with the highest network involvement, which may be potentially used in monitoring vocal disorders and tracking rehabilitation progress.


title: Basic reproduction numbers of three strains of mouse hepatitis viruses in mice

abstract: Mouse hepatitis virus (MHV) is a murine coronavirus and one of the most important pathogens in laboratory mice. Although various strains of MHV have been isolated, they are generally excreted in the feces and transmitted oronasally via aerosols and contaminated bedding. In this study, we attempted to determine the basic reproduction numbers of three strains of MHV to improve our understanding of MHV infections in mice. Five-week-old female C57BL/6J mice were inoculated intranasally with either the Y, NuU, or JHM variant strain of MHV and housed with two naive mice. After 4 weeks, the presence or absence of anti-MHV antibody in the mice was determined by the enzyme-linked immunosorbent assay. We also examined the distribution of MHV in the organs of Y, NuU, or JHM variant-infected mice. Our data suggest that the transmissibility of MHV is correlated with viral growth in the gastrointestinal tract of infected mice. To the best of our knowledge, this is the first report to address the basic reproduction numbers among pathogens in laboratory animals.

category: microbiology


title: A phenotypic screen using splitCas9 identifies essential genes required for actin regulation during host cell egress and invasion by Toxoplasma gondii

abstract: Apicomplexan parasites, such as Toxoplasma gondii, possess unique organelles, cytoskeletal structures, signalling cascades, replicate by internal budding within a specialised compartment and actively invade and exit the host cell, to name a few aspects of the unique biology that characterise this phylum. Due to their huge phylogenetic distance from well established model organisms, such as opisthokonts, comparative genomics has a limited capacity to infer gene functions and conserved proteins can fulfil different roles in apicomplexans. Indeed, approximately 30% of all genes are annotated as hypothetical and many had a crucial role during the asexual life cycle in genome-wide screens. While the current CRISPR/Cas9-based screens allow the identification of fitness conferring genes, only little information about the respective functions can be obtained. To overcome this limitation, and to group genes of interest into functional groups, we established a conditional Cas9-system in T. gondii that allows phenotypic screens. Using an indicator strain for F-actin dynamics and apicoplast segregation, we identified critical genes required for defined steps during the asexual life cycle. The detailed characterisation of two of these candidates revealed them to be critical for host cell egress and invasion and to act at different time points in the disassembly of the intravacuolar F-actin network. While the signalling linking factor (SLF) is an integral part of a signalling complex required for early induction of egress, a novel conoid protein (conoid gliding protein, CGP) acts late during egress and is required for the activation of gliding motility.


title: Towards a combined therapy for spinal muscular atrophy based on opposing effects of an antisense oligonucleotide on chromatin and splicing

abstract: Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by loss-of-function mutations of the SMN1 gene. Humans have a paralog, SMN2, whose exon 7 is predominantly skipped, and so it cannot fully compensate for the lack of SMN1. Nusinersen (Spinraza) is a splicing-correcting antisense oligonucleotide drug (ASO) approved for clinical use. Nusinersen targets a splicing silencer located in SMN2 intron 7 pre-mRNA and, by blocking the binding of the splicing repressors hnRNPA1 and A2, it promotes higher E7 inclusion, increasing SMN protein levels. We show here that, by promoting transcriptional elongation, histone deacetylase (HDAC) inhibitors cooperate with a nusinersen-like ASO to upregulate E7 inclusion. Surprisingly, the ASO also elicits the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that acts negatively on E7 inclusion. By removing the roadblock, HDAC inhibition counteracts the undesired chromatin effects of the ASO, resulting in higher E7 inclusion. Combined systemic administration of the nusinersen-like ASO and HDAC inhibitors in neonate SMA mice had strong synergistic effects on SMN expression, growth, survival, and neuromuscular function. Thus, we suggest that HDAC inhibitors have the potential to increase the clinical efficacy of nusinersen, and perhaps other splicing-modulatory ASO drugs, without large pleiotropic effects, as assessed by genome-wide analyses.

category: molecular biology


title: A method to enrich and purify centromeric DNA from human cells

abstract: Centromeres are key elements for chromosome segregation. Canonical centromeres are built over long-stretches of tandem repetitive arrays. Despite being quite abundant compared to other loci, centromere sequences overall still represent only 2 to 5% of the human genome, therefore studying their genetic and epigenetic features is a major challenge. Furthermore, sequencing of centromeric regions requires high coverage to fully analyze length and sequence variations, which can be extremely costly. To bypass these issues, we have developed a technique based on selective restriction digestion and size fractionation to enrich for centromeric DNA from human cells. Combining enzymes capable of cutting at high frequency throughout the genome, except within most human centromeres, with size-selection of >20 kb fragments resulted in over 25-fold enrichment in centromeric DNA. Sequencing of the enriched fractions revealed that up to 60% of the enriched material is made of centromeric DNA. This approach has great potential for making sequencing of centromeric DNA more affordable and efficient and for single DNA molecule studies.


title: FAIR enough? A perspective on the status of nucleotide sequence data and metadata on public archives

abstract: Knowledge derived from nucleotide sequence data is increasing in importance in the life sciences, as well as decision making (mainly in biodiversity policy). Metadata standards have been established to facilitate sustainable sequence data management according to the FAIR principles (Findability, Accessibility, Interoperability, Reusability). Here, we review the status of metadata available for raw read Illumina amplicon and whole genome shotgun sequencing data derived from ecological metagenomic material that are accessible at the European Nucleotide Archive (ENA), as well as the compliance of the primary sequence data (fastq files) with data submission requirements. While overall basic metadata, such as geographic coordinates, were retrievable in 98% of the cases for this type of sequence data, interoperability was not always ensured and other (mainly conditionally) mandatory parameters were often not provided at all. Metadata standards, such as the  Minimum Information about any(x) Sequence (MIxS), were only infrequently used despite a demonstrated positive impact on metadata quality. Furthermore, the sequence data itself did not meet the prescribed requirements in 31 out of 39 studies that were manually inspected. To tackle the most immediate needs to improve FAIR sequence data management, we provide a list of minimal suggestions to researchers, research institutions, funding agencies, reviewers, publishers, and databases, that we believe might have a potentially large positive impact on sequence data and metadata FAIRness, which is crucial for further research and its derived applications.


title: γ-TuRCs are required for asymmetric microtubule nucleation from the somatic Golgi of Drosophila neurons

abstract: Microtubules are polarised polymers nucleated by multi-protein {gamma}-tubulin ring complexes ({gamma}-TuRCs). Within neurons, microtubule polarity is plus-end-out in axons and mixed or minus-end-out in dendrites. Previously we showed that within the soma of Drosophila sensory neurons {gamma}-tubulin localises asymmetrically to Golgi stacks, Golgi-derived microtubules grow asymmetrically towards the axon, and growing microtubule plus-ends are guided towards the axon and restricted from entering dendrite in a Kinesin-2-dependent manner (Mukerjee et al., 2020). Here we show that depleting {gamma}-TuRCs perturbs the direction of microtubule growth from the Golgi stacks, consistent with a model for asymmetric microtubule nucleation involving {gamma}-TuRCs and other nucleation-promoting factors. We also directly observe microtubule turning along microtubule bundles and show that depleting APC, proposed to link Kinesin-2 to plus ends, reduces microtubule turning and increases plus end growth into dendrites. These results support a model of asymmetric nucleation and guidance within the neuronal soma that helps establish and maintain overall microtubule polarity.

category: cell biology


title: Developmental dynamics of sex reprogramming by high incubation temperatures in a dragon lizard

abstract: In some vertebrate species, gene-environment interactions can determine sex, driving bipotential gonads to differentiate into either ovaries or testes. In the central bearded dragon (Pogona vitticeps), the genetic influence of sex chromosomes (ZZ/ZW) can be overridden by high incubation temperatures, causing ZZ male to female sex reversal. Previous research showed ovotestes, a rare gonadal phenotype with traits of both sexes, develop during sex reversal, leading to the hypothesis that sex reversal relies on high temperature feminisation to outcompete the male genetic cue. To test this, we conducted temperature switching experiments at key developmental stages, and analysed the effect on gonadal phenotypes using histology and transcriptomics. We found sexual fate is more strongly influenced by the ZZ genotype than temperature. Any exposure to low temperatures (28{degrees}C) caused testes differentiation, whereas sex reversal required longer exposure to high temperatures. We revealed ovotestes exist along a spectrum of female-ness to male-ness at the transcriptional level. We found inter-individual variation in gene expression changes following temperature switches, suggesting both genetic sensitivity to, and the timing and duration of the temperature cue influences sex reversal. These findings bring new insights to the mechanisms underlying sex reversal, improving our understanding of thermosensitive sex systems in vertebrates.

category: developmental biology


title: Coat color mismatch improves survival of a keystone boreal herbivore: energetic advantages exceed lost camouflage

abstract: Climate warming is causing asynchronies between animal phenology and environments. Mismatched traits, like coat color change mismatched with snow, can decrease survival. However, coat change does not serve a singular adaptive benefit of camouflage, and alternate coat change functions may confer advantages that supersede mismatch costs. We found that mismatch reduced rather than increased, autumn mortality risk of snowshoe hares in Yukon by 86.5 %. We suggest that the increased coat insulation and lower metabolic rates of winter acclimatized hares confer energetic advantages to white mismatched hares that reduce their mortality risk. We found that white mismatched hares forage 17-77 minutes less per day than matched brown hares between 0 and -10 {degrees}C, thus lowering their predation risk and increasing survival. We found no effect of mismatch on spring mortality risk, where mismatch occurred at warmer temperatures, suggesting a potential temperature limit where the costs of conspicuousness outweigh energetic benefits.

category: ecology


title: On the hybrid origin of the C2 Salsola divaricata agg. (Amaranthaceae) from C3 and C4 parental lineages

abstract:
O_LIC2 photosynthesis is characterized by recapturing photorespiratory CO2 by RuBisCO in Kranz-like cells and is therefore physiologically intermediate between C3 and C4 photosynthesis. C2 can be interpreted as an evolutionary precursor of C4 and/or as the result of hybridization between a C3 and C4 lineage.
C_LIO_LIWe compared the expression of photosynthetic traits among populations of the Salsola divaricata agg. (C2) from humid subtropical to arid habitats on the coasts of the Canary Islands and Morocco and subjected them to salt and drought treatments. We screened for enhanced C4-like expression of traits related to habitat or treatment. We estimated species trees with a transcriptome dataset of Salsoleae and explored patterns of gene tree discordance. With phylogenetic networks and hybridization analyses we tested for hybrid origin of the Salsola divaricata agg.
C_LIO_LIWe observed distinct independent variation of photosynthetic traits within and among populations and no clear evidence for selection towards C4-like trait expression in more stressful habitats or treatments. We found reticulation and gene tree incongruence in Salsoleae supporting a putative hybrid origin of the Salsola divaricata agg.
C_LIO_LIC2 photosynthesis in the Salsola divaricata agg. combines traits inherited from its C3 and C4 parental lineages and seems evolutionarily stable, possibly well adapted to a wide climatic amplitude.
C_LI

category: evolutionary biology


title: Drivers of an epic radiation: the role of climate and islands in species diversification and reproductive-mode evolution of Old-World tree frogs

abstract: Although large diversifications of species occur unevenly across space and evolutionary lineages, the relative importance of their driving mechanisms, such as climate, ecological opportunity and key innovations, remains poorly understood. Here, we explore the remarkable diversification of rhacophorid frogs, which represent six percent of global amphibian diversity, utilize four distinct reproductive modes, and span a climatically variable area across mainland Asia, associated continental islands, and Africa. Using a complete species-level phylogeny, we find near-constant diversification rates but a highly uneven distribution of species richness. Montane regions on islands and some mainland regions have higher phylogenetic diversity and unique assemblages of taxa; we identify these as cool-wet refugia. Starting from a centre of origin, rhacophorids reached these distant refugia by adapting to new climatic conditions ( niche evolution-dominant), especially following the origin of key innovations such as terrestrial reproduction (in the Late Eocene) or by dispersal during periods of favourable climate ( niche conservatism-dominant).


title: The mutation effect reaction norm (MERN) highlights environmentally dependent mutation effects and genetic interactions

abstract: Since the modern synthesis, the fitness effects of mutations and epistasis have been central yet provocative concepts in evolutionary and population genetics. Studies of how the interactions between parcels of genetic information can change as a function of environmental context have added a layer of complexity to these discussions. Here I introduce the "mutation effect reaction norm" (Mu-RN), a new instrument through which one can analyze the phenotypic consequences of mutations and interactions across environmental contexts. It embodies the fusion of measurements of genetic interactions with the reaction norm, a classic depiction of the performance of genotypes across environments. I demonstrate the utility of the Mu-RN through the signature of a "compensatory ratchet" mutation that undermines reverse evolution of antimicrobial resistance. More broadly, I argue that the mutation effect reaction norm may help us resolve the dynamism and unpredictability of evolution, with implications for theoretical biology, genetic modification technology, and public health.


title: The mutation effect reaction norm (Mu-RN) highlights environmentally dependent mutation effects and genetic interactions


title: Local and temporal adaptation to climatic change in a wild tomato species via selective sweeps.

abstract:
O_LIPositive Darwinian selection is the driving force underpinning local adaptation, and leaves footprints of selective sweeps at the underlying major genes. Quantifying the timing of selection and revealing the genetic bases of local adaptation in plants species occurring in steep and varying environmental gradients is crucial to predict a species ability to respond to climate changes and explore new niches.
C_LIO_LIWe use whole genome sequence data from six populations across three different habitats of the wild tomato species Solanum chilense, to 1) infer the past demographic history, and 2) search for genes under strong positive selection. We then correlate current and past climatic projections with the demographic history, allele frequencies in space and time, the age of selection events, and changes in habitat suitability.
C_LIO_LIWe find evidence for several selective sweeps targeting regulatory networks involved in root hair development in low altitude, and response to photoperiod and vernalization in high altitude populations. These sweeps occur in a concerted fashion in a given regulatory gene network at particular periods of substantial climatic change.
C_LIO_LIWe decipher the genetic bases and the timing of local adaptation during plant colonization of semi-arid habitats using a unique combination of genome scans for selection and modelling of past climatic data.
C_LI


title: Local adaptation to novel habitats and climatic changes in a wild tomato species via selective sweeps.


title: Meta-analysis of immune induced gene expression changes in diverse Drosophila melanogaster innate immune responses

abstract:
BackgroundOrganisms are commonly infected by a diverse array of pathogen types including bacteria, fungi, viruses, and parasites, and mount functionally distinct responses to each of these varied immune challenges. Host immune responses are characterized by the induction of gene expression in response to infection. However, the extent to which expression changes are shared among responses to distinct pathogens is largely unknown.

ResultsWe performed meta-analysis of gene expression data collected from Drosophila melanogaster following infection with a wide array of pathogens. We identified 62 genes that are significantly induced by infection. While many of these infection-induced genes encode known immune response factors, we also identified 21 genes that have not been previously associated with host immunity. Examination of the upstream flanking sequences of the infection-induced genes lead to the identification of two conserved enhancer sites. These sites correspond to conserved binding sites for GATA and nuclear factor {kappa}B (NF{kappa}B) family transcription factors and are associated with higher levels of transcript induction. We further identified 31 genes with predicted functions in metabolism and organismal development that are significantly downregulated following infection by diverse pathogens.

ConclusionsOur study identifies conserved gene expression changes in Drosophila melanogaster following infection with varied pathogens, and transcription factor families that may regulate this immune induction. These findings provide new insight into transcriptional changes that accompany Drosophila immunity. They may suggest possible roles for the differentially regulated genes in innate immune responses to diverse classes of pathogens, and serve to identify candidate genes for further empirical study of these processes.

category: genetics


title: RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome associated quality control

abstract: Nucleotide repeat sequences are prevalent in the genome and expansion of these sequences is associated with more than 40 neuromuscular disorders. To understand the pathogenic mechanisms underlying RNA-repeat toxicity, we performed a genetic screen in a Caenorhabditis elegans model expressing an expanded CUG repeat specifically in the muscle. Here, we show that expression of this RNA repeat impairs motility by mitochondrial dysfunction, disrupting mitochondrial morphology and respiration. The phenotype is dependent on the RNA-binding factor MBL-1 and requires factors from the ribosome-associated protein quality control complex. Furthermore, Coenzyme Q supplementation rescued the motility impairment and all of the mitochondrial phenotypes. Together, our data reveal the importance of mitochondrial dysfunction in the molecular pathogenesis of RNA repeat expansion disorders.


title: High-resolution mapping of DNA alkylation damage and base excision repair at yeast transcription factor binding sites

abstract: DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), to characterize alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data shows that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs Abf1 and Reb1, but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. The observed effects are caused by the TF-DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.

category: genomics


title: Gene regulation by DNA methylation is contingent on chromatin accessibility during transgenerational plasticity in the purple sea urchin

abstract: Epigenetic processes are proposed to contribute to phenotypic plasticity. In invertebrates, DNA methylation commonly varies across environments and can correlate or causally associate with phenotype, but its role in transcriptional responses to the environment remains unclear. Maternal environments experienced by the sea urchin Strongylocentrotus purpuratus induce 3 - 6x greater differential CpG methylation in offspring larvae relative to larval developmental environments, suggesting a role for DNA methylation in transgenerational plasticity (TGP). However, a negligible association has been observed between differentially methylated and differentially expressed genes. What gene regulatory roles does invertebrate DNA methylation possess under environmental change, if any? We quantified DNA methylation and gene expression in S. purpuratus larvae exposed to different ecologically relevant conditions during gametogenesis (maternal conditioning) or embryogenesis (developmental conditioning). We modeled differential gene expression and differential splicing under maternal conditioning as functions of DNA methylation, incorporating variables for genomic feature and chromatin accessibility. We detected significant interactions between differential methylation, chromatin accessibility, and genic architecture associated with differential expression and splicing. Observed transcriptional responses to maternal conditioning were also 4 - 13x more likely when accounting for interactions between methylation and chromatin accessibility. Our results provide evidence that DNA methylation possesses multiple functional roles during TGP in S. purpuratus, but its effects are contingent upon other genomic and epigenomic states. Singularly unpredictive of transcription, DNA methylation is likely one cog in the epigenomic machinery contributing to environmental responses and phenotypic plasticity in S. purpuratus and other invertebrates.


title: Early life sleep disruption drives lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

abstract: Sleep disruption is a common comorbidity in patients with autism spectrum disorder (ASD), a condition diagnosed with a striking male bias of [~]4:1. It is unclear how sleep disruption contributes to ASD susceptibility, and the sex biased vulnerability. We examined sleep behavior and the effects of early life sleep disruption (ELSD) in developing mice bearing C-terminal truncation ({Delta}C) in ASD risk gene Shank3. Male and female Shank3{Delta}C/{Delta}C homozygotes showed clear sleep disruption early in postnatal life, compared to Shank3WT/{Delta}C heterozygotes and wild-type littermates, suggesting that sleep disruption may be an early symptom in the expression of ASD. We find that ELSD interacts with genetic vulnerability in Shank3WT/{Delta}C heterozygotes to drive lasting and sex-specific changes in behavior. Our results clearly show that sleep disruption during sensitive periods of postnatal development is causative of lasting changes in behavior in genetically vulnerable individuals, but in a striking sex-specific manner.

category: animal behavior and cognition


title: Aversive View Memory and Navigational Risk Sensitivity in the Desert Ant, Cataglyphis Velox

abstract: Many ants establish foraging routes through learning views of the visual panorama. Route models have focused primarily on attractive view use, which experienced foragers orient towards to return to known sites. However, aversive views have recently been uncovered as a key component of route learning. Here, Cataglyphis velox rapidly learned aversive views, when associated with a negative outcome, a period of captivity in brush, triggering an increase in hesitation behavior. These memories were based on the accumulation of experiences over multiple trips with each new experience regulating foragers hesitancy. Foragers were also sensitive to captivity time differences, suggesting they possess some mechanism to quantify duration. Finally, we analyzed foragers perception of risky (i.e. variable) versus stable aversive outcomes by associating two sites along the route with distinct captivity schedules, a fixed or variable duration, with the same mean across training. Foragers exhibited significantly less hesitation to the risky outcome compared to the fixed, indicating they perceived risky outcomes as less severe. Results align with a logarithmic relationship between captivity duration and hesitations, suggesting that aversive stimulus perception is a logarithm of its actual value. We conclude by characterizing how these behaviors can be executed within the mushroom bodies neural circuitry.


title: Constitutive depletion of brain serotonin differentially affects rats' social and cognitive abilities

abstract:
BackgroundCentral serotonin is an essential neuromodulator for mental disorders. It appears a promising transdiagnostic marker of distinct psychiatric disorders and a common modulator of some of their key behavioral symptoms. We aimed to identify the behavioral markers of serotonergic function in rats and compare them to human deficits.

MethodsWe applied a comprehensive profiling approach in adult male Tph2-/- rats constitutively lacking central serotonin. Under classical and ethological testing conditions, we tested each individuals cognitive, social and non-social abilities and characterized the group organization (i.e. social network, hierarchy). Using unsupervised machine learning, we identified the functions most dependent on central serotonin.

ResultsIn classical procedures, Tph2-/- rats presented an unexpected normal cognitive profile. Under the complex and experimenter-free conditions of their home-cage, the same Tph2-/- rats presented drastic changes in their daily life. Brain serotonin depletion induced compulsive aggression and sexual behavior, hyperactive and hypervigilant stereotyped behavior, reduced self-care and body weight, and exacerbated corticosterone levels. Group-housed Tph2-/- rats showed strong social disorganization with disrupted social networks and hierarchical structure, which may arise from communication deficits and cognitive blunting.

ConclusionsSerotonin depletion induced a profile reminiscent of the symptomatology of impulse control and anxiety disorders. Serotonin was necessary for behavioral adaptation to dynamic social environments. In classical testing conditions, our animal model challenged the concept of an essential role of serotonin in decision-making, flexibility, and impulsivity, although developmental compensations may have occurred. These contrasting findings highlight the need to generalize the evaluation of animal models multidimensional functions within the complexity of the social living environment.


title: Solvent Precipitation SP3 (SP4) enhances recovery for proteomics sample preparation without magnetic beads

abstract:
Complete, reproducible extraction of protein material is essential for comprehensive and unbiased proteome analyses. A current gold standard is single-pot, solid-phase-enhanced sample preparation (SP3), in which organic solvent and magnetic beads are used to denature and capture proteins, with subsequently washes allowing contaminant removal. However, SP3 is dependent on effective protein immobilisation onto beads, risks losses during wash steps, and experiences a drop-off in protein recovery at higher protein inputs. Magnetic beads may also contaminate samples and instruments, and become costly for larger scale protein preparations. Here, we propose solvent precipitation SP3 (SP4) as an alternative to SP3, omitting magnetic beads and employing brief centrifugation--either with or without low-cost inert glass beads--as the means of aggregated protein capture. SP4 recovered equivalent or greater protein yields for 1-5000 {micro}g preparations and improved reproducibility (median protein R2 0.99 (SP4) vs. 0.97 (SP3)). Deep proteome profiling (n = 9,076) also demonstrated improved recovery by SP4 and a significant enrichment of membrane and low-solubility proteins vs. SP3. The effectiveness of SP4 was verified in three other labs, each confirming equivalent or improved proteome characterisation over SP3. This work suggests that protein precipitation is the primary mechanism of SP3, and reliance on magnetic beads presents protein losses, especially at higher concentrations and amongst hydrophobic proteins. SP4 represents an efficient and effective alternative to SP3, provides the option to omit beads entirely, and offers virtually unlimited scalability of input and volume--all whilst retaining the speed and universality of SP3.

BRIEFSolvent precipitation SP3 (SP4) captures aggregated protein for proteomics sample clean-up by omitting magnetic beads, instead employing brief centrifugation--with or without low-cost inert glass beads. SP4 offers improvements to protein yields, higher reproducibility, and greater recovery of membrane proteins, with verifications from three labs. Protein precipitation appears to be the primary mechanism of SP3, with reliance on magnetic beads presenting protein losses, especially at higher concentrations. SP4 presents an effective alternative to SP3 with improved scalability and equal speed and universality.

GRAPHICAL ABSTRACT

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category: biochemistry


title: Bio-hybrid Soft Robotic Bioreactors for Mimicking Multi-Axial Femoropopliteal Artery Mechanobiology

abstract: The emerging field of soft robotics aims to emulate dynamic physiological locomotion. Soft robotics mimicry of naturally complex biomechanics makes them ideal platforms for exerting mechanical stimuli for patient-specific tissue maturation and disease modeling applications. Such platforms are essential for emulating highly flexible tissues such as the kneecaps femoropopliteal artery (FPA), one of the most flexible arteries in the body, which flexes and bends during walking, standing, and crouching movements. The FPA is a frequent site of disease, where 80% of all peripheral artery diseases manifest, affecting over 200 million people worldwide. The complex biomechanical and hemodynamic forces within the FPA have been implicated in the frequent occurrence of PAD and lead to debilitating morbidities, such as limb-threatening ischemia. To better mimic these complex biomechanics, we developed an in-vitro bio-hybrid soft robot (BSR). First, Platsil OO-20 was identified as an ideal hyperelastomer for both cell culture and BSR fabrication using 3D printed molds. Then, employing a simulation-based design workflow, we integrated pneumatic network (PneuNet) actuators cast with Platsil OO-20, which extend in angular, longitudinal, and radial dimensions. Pressurizing the BSR PneuNets enabled a range of mechanical stimuli to be dynamically applied during tissue culture to mimic normal and diseased FPA flexions during daily walking and sitting poses, the most extreme being radial distensions of 20% and angular flexions of 140{degrees}. Finally, these designed, manufactured, and programmed vascular BSRs were seeded with mesenchymal stem cells and conditioned for 24 hours to highlight the effect of dynamic conditioning on cultured cell alignment, as well as type IV collagen production and the upregulation of smooth muscle phenotypes. Soft robotic bioreactor platforms that accurately mimic patient-, disease-, and lifestyle-specific mechanobiology will develop fundamental disease understanding, preoperative laboratory simulations for existing therapeutics, and biomanufacturing platforms for tissue-engineered implants.

category: bioengineering


title: Batch effects removal for microbiome data via conditional quantile regression (ConQuR)

abstract: Batch effects in microbiome data arise from differential processing of specimens and can lead to spurious findings and obscure true signals. Most existing strategies for mitigating batch effects rely on approaches designed for genomic analysis, failing to address the zero-inflated and over-dispersed microbiome data. Strategies tailored for microbiome data are restricted to association testing, failing to allow other analytic goals such as visualization. We develop the Conditional Quantile Regression (ConQuR) approach to remove microbiome batch effects using a two-part quantile regression model. It is a fundamental advancement in the field because it is the first comprehensive method that accommodates the complex distributions of microbial read counts, and it generates batch-removed zero-inflated read counts that can be used in and benefit all usual subsequent analyses. We apply ConQuR to real microbiome data sets and demonstrate its state-of-the-art performance in removing batch effects while preserving or even amplifying the signals of interest.

category: bioinformatics


title: Single Object Profiles Regression Analysis (SOPRA): A novel method for analyzing high content cell-based screens

abstract:
MotivationHigh content screening (HCS) experiments generate complex data from multiple object features for each cell within a treated population. Usually these data are analyzed by using population-averaged values of the features of interest, increasing the amount of false positives and the need for intensive follow-up validation. Therefore, there is a strong need for novel approaches with reproducible hit prediction by identifying significantly altered cell populations.

ResultsHere we describe SOPRA, a workflow for analyzing image-based HCS data based on regression analysis of non-averaged object features from cell populations, which can be run on hundreds of samples using different cell features. Following plate-wise normalization the values are counted within predetermined binning intervals, generating unique frequency distribution profiles (histograms) for each population, which are then normalized to control populations. Statistically significant differences are identified using a regression model approach. Significantly changed profiles can be used to generate a heatmap from which altered cell populations with similar phenotypes are identified, enabling detection of siRNAs and compounds with the same  on-target profile, reducing the number of false positive hits. A screen for cell cycle progression was used to validate the workflow, which identified statistically significant changes induced by siRNA-mediated gene perturbations and chemical inhibitors of different cell cycle stages.


title: Dirichlet variational autoencoders for de novo motif discovery from accessible chromatin

abstract: Determining the cell type-specific and genome-wide binding locations of transcription factors (TFs) is an important step towards decoding gene regulatory programs. Profiling by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) reveals open chromatin sites that are potential binding sites for TFs but does not identify which TFs occupy a given site. We present a novel unsupervised deep learning approach called BindVAE, based on Dirichlet variational autoencoders, for jointly decoding multiple TF binding signals from open chromatin regions. Our approach automatically learns distinct groups of kmer patterns that correspond to cell type-specific in vivo binding signals. Latent factors found by BindVAE generally map to TFs that are expressed in the input cell type. BindVAE finds different TF binding sites in different cell types and can learn composite patterns for TFs involved in co-operative binding. BindVAE therefore provides a novel unsupervised approach to deconvolve the complex TF binding signals in chromatin accessible sites.


title: BionetBF: A Novel Bloom Filter for Faster Membership Identification of Paired Biological Network Data

abstract: Biological network represents the interaction or relationship between the biological entities such as proteins and genes of a biological process. A biological network with thousands of millions of vertices makes its processing complex and challenging. In this article, we propose a novel Bloom Filter called Biological network Bloom Filter (BionetBF) fast membership identification of the biological network edges or paired biological data. BionetBF is capable of executing millions of operations within a second while occupying a tiny amount of main memory. We have conducted rigorous experiments to prove the performance of BionetBF with large datasets. The experiment is conducted using 12 generated datasets and three biological network datasets. It takes less than 8 sec for insertion and query of 40 million paired data. It demonstrates higher performance while maintaining a 0.001 false positive probability. BionetBF is also compared with other filters: Cuckoo Filter and Libbloom, where BionetBF proves its supremacy by exhibiting higher performance with a smaller sized memory compared with large sized filters of Cuckoo Filter and Libbloom.


title: Differential Network Analysis of Longitudinal Gene Expression in Response to Perturbations.

abstract: Understanding changes in gene expression under the effects of a perturbation is a key goal of systems biology. A powerful approach to address this goal uses gene networks and describes the perturbations effects as a rewiring of each genes connections. This approach is known as differential network (DN) analysis. Here, we used DNs to analyze RNA-sequencing time series datasets, focusing on expression changes: (i) In the saliva of a human subject after vaccination with a pneumococcal vaccine (PPSV23), and (ii) in B cells treated ex vivo with a monoclonal antibody drug (Rituximab). Using network community detection, we revealed the collective behavior of clusters of genes, and detected communities of genes based on their longitudinal behavior, and corresponding pathway activations. We identified biological pathways consistent with the mechanism of action of the vaccine and with Rituximabs targets. The approach may be useful in drug development by providing an effective analysis of expressing changes in response to a drug.


title: Single shot detector application for image disease localization

abstract: Bounding box algorithms are useful in localization of image patterns. Recently, utilization of convolutional neural networks on X-ray images has proven a promising disease prediction technique. However, pattern localization over prediction has always been a challenging task with inconsistent coordinates, sizes, resolution and capture positions of an image. Several model architectures like Fast R-CNN, Faster R-CNN, Histogram of Oriented Gradients (HOG), You only look once (YOLO), Region-based Convolutional Neural Networks (R-CNN), Region-based Fully Convolutional Networks (R-FCN), Single Shot Detector (SSD), etc. are used for object detection and localization in modern-day computer vision applications. SSD and region-based detectors like Fast R-CNN or Faster R-CNN are very similar in design and implementation, but SSD have shown to work efficiently with larger frames per second (FPS) and lower resolution images. In this article, we present a unique approach of SSD with a VGG-16 network as a backbone for feature detection of bounding box algorithm to predict the location of an anomaly within chest X-ray image.


title: Structural basis of substrate recognition and translocation by human ABCD1

abstract: Human ATP-binding cassette (ABC) transporter ABCD1 transports CoA esters of saturated/monounsaturated very long chain fatty acid from cytosol to the peroxisome for {beta}-oxidation. Dysfunction of human ABCD1 usually causes the severe progressive genetic disorder X-linked adrenoleukodystrophy, which eventually affects the adrenal glands and/or the central nervous system. Here, we report three cryo-EM structures of human ABCD1 in various states. The apo-form ABCD1 at 3.53 [A] resolution adopts an inward-facing conformation, harboring a phosphatidyl ethanolamine (PE) molecule at each lateral entry of substrate cavity. In the substrate-bound ABCD1 structure at 3.59 [A] resolution, two molecules of C22:0-CoA (one of the physiological substrates of ABCD1) is symmetrically bound to the transmembrane domains (TMDs). Each C22:0-CoA adopts an unpresented L-shape configuration: the CoA portion inserts into a polar pocket at the TMD at a pose parallel to the membrane plane, whereas the acyl chain portion perpendicular to membrane plane is embedded in a hydrophobic pocket at the opposite TMD. Upon binding the two C22:0-CoA molecules, which resemble a pair of hinges crossing the two TMDs, the two nucleotide-binding domains (NBDs) of ABCD1 approach towards each other. Addition ATP to the substrate-bound ABCD1 enabled us to reveal an ATP-bound structure at 2.79 [A], which shows an outward-facing conformation with the dimerized NBDs succeeding substrate release. These three structures combined with biochemical assays exhibit a snapshot of ABCD1-mediated substrate recognition, translocation and release. These findings provide the structural insights into the transport mechanism of ABC transporters that transport amphipathic molecules with long acyl chains.

category: biophysics


title: Targeting of MCL-1 in breast cancer associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties

abstract:
Cancer associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFS) typically express MCL-1. We show here that targeting this regulator of mitochondrial integrity using a specific BH-3 mimetic promotes fragmentation of these organelles without inducing cell death. MCL-1 antagonism in primary bCAFs directly derived from human samples mitigates myofibroblastic features and decreases expression of genes involved in actomyosin organization and contractility, associated with a cytoplasmic retention of the transcriptional regulator, Yes-Associated Protein (YAP). Such treatment decreases bCAFs ability to promote cancer cells invasion in 3D co-culture assays. These effects are counteracted by an inhibitor of the mitochondrial fission protein DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve.

The authors declare no conflict of interest.

category: cancer biology


title: Concurrent tau pathologies in frontotemporal lobar degeneration with TDP-43 pathology

abstract:
AimsAccumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP-43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP-43 pathology (FTLD-TDP).

MethodsThe study included 146 autopsy-confirmed cases of FTLD-TDP and 55 cases of FTLD-TDP with motor neuron disease (FTLD-MND). Sections from the basal forebrain were screened for tau pathology with phospho-tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9ORF72, GRN, and MAPT was performed on select cases.

ResultsAmong 201 cases, we found 72 cases (36%) with primary age-related tauopathy (PART), 85 (42%) with aging-related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD), and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD-TDP and CBD had C9ORF72 mutation and relatively mild tau pathology, consistent with incidental CBD.

ConclusionThe coexistence of TDP-43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, individual patients with FTLD can have multiple concurrent proteinopathies. The absence of TDP-43-positive astrocytic plaques may suggest that CBD and FTLD-TDP were independent disease processes in the two patients with both tau and TDP-43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

category: pathology


title: Enculturating a Community of Action (CoA): A qualitative study of health professions educators' perspectives on teaching with Wikipedia

abstract:
PurposeThere is a growing desire for health professions educators to engage learners in more meaningful instruction. Many have tapped Wikipedia to offer an applied approach to engage learners, particularly as it relates to evidence-based medicine (EBM). However, little is known about the benefits and challenges of using Wikipedia as a pedagogical tool from the collective experience of educators who have sought to improve their instructional practice with it. This study aims to uncover and synthesize the perspectives of health professions education (HPE) instructors who have incorporated Wikipedia in their HPE courses.

MethodsApplying a constructivist approach, the authors conducted semi-structured interviews with 17 participating HPE instructors who had substantively integrated Wikipedia into their curriculum. Participants were interviewed about their experiences of integrating Wikipedia editing into their courses. Thematic analysis was conducted on resulting transcripts.

ResultsAuthors observed two broad themes among participants expressed benefits of teaching with Wikipedia: 1) provides a meaningful instructional alternative that also benefits society and develops learners information literacy and EBM skills, and 2) supports learners careers and professional identity formation. Identified challenges included: 1) high effort and time, 2) issues with sourcing references, and 3) challenging interactions with skeptics, editors, and students.

DiscussionFindings build on known benefits, such as providing a real-world collaborative project that contextualizes students learning experiences. They also echo known challenges, such as the resource-intensive nature of teaching with Wikipedia. At the same time, findings extend the current literature by revealing a potential opportunity to approach crowd-sourced information tools, like Wikipedia, as a vehicle to engage and enculturate HPE students within a situated learning context. These findings present implications for HPE programs considering implementing Wikipedia and faculty development needed to help instructors harness crowd-sourced information tools pedagogical opportunities as well as anticipate their challenges.

category: scientific communication and education


title: A cortico-cortical pathway targets inhibitory interneurons and modulates paw movement during locomotion in mice

abstract:
The primary somatosensory cortex (S1) is important for the control of movement as it encodes sensory input from the body periphery and external environment during ongoing movement. Mouse S1 consists of several distinct sensorimotor subnetworks that receive topographically organized cortico-cortical inputs from distant sensorimotor areas, including the secondary somatosensory cortex (S2) and primary motor cortex (M1). The role of the vibrissal S1 area and associated cortical connections during active sensing is well documented, but whether (and if so, how) non-whisker S1 areas are involved in movement control remains relatively unexplored. Here, we demonstrate that unilateral silencing of the non-whisker S1 area in both male and female mice disrupts hind paw movement during locomotion on a rotarod and a runway. S2 and M1 provide major long-range inputs to this S1 area. Silencing S2 [->] non-whisker S1 projections alters the hind paw orientation during locomotion while manipulation of the M1 projection has little effect. Using patch-clamp recordings in brain slices from male and female mice, we show that S2 projection preferentially innervates inhibitory interneuron subtypes. We conclude that interneuron-mediated S2-S1 cortico-cortical interactions are critical for efficient locomotion.

SignificanceSomatosensory cortex participates in controlling rhythmic movements such as whisking and walking, but the neural circuitry underlying movement control by somatosensory cortex remains relatively unexplored. We uncover a cortico-cortical circuit in primary somatosensory cortex that regulates paw orientation during locomotion in mice. We identify neuronal elements that comprise these cortical pathways using pharmacology, behavioral assays and circuit-mapping methods.

category: neuroscience


title: Traumatic Brain Injury Exacerbates Alzheimer's Disease Pathology in the Retinas of TgF344-AD Rats

abstract:
Alzheimers disease (AD) is a neurodegenerative condition that affects 6.2 million people age 65 and older in the U.S. alone, and is the leading cause of dementia. Moreover, AD can lead to visual impairment, and AD histopathology also manifests in the retina. However, the factors that modulate AD pathophysiology and lead to varied susceptibility and presentation in the population are not well understood. In this context, traumatic brain injury (TBI), which can arise from sport concussions, military combat, and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias (ADRD). Thus, we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology.

Several animal models have been developed to investigate the mechanisms underlying AD, but many have been limited by imperfect recapitulation of human pathology, and no model of TBI-associated AD (AD-TBI) has been characterized. To address this gap, we generated an innovative model of AD-TBI by taking advantage of a transgenic rat model (Tg-F344-AD) shown to recapitulate the main features of human AD pathology, and combining it with a twotime unilateral controlled cortical impact paradigm to mimic repetitive mild TBI (rmTBI). Histopathological analyses at four months post-impact confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. Together, these results contribute to our understanding of the effects of TBI on AD retinopathy, with implications for patient care and therapeutic development.


title: Vertex-wise characterization of Non-Human Primate cortical development with prenatal insights.

abstract: Characterization of the interwoven complexities of early cortical thickness development has been an ongoing undertaking in neuroscience research. Longitudinal studies of Non-Human Primates (NHP) offer unique advantages to categorizing the diverse patterns of cortical growth trajectories. Here, we used latent growth models to characterize the trajectories of typical cortical thickness development in Japanese macaques at each cortical surface vertex (i.e. grayordinate). Cortical thickness from 4 to 36 months showed regional specific linear and non-linear trajectories and distinct maturation timing across the cortex. Intriguingly, we revealed a "accumulation/ablation phenomenon" of cortical maturation where the most profound development changes in cortical thickness occur in the accumulation or ablation zones surrounding the focal points (i.e., a center of a delineated regions where cortical thickness is thickest or thinnest) throughout the brain. We further examined maternal diet and inflammation in the context of these typical brain trajectories and known network architecture. A well-controlled NHP model of a maternal "Western-style" diet was used alongside measures of inflammatory cytokine interleukin-6 (IL-6) in the mothers during gestation. We observed that these accumulation and ablation zones of variable change might be most susceptible to environmental effects. The maternal factors, diet and inflammation during pregnancy were distinctively associated with different aspects of offspring cortical development reflected in regions related to distinctive functional networks. Our findings characterize the versatile intricacies of typical cortical thickness development and highlight how the maternal environment plays a role in offspring cortical development.


title: Parallel systems for social and spatial reasoning within the cortical apex

abstract: What is the cognitive and neural architecture for high-level reasoning? We hypothesize that systems for understanding people and places remain separate throughout the brain, but share a parallel organization. We test this hypothesis using deep neuroimaging of individual human brains on diverse tasks involving reasoning and memory about familiar people, places, and objects. We find that thinking about people and places elicits responses in distinct areas of high-level association cortex, spanning the frontal, parietal, and temporal lobes. Person- and place-preferring brain regions are systematically yoked across cortical zones. These areas have strongly domain-specific response profiles across visual, semantic, and episodic tasks, and are specifically functionally connected to other parts of association cortex with like category preference. Social and spatial networks are anatomically separated even at the top of the cortical hierarchy, and include parts of cortex with anatomical connections to the hippocampal formation. These results demonstrate parallel, domain-specific networks within the cortical apex. They suggest that domain-specific systems for reasoning constitute components of a broader cortico-hippocampal system for long-term memory.


title: Chronic THC vapor rescues inflammation-related thermal hyperalgesia and causes cell type-specific modifications in vlPAG neurons

abstract:
To reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain and/or as a strategy for reducing opioid drug dosage and duration of treatment (i.e., so-called opioid-sparing effects). Previous preclinical work has shown robust anti-hyperalgesic effects of systemic THC and acute anti-hyperalgesic effects of vaporized THC. Here, we used a vapor inhalation model in rats to test chronic THC vapor inhalation effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., periaqueductal gray [PAG]) neuronal function, in adult male rats with chronic inflammatory pain. We report that chronic THC vapor inhalation produces a robust anti-hyperalgesic effect in rats with chronic inflammatory pain, and that this effect persists 24 hours after cessation of THC exposure. We demonstrate that chronic THC vapor inhalation also modulates intrinsic and synaptic properties of ventrolateral PAG (vlPAG) neurons, including reductions in action potential firing rate and reductions in spontaneous inhibitory synaptic transmission, and that these effects occur specifically in neurons that respond to current input with a delayed firing phenotype. Finally, we show that the suppressive effect of the bath-applied mu-opioid receptor (MOR) agonist DAMGO on synaptic inhibition in the vlPAG is enhanced in slices taken from rats with a history of chronic THC vapor inhalation. Collectively, these data show that chronic THC vapor inhalation produces lasting attenuation of thermal hyperalgesia and reduces synaptic inhibition in the vlPAG of rats with chronic inflammatory pain.

Significance StatementMany adults in the U.S. with pain self-medicate with THC and cannabis, and many cannabis users are increasingly using e-cigarette type devices filled with cannabis extracts to self-administer THC and other constituents of the marijuana plant. Until recently, most rodent studies of THC effects on brain and behavior have not used vapor inhalation techniques. Here, we designed a series of studies to test the effect of chronic THC vapor inhalation on pain-related behaviors and midbrain neural circuit function in adult male Wistar rats. We hypothesized that chronic THC vapor would have anti-hyperalgesic effects in rats with chronic inflammatory pain, and that it would produce disinhibition of midbrain pain modulation neurons.


title: A rise-to-threshold signal for a relative value deliberation

abstract: Whereas progress has been made in identifying neural signals related to rapid, cued decisions1-4, less is known about how brains guide and terminate more ethologically relevant deliberations, where an animals own behavior governs the options experienced over minutes5-8. Drosophila search for many seconds to minutes for egg-laying sites with high relative value9, 10 and neurons, called oviDNs, exist whose activity fulfills necessity and sufficiency criteria for initiating the egg-deposition motor program11. Here we show that oviDNs express a calcium signal that rises over seconds to minutes as a fly deliberates whether to lay an egg. The calcium signal dips when an egg is internally prepared (ovulated), rises at a rate related to the relative value of the current substrate being experienced, and reaches a consistent peak just prior to the abdomen bend for egg deposition. We provide perturbational evidence that the egg-deposition motor program is initiated once this signal hits a threshold and that sub-threshold variation in the signal regulates the time spent deliberating and, ultimately, the option chosen. These results argue that a rise-to-threshold signal guides Drosophila to lay eggs on substrate options with high relative value, with each egg-laying event representing a self-paced decision similar to real-world decisions made by humans and other mammals.


title: Leveling up: improving power in fMRI by moving beyond cluster-level inference

abstract: Inference in neuroimaging commonly occurs at the level of "clusters" of neighboring voxels or connections, thought to reflect functionally specific brain areas. Yet increasingly large studies reveal effects that are shared throughout the brain, suggesting that reported clusters may only reflect the "tip of the iceberg" of underlying effects. Here, we empirically compare power of traditional levels of inference (edge and cluster) with broader levels of inference (network and whole-brain) by resampling functional connectivity data from the Human Connectome Project (n=40, 80, 120). Only network- and whole brain-level inference attained or surpassed "adequate" power ({beta}=80%) to detect an average effect, with almost double the power for network-compared with cluster-level procedures at more typical sample sizes. Likewise, effects tended to be widespread, and more widespread pooling resulted in stronger magnitude effects. Power also substantially increased when controlling FDR rather than FWER. Importantly, there may be similar implications for task-based activation analyses where effects are also increasingly understood to be widespread. However, increased power with broader levels of inference may diminish the specificity to localize effects, especially for non-task contexts. These findings underscore the benefit of shifting the scale of inference to better capture the underlying signal, which may unlock opportunities for discovery in human neuroimaging.


title: AI-driven high-throughput automation of behavioral analysis and dual-channel wireless optogenetics for multiplexing brain dynamics

abstract:
Advances in behavioral optogenetics are limited by the absence of high-throughput pipelines for the automated analysis of behavior in freely behaving animals. Although a variety of AI algorithms has been proposed that enable automation of behavioral analysis, existing methods are generally low-throughput. In addition, optogenetic manipulation of neural circuits typically requires physical tethers to light sources, which limits the number of brain areas that can be targeted and thus constrains behavioral testing. Here, we develop a new wireless platform that combines a battery-free dual-channel optogenetic implant with an AI algorithm for high-throughput behavioral analysis. In our platform, a customized AI algorithm detected and quantified freezing behavior of rats that had undergone fear conditioning. Notably, our platform allows up to four enclosures to be monitored simultaneously. Wireless dual-channel optogenetic devices were implanted in the basolateral amygdala (BLA) to permit independent modulation of BLA principal neurons (red light, AAV-CaMKII-JAWS) or BLA interneurons (blue light, AAV-mDlx-ChR2) in freely behaving animals. In vivo validation with behaving rats demonstrates the utility of the telemetry system for large-scale optogenetic studies.

SignificanceAI algorithms can enable automation of behavioral analysis and thereby facilitate the progress on behavioral optogenetics. Successful integration of advanced wireless dual-channel optoelectronic devices with biological systems can also yield new tools and techniques for neuroscience research, particularly in the context of techniques for optogenetics. Here, we propose a new approach that combines an advanced AI algorithm with a low power wireless telemetry system, yielding powerful capabilities in the understanding of brain functions and the evaluation of the behavioral consequences of neural circuit manipulations. In vivo studies using optimized systems demonstrate high-throughput automation of behavioral manipulation and analysis via AI-powered wireless telemetry.


title: LXR agonist Prevents Peripheral Neuropathy and modifies PNS immune cells in Aged Mice

abstract: Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities and increases the risk of injury. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist GW3965, alleviates pain in a diet-induced obesity model. Because cholesterol had also been linked to neuropathy during aging, we sought to test whether LXR activation may improve neuropathy and pain in aged mice by treating 21-month-old mice for 3 months with GW3965. Treatment resulted in a significant increase in nerve fibers of the sub-basal plexus, accompanied by a change in polarization, metabolism, and cholesterol content of macrophages in the sciatic nerve. These results suggest that activation of the LXR may block the progression of neuropathy associated with aging by modifying nerve-immune cell cholesterol, thereby providing new pathways to target in efforts to delay neuropathy during aging.


title: Neonatal multi-modal cortical profiles predict 18-month developmental outcomes

abstract: Developmental delays in infanthood often persist, turning into life-long difficulties, and coming at great cost for the individual and community. By examining the developing brain and its relation to developmental outcomes we can start to elucidate how the emergence of brain circuits is manifested in variability of infant motor, cognitive and behavioural capacities. In this study, we examined if cortical structural covariance at birth, indexing coordinated development, is related to later infant behaviour. We included 193 healthy term-born infants from the Developing Human Connectome Project (dHCP). An individual cortical connectivity matrix derived from morphological and microstructural features was computed for each subject (morphometric similarity networks, MSNs) and was used as input for the prediction of behavioural scores at 18 months using Connectome-Based Predictive Modeling (CPM). Neonatal MSNs successfully predicted social-emotional performance. Predictive edges were distributed between and within known functional cortical divisions with a specific important role for primary and posterior cortical regions. These results reveal that multi-modal neonatal cortical profiles showing coordinated maturation are related to developmental outcomes and that network organization at birth provides an early infrastructure for future functional skills.


title: Domain General Processes for Interactive Touch

abstract: The nexus model of social processing proposes that the right temporal parietal junction (rTPJ) serves as a neural hub for cognitive social functions. We test the hypothesis that the rTPJ is a domain general region including somatosensory social functions. Neuroimaging findings and cross-brain coherence for right- and left-hand handclasps with real vs. simulated hands were consistent with the domain general model.


title: On the edge of criticality: strength-dependent perturbation unveils delicate balance between fluctuation and oscillation in brain dynamics

abstract: Despite decades of research, there is still a lack of understanding of the role and generating mechanisms of the ubiquitous fluctuations and oscillations found in recordings of brain dynamics. Here, we used a strength-dependent perturbative framework to provide a causal mechanistic description of how human brain function is perched at the delicate balance between fluctuation and oscillation. Applying local strength-dependent perturbations and subsequently measuring the perturbative complexity index clearly demonstrates that the overall balance of brain dynamics is shifted towards fluctuations for providing much needed flexibility. Importantly, stimulation in the fluctuation regime modulates specific resting state network, thus providing a mechanistic explanation of experimentally reported brain dynamics. Furthermore, this framework generates specific, testable empirical predictions for human stimulation studies using strength-dependent rather than constant perturbation. Overall, the strength-dependent perturbative framework demonstrates how the human brain is poised on the edge of criticality, between fluctuations to oscillations, allowing for maximal flexibility.


title: NMDAr BLOCKING BY MK801 ALTERS HIPPOCAMPAL AND PREFRONTAL CORTEX OSCILLATIONS AND IMPAIRS SPATIAL WORKING MEMORY IN MICE.

abstract:
Abnormal NMDAr function has been linked to rhythmopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal hippocampus and medial prefrontal cortex (mPFC), administered the NMDAr antagonist MK801, and recorded oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade increased locomotor activity, impaired spatial working memory, and disrupted the correlation between oscillations and speed of movement, crucial for internal representations of distance. In the hippocampus, MK801 increased gamma oscillations and disrupted theta/gamma coupling, while in the mPFC, it increased the power of theta and gamma, and generated high-frequency oscillations (HFO 155-185 Hz), also disrupting theta/gamma coupling. Spatial working memory tests in the y-maze revealed that theta/gamma coupling was consistently higher in correct trials after MK801 administration but were lower in the baseline condition. Theta/gamma co- modulation mediated by NMDAr function might be essential to explaining several of SCZs cognitive symptoms and might be crucial to explain hippocampal-PFC interaction.

Significance StatementNMDAr hypofunction might be at the bases of cognitive symptoms and oscillopathies found in Schizophrenia. In this work we aimed to understand further this link. We found that NMDAr hypofunction altered theta/gamma co-modulation in the hippocampus and the PFC explaining spatial working memory deficits.


title: A network model of glymphatic flow under different experimentally-motivated parametric scenarios

abstract: Rapidly growing evidence demonstrates that flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) - annular channels surrounding vasculature in the brain - is a critically-important component of neurophysiology. CSF inflow contributes during physiological conditions to clearance of metabolic waste and in pathological situations to edema formation. However, brain-wide imaging methods cannot resolve PVSs, and high-resolution methods cannot access deep tissue or be applied to human subjects, so theoretical models provide essential insight. We model this CSF pathway as a network of hydraulic resistances, built from published parameters. A few parameters have very wide uncertainties, so we focus on the estimated limits of their feasible ranges by analyzing different parametric scenarios. We identify low-resistance PVSs and high-resistance parenchyma (brain tissue) as the scenario that best explains experimental observations. Our results point to the most important parameters that should be measured in future experiments. Extensions of our modeling may help predict stroke severity or lead to neurological disease treatments and drug delivery methods.


title: Characterizing brain state-dependent pupil dynamics based on lateral hypothalamic activity

abstract: Pupil dynamics presents varied correlation features with brain activity under different vigilant levels. The modulation of brain state changes can arise from the lateral hypothalamus (LH), where diverse neuronal cell types contribute to arousal regulation in opposite directions via the anterior cingulate cortex (ACC). However, the relationship of the LH and pupil dynamics has seldom been investigated. Here, we performed local field potential (LFP) recordings at the LH and ACC, and the whole brain fMRI with simultaneous fiber photometry Ca2+ recording in the ACC, to evaluate their correlation with brain state-dependent pupil dynamics. Both LFP and functional MRI (fMRI) data showed opposite correlation features to pupil dynamics, demonstrating an LH activity-dependent manner. Our results demonstrate that the correlation of pupil dynamics with ACC LFP and whole-brain fMRI signals depends on LH activity, indicating a role of the latter in brain state regulation.


title: Live Monitoring of Inflammation Reveals Tissue and Sex-specific Responses to Western Diet and Butyrate treatment

abstract: Obesity is a current epidemic, affecting millions of individuals worldwide. Chronic obesity is characterized by a low-grade systemic inflammation besides not being a classic inflammatory disease. Many studies have tried to identify inflammatory insults dysregulated by a Westernized diet - consisted of high fat, high sucrose, and high cholesterol -mainly focusing on production and secretion of inflammatory cytokines. The gut microbiome and derived metabolites, including the short-chain fatty acid butyrate, have received increased attention as underlying some of the obesogenic features. In the present work, we utilized a novel biosensor mouse model capable of monitoring in vivo inflammation. We observed tissue- and sex- specific caspase-1 activation patterns in obese mice and treated with butyrate. Our work utilizing a caspase-1 biosensor mouse model, flow cytometry and computational analyses and offers new mechanistic insights underlying the effect of butyrate in obesity and its complications.


title: Purinergic receptor P2RY14 cAMP signaling regulates EGFR-driven Schwann cell precursor self-renewal and nerve tumor initiation in neurofibromatosis.

abstract: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) lack NF1 and show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. Gene expression profiling and protein expression identified P2RY14 in SCs and SC precursors (SCPs) implicating P2RY14 as a candidate upstream regulator of cAMP in EGF-dependent SCP. We found that SCP self-renewal was reduced by genetic or pharmacological inhibition of P2RY14. In NF1 deficient SCs and malignant peripheral nerve sheath tumor (MPNST) cells, P2RY14 inhibition decreased EGFR-driven phospho-Akt and increased cAMP signaling. In a neurofibroma mouse model, genetic deletion of P2RY14 increased mouse survival, delayed neurofibroma initiation and rescued cAMP signaling. Conversely, elevation of cAMP diminished SCP number in vitro and diminished SC proliferation in neurofibroma bearing mice in vivo. These studies identify the purinergic receptor P2RY14 as a critical G-protein-coupled receptor (GPCR) in NF1 mutant SCPs and SCs and suggest roles for EGFR-GPCR crosstalk in facilitating SCP self-renewal and neurofibroma initiation via cAMP and EGFR-driven phospho-Akt.


title: The genomic context for aflatoxin B1-degrading Pseudomonas strains

abstract: The whole genomes of three strains were sequenced and annotated. COG (Clusters of Orthologous Groups) and GO (Gene Ontology) annotations of the protein-coding genes from three strains show a conservation of genome-wide protein functions in genus Pseudomonas. However, the AFB1-degrading strains HAI2 and HT3 harbor much more genes belonged to the pathway of xenobiotics biodegradation and metabolism than non-degrading strain 48. Besides, the enzyme families potentially involved in the AFB1 degradation of bacteria are more abundant in the two AFB1-degrading strains. A pan-genome profile was then formed by comparing the genomes against other reference genomes of the corresponding Pseudomonas species. Accordingly, a total of 1,528 genes were found to be specific in AFB1-degrading strains, and 65 genes of them are related to oxidoreductase activity.

category: microbiology