title: Heterogeneous pdgfrβ+ cells regulate coronary vessel development and revascularization during heart regeneration

abstract:
Endothelial cells emerge from the atrioventricular canal (AVC) to form nascent coronary blood vessels in the juvenile zebrafish heart. We found that pdgfr{beta} is first expressed in the epicardium around the AVC and later becomes localized mainly in the mural cells. pdgfr{beta} mutant fish display severe defects in mural cell recruitment and coronary vessel development. pdgfr{beta}+ mural cells are heterogeneous and those associated with coronary arteries also express cxcl12b. Mural cells positive for both pdgfr{beta} and cxcl12b transgenic reporters had elevated expression of smooth muscle cell genes. Interestingly, these mural cells were associated with coronary arteries even in the absence of Pdgfr{beta}, although smooth muscle gene expression was downregulated in these cells. We found that pdgfr{beta} expression dynamically changes in the epicardium derived cells, which we found to be a heterogeneous population. mdka was identified as a gene upregulated in subpopulations of pdgfr{beta}+ cells during heart regeneration. However, pdgfr{beta} but not mdka mutants showed defects in heart regeneration. Our results demonstrated that pdgfr{beta}+ cells and Pdgfr{beta} signaling are essential for coronary development and heart regeneration.

SUMMARY STATEMENTHeterogeneous pdgfr{beta} positive cells are present in developing and regenerating zebrafish hearts and are required for development of mural cells and their association with the nascent coronary vessels during zebrafish heart development and regeneration.


title: Neurotrophic control of size regulation during axolotl limb regeneration

abstract: The mechanisms that regulate the sizing of the regenerating limb in tetrapods such as the Mexican axolotl are unknown. Upon the completion of the developmental stages of regeneration, when the regenerative organ known as the blastema completes patterning and differentiation, the limb regenerate is proportionally small in size. It then undergoes a phase of regeneration that we have called the "tiny-limb" stage, that is defined by rapid growth until the regenerate reaches the proportionally appropriate size. In the current study we have characterized this growth and have found that signaling from the limb nerves is required for its maintenance. Using the regenerative assay known as the Accessory Limb Model, we have found that the size of the limb can be positively and negatively manipulated by nerve abundance. We have additionally developed a new regenerative assay called the Neural Modified-ALM (NM-ALM), which decouples the source of the nerve from the regenerating host environment. Using the NM-ALM we discovered that non-neural extrinsic factors from differently sized host animals do not play a prominent role in determining the size of the regenerating limb. We have also discovered that the regulation of limb size is not autonomously regulated by the limb nerves. Together, these observations show that the limb nerves provide essential and instructive cues to regulate the final size of the regenerating limb.

category: developmental biology


title: Sustained coevolution of phage Lambda and Escherichia coli involves inner as well as outer membrane defenses and counter-defenses

abstract:
Bacteria often evolve resistance to phage through the loss or modification of cell-surface receptors. In Escherichia coli and phage {lambda}, such resistance can catalyze a coevolutionary arms race focused on host and phage structures that interact at the outer membrane. Here, we analyze another facet of this arms race involving interactions at the inner membrane, whereby E. coli evolves mutations in mannose permease-encoding genes manY and manZ that impair {lambda}s ability to eject its DNA into the cytoplasm. We show that these man mutants arose concurrently with the arms race at the outer membrane. We tested the hypothesis that {lambda} evolved an additional counter-defense that allowed them to infect bacteria with deleted man genes. The deletions severely impaired the ancestral {lambda}, but some evolved phage grew well on the deletion mutants, indicating they regained infectivity by evolving the ability to infect hosts independently of the mannose permease. This coevolutionary arms race fulfills the model of an inverse-gene-for-gene infection network. Taken together, the interactions at both the outer and inner membranes reveal that coevolutionary arms races can be richer and more complex than is often appreciated.

IMPACT STATEMENTLaboratory studies of coevolution help us understand how host defenses and pathogen counter-defenses change over time, which is often essential for predicting the future dynamics of host-pathogen interactions. One particular model, termed "inverse-gene-for-gene" coevolution, predicts that coevolution proceeds through alternating steps, whereby hosts lose the features exploited by pathogens, and pathogens evolve to exploit alternative features. Using a classic model system in molecular biology, we describe the nature and timing of a previously overlooked step in the coevolution of E. coli and bacteriophage lambda. Our work demonstrates that this mode of coevolution can profoundly re-shape the interactions between bacteria and phage.

category: microbiology


title: Resource sharing by outer membrane vesicles from a citrus pathogen

abstract:
The causative agent of citrus canker disease, Xanthomonas citri pv. citri, was found to produce copious amounts of outer membrane vesicles (OMVs), frequently forming long membranous tubes under different culture conditions. Lipidomic analysis revealed significant differences in lipid composition between purified vesicles in relation to whole cells. The results suggest an enrichment in saturated cardiolipins and a decrease in unsaturated lipids in the OMV samples, possibly granting them a more rigid structure while allowing their high degree of curvature caused by their small diameters. The vesicles proteome was found to be significantly enriched in TonB-dependent receptors related to the acquisition of different nutrients. These proteins are known to transport siderophores, which were evidenced to be present in purified X. citri OMVs, along with essential metals including iron, zinc, and manganese quantified by elemental analysis. The availability of vesicle-associated nutrients to be incorporated by cells was demonstrated by the use of OMVs as the sole carbon source for bacterial growth. At last, the vesicles also presented esterase and protease activities, which have been associated with virulence in phytopathogens. These evidences point that X. citri cells can use OMVs to share resources within microbial communities, which has potential implications for microbial interactions and plant colonization, affecting their survival and persistence on the host and in the environment.

ImportanceThe shedding of outer membrane vesicles appears to be universal in Gram-negative bacteria and effectively constitutes a unique secretion pathway for diverse molecules and proteins. To study their possible functions in the citrus pathogen Xanthomonas citri, purified vesicles from this bacterium were studied by omics and functional approaches. Nutrient transporters were found associated to these structures, which were evidenced to contain siderophores and essential metals. The availability of these nutrients to be incorporated by cells was then demonstrated by showing that purified vesicles can be used as sole carbon sources for microbial growth. Additionally, the samples also presented esterase and protease activities which can contribute to the release of substrates from plant host tissues. These observations help to establish the developing idea of vesicles as shared bacterial resources which can participate in shaping host-associated microbial communities in contrast to other interactions such as bacterial competition.


title: Local density determines nuclear movements during syncytial blastoderm formation in a cricket

abstract: Animal embryos pass through an early stage called the blastoderm, in which cells are arranged in a continuous layer at the periphery of the embryo. Despite the broad evolutionary conservation of this embryonic stage, the cellular behaviours that lead to blastoderm formation vary across animals, and the mechanisms that regulate these behaviours are poorly understood. In most insects, pre-blastoderm development begins as a syncytium: that is, many nuclei divide and move throughout the single shared cytoplasm of the embryo. Then these syncytial nuclei must move from their scattered positions within the cytoplasm to form a single layer at the cortex. Recent work showed that in the fruit fly Drosophila melanogaster, some of these early nuclear movements are caused by pulses of cytoplasmic flows that are coupled to synchronous divisions. Here, we show that the cricket Gryllus bimaculatus has an altogether different solution to the problem. We quantified nuclear dynamics during the period of syncytial cleavages and movements that lead to blastoderm formation in G. bimaculatus embryos with transgenically labeled nuclei. We found that: (1) cytoplasmic flows were unimportant for nuclear movement, and (2) division cycles, nuclear speeds, and the directions of nuclear movement were not synchronized across the embryo as in D. melanogaster, but instead were heterogeneous in space and time. Moreover, several aspects of nuclear divisions and movements were correlated with local nuclear density. We show that previously proposed models for the movement of D. melanogaster syncytial nuclei cannot explain the behaviours of G. bimaculatus syncytial nuclei. We introduce a novel geometric model based on asymmetric local pulling forces on nuclei, which recapitulates the density-dependent nuclear speeds and orientations of unperturbed G. bimaculatus embryos, without invoking the common paradigms of localized polarity cues or cell lineage as determinants of nuclear activity. Our model also accurately predicts nuclear behavior in embryos physically manipulated to contain regions of atypical nuclear densities. We show that this model can be used to generate falsifiable predictions about the dynamics of blastoderm formation in other insect species.


title: Standardized genome-wide function prediction enables comparative functional genomics in plants: a new application area for Gene Ontologies

abstract:
BackgroundGenome-wide gene function annotations are useful for hypothesis generation and for prioritizing candidate genes potentially responsible for phenotypes of interest. We functionally annotated the genes of 18 crop plant genomes across 14 species using the GOMAP pipeline.

ResultsBy comparison to existing GO annotation datasets, GOMAP-generated datasets cover more genes, contain more GO terms, and produce datasets similar in quality (based on precision and recall metrics using existing gold standards as the basis for comparison). From there, we sought to determine whether the datasets across multiple species could be used together to carry out comparative functional genomics analyses in plants. To test the idea and as a proof of concept, we created dendrograms of functional relatedness based on terms assigned for all 18 genomes. These dendrograms were compared to well-established species-level evolutionary phylogenies to determine whether trees derived were in agreement with known evolutionary relationships, which they largely are. Where discrepancies were observed, we determined branch support based on jack-knifing then removed individual annotation sets by genome to identify the annotation sets causing unexpected relationships.

ConclusionsGOMAP-derived functional annotations used together across multiple species generally retain sufficient biological signal to recover known phylogenetic relationships based on genome-wide functional similarities, indicating that comparative functional genomics across species based on GO data hold promise for generating novel hypotheses about comparative gene function and traits.

category: bioinformatics


title: Standardized genome-wide function prediction enables comparative functional genomics: a new application area for Gene Ontologies in plants


title: Surface-Shaving Proteomics of Mycobacterium marinum Identifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance and Persistence

abstract:
The complex cell wall and biofilm matrix (ECM) act as key barriers to antibiotics in mycobacteria. Here, the ECM-proteins of Mycobacterium marinum ATCC927, a non-tuberculous mycobacterial model, was monitored over three months by label-free proteomics and compared with cell-surface proteins on planktonic cells to uncover pathways leading to virulence, tolerance, and persistence. We show that ATCC927 forms pellicle-type (PBFs) and submerged-type (SBFs) biofilms after two weeks and two days of growth, respectively, and that the increased CelA1 synthesis in this strain prevents biofilm formation and leads to reduced rifampicin tolerance. The proteomic data suggests that specific changes in mycolic acid synthesis (cord factor), Esx1-secretion, and cell-wall adhesins explain the appearance of PBFs as ribbon-like cords and SBFs as lichen-like structures. A subpopulation of cells resisting the 64 x MIC rifampicin (persisters) were detected in both biofilm subtypes, and already in one-week-old SBFs. The key forces boosting their development could include subtype-dependent changes in asymmetric cell division, cell wall biogenesis, tricarboxylic acid/glyoxylate cycle activities, and energy/redox/iron metabolisms. The effect of varying ambient oxygen tensions on each cell type and non-classical protein secretion are likely factors explaining majority of the subtype-specific changes. The proteomic findings also imply that Esx1-type protein secretion is more efficient in PL and PBF cells, while SBF may prefer both the Esx5- and non-classical pathways to control virulence and prolonged viability/persistence. In conclusion, this study reports a first proteomic insight into aging mycobacterial biofilm-ECMs and indicates biofilm subtype-dependent mechanisms conferring increased adaptive potential and virulence on non-tuberculous mycobacteria.

IMPORTANCEMycobacteria are naturally resilient and mycobacterial infections are notoriously difficult to treat with antibiotics, with biofilm formation being the main factor complicating the successful treatment of TB. The present study shows that non-tuberculous Mycobacterium marinum ATCC927 forms submerged- and pellicle-type biofilms with lichen- and ribbon-like structures, respectively, as well as persister cells under the same conditions. We show that both biofilm subtypes differ in terms of virulence-, tolerance- and persistence-conferring activities, highlighting the fact that both subtypes should be targeted to maximize the power of antimycobacterial treatment therapies.


title: Video-rate remote refocusing through continuous oscillation of a membrane deformable mirror.

abstract: This paper presents the use of a deformable mirror (DM) configured to rapidly refocus a microscope employing a high numerical aperture objective lens. An Alpao DM97-15 membrane DM was used to refocus a 40x/0.80 NA water-immersion objective through a defocus range of -50 to 50 m at 26.3 sweeps per second. We achieved imaging with a mean Strehl metric of > 0.6 over a field of view in the sample of 200x200 m2 over a defocus range of 77 m. We describe an optimisation procedure where the mirror is swept continuously in order to avoid known problems of hysteresis associated with the membrane DM employed. This work demonstrates that a DM-based refocusing system could in the future be used in light-sheet fluorescence microscopes to achieve video-rate volumetric imaging.

category: bioengineering


title: CYCLeR - a novel tool for the full isoform assembly and quantification of circRNAs

abstract: Splicing is one key mechanism determining the state of any eukaryotic cell. Apart from linear splice variants, circular splice variants (circRNAs) can arise via non-canonical splicing involving a back-splice junction (BSJ). Most existing methods only identify circRNAs via the corresponding BSJ, but do not aim to estimate their full sequence identity or to identify different, alternatively spliced circular isoforms arising from the same BSJ. We here present CYCLO_SCPLOWEC_SCPLOWR, the first computational method for identifying the full sequence identify of new and alternatively spliced circRNAs and their abundances while simultaneously co-estimating the abundances of known linear splicing isoforms. We show that CYCLO_SCPLOWEC_SCPLOWR significantly out-performs existing methods in terms of sensitivity, precision and quantification of transcripts. When analysing D. melanogaster data, CYCLO_SCPLOWEC_SCPLOWR uncovers biological patterns of circRNA expression that other methods fail to observe.


title: SMURF2 phosphorylation at Thr249 modifies the stemness and tumorigenicity of glioma stem cells by regulating TGF-β receptor stability

abstract: Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma, the most malignant form of glioma. The implication and underlying mechanisms of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) on the GSC phenotypes remain unknown. We previously demonstrated that SMURF2 phosphorylation at Thr249 (SMURF2Thr249) activates its E3 ubiquitin ligase activity. Here, we demonstrate that SMURF2Thr249 phosphorylation plays an essential role in maintaining GSC stemness and tumorigenicity. SMURF2 silencing augmented the self-renewal potential and tumorgenicity of patient-derived GSCs. The SMURF2Thr249 phosphorylation level was low in human glioblastoma pathology specimens. Introduction of the SMURF2T249A mutant resulted in increased stemness and tumorgenicity of GSCs, recapitulating the SMURF2 silencing. Moreover, the inactivation of SMURF2Thr249 phosphorylation increases TGF-{beta} receptor (TGFBR) protein stability. Indeed, TGFBR1 knockdown markedly counteracted the GSC phenotypes by SMURF2T249A mutant. These findings highlight the importance of SMURF2Thr249 phosphorylation in maintaining GSC phenotypes, thereby demonstrating a potential target for GSC-directed therapy.

category: cancer biology


title: The efficiency of neutral honey as a tissue fixative in histopathology

abstract: In the routine laboratory, 10% neutral buffered formalin (NBF) is the fixative of choice. However, formalin is a human carcinogen. To the best of our knowledge, neutral honey, not natural or artificial honey, has not been tested to fix histological tissues. This study aimed to examine the efficiency of neutral buffered honey and other types of honey fixatives to fix histological tissues. The most two natural common Omani honey were used as fixatives, namely Sumar and date. We tested samples of rat liver, kidney, and stomach. Nine types of fixatives were used. All tissues were treated equally. The evaluation was performed blindly by three senior biomedical scientists who work in a histopathology laboratory. Hematoxylin and eosin showed adequate staining in all groups when compared to 10% NBF. The intensity and specificity of Jones Methenamine silver stain in 10% Sumer and Date honey and 10% alcoholic Sumer honey showed similar findings of 10% NBF. The specificity and intensity of all groups for Periodic acid-Schiff were comparable with 10% neutral buffered formalin accepts for 10% Sumer honey and 10% Alcoholic Date honey. However, all honey groups showed weak staining for the reticulin fibers using Gordon and Sweets method. Vimentin showed comparable findings with 10% NBF as there were no significant differences. The findings of this study are promising. Further in depth research on honey as a possible safe substitute fixative for formalin should be conducted.

category: pathology


title: Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration

abstract:
Lymphotoxin alpha (LT) plays an important role in lymphoid organ development and cellular cytotoxicity in the immune system. LT expression is increased in the cerebrospinal fluid of naive and progressive multiple sclerosis (MS) patients and post-mortem meningeal tissue. Here we show that persistently increased levels of LT in the cerebral meninges can give rise to lymphoid-like structures and underlying MS-like cortical pathology. Stereotaxic injections of recombinant LT into the rat meninges leads to acute meningeal inflammation and subpial demyelination that resolves after 28 days. Injection of an LT lentiviral vector induces lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin+ fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial activation, subpial demyelination and marked neuronal loss occurs in the underlying cortical parenchyma. These results show that chronic LT overexpression is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration.

SummaryIncreased release of lymphotoxin-alpha contributes to the pro-inflammatory milieu of the cerebrospinal fluid of MS patients. A persistent elevated expression of this cytokine in the meninges of rats gives rise to chronic inflammation with lymphoid tissue induction and accompanying neurodegenerative and demyelinating pathology in the underlying brain tissue.

category: neuroscience


title: Proteomic signature of the Dravet syndrome in the genetic Scn1a-A1783V mouse model

abstract:
BackgroundDravet syndrome is a rare, severe pediatric epileptic encephalopathy associated with intellectual and motor disabilities. Proteomic profiling in a mouse model of Dravet syndrome can provide information about the molecular consequences of the genetic deficiency and about pathophysiological mechanisms developing during the disease course.

MethodsA knock-in mouse model of Dravet syndrome with Scn1a haploinsufficiency was used for whole proteome, seizure and behavioral analysis. Hippocampal tissue was dissected from two-(prior to epilepsy manifestation) and four-(following epilepsy manifestation) week-old male mice and analyzed using LC-MS/MS with label-free quantification. Proteomic data sets were subjected to bioinformatic analysis including pathway enrichment analysis. The differential expression of selected proteins was confirmed by immunohistochemical staining.

ResultsThe findings confirmed an increased susceptibility to hyperthermia-associated seizures, the development of spontaneous seizures, and behavioral alterations in the novel Scn1a-A1873V mouse model of Dravet syndrome. As expected, proteomic analysis demonstrated more pronounced alterations following epilepsy manifestation. In particular, proteins involved in neurotransmitter dynamics, receptor and ion channel function, synaptic plasticity, astrogliosis, neoangiogenesis, and nitric oxide signaling showed a pronounced regulation in Dravet mice. Pathway enrichment analysis identified several significantly regulated pathways at the later time point, with pathways linked to synaptic transmission and glutamatergic signaling dominating the list.

ConclusionIn conclusion, the whole proteome analysis in a mouse model of Dravet syndrome demonstrated complex molecular alterations in the hippocampus. Some of these alterations may have an impact on excitability or may serve a compensatory function, which, however, needs to be further confirmed by future investigations. The proteomic data indicate that, due to the molecular consequences of the genetic deficiency, the pathophysiological mechanisms may become more complex during the course of the disease. Resultantly, the management of Dravet syndrome may need to consider further molecular and cellular alterations. Ensuing functional follow-up studies, this data set may provide valuable guidance for the future development of novel therapeutic approaches.


title: Nasal BCG Exposure Accelerates Dural Lymphatics Development via Macrophages' Role in Newborn Mice

abstract: The dural lymphatics develop mainly during the first postnatal month. Lymphatics may be shaped by immune activation when bacterial infection happens. BCG, a strong immune activator, is widely injected to newborns. Moreover, human beings are nasally exposed in daily life to bacterial stimuli. These background prompted us to investigate whether neonatal BCG injection combined with nasally exposure exerts an influence on dural lymphatics develop. Here, mice received a single dose intracutaneous (i.c.) BCG injection immediately after birth followed by repeated nasal BCG challenge once a day (i.c./nasal group). These mice had an accelerated dural lymphatics growth and increased levels of several cytokines and VEGFR-3. Furthermore, macrophages were identified as a key mediator of these alterations. Mice that received mere one dose i.c. BCG injection showed no significant alterations in these indexes. Additionally, mere repeated nasal BCG challenge induced similar effects to i.c./nasal challenge but with a slighter extent. Taken together, these findings show that repeated nasal BCG vaccination accelerates dural lymphatics development in neonatal mice, especially in the presence of neonatal i.c. BCG injection.


category: immunology


title: Optimism and Pessimism in Optimised Replay

abstract: The replay of task-relevant trajectories is known to contribute to memory consolidation and improved task performance. A wide variety of experimental data show that the content of replayed sequences is highly specific and can be modulated by reward as well as other prominent task variables. However, the rules governing the choice of sequences to be replayed still remain poorly understood. One recent theoretical suggestion is that the prioritization of replay experiences in decision-making problems is based on their effect on the choice of action. We show that this implies that subjects should replay sub-optimal actions that they dysfunctionally choose rather than optimal ones, when, by being forgetful, they experience large amounts of uncertainty in their internal models of the world. We use this to account for recent experimental data demonstrating exactly pessimal replay, fitting model parameters to the individual subjects choices.


title: Optimism and pessimism in optimised replay


title: Multidimensional natal isotopic niches reflect migratory patterns in birds

abstract:
Naturally occurring stable isotope ratios in animal tissues allow estimation of species trophic position and ecological niche. Measuring multiple isotopes of migratory species along flyway bottlenecks offers the opportunity to sample multiple populations and species whose tissues carry information at continental scales.

We measured{delta} 2H,{delta} 18O,{delta} 13C,{delta} 15N in juvenile feathers of 21 bird species captured at a migratory bottleneck in the Italian Alps.

We examined if trends in individual isotopes reflected known migratory strategies and whether dietary ({delta}13C-{delta}15N) and spatially-explicit breeding origin ({delta}2H-{delta}18O) niche breadth (NB) differed among long-distance trans-Saharan (TS), short-distance (IP) and irruptive (IR) intra-Palearctic migrants, and whether they correlated with reported populations long-term trends.

In both TS and IP groups, species{delta} 2H declined with capture date, indicating that northern populations reached the stopover site later in the season, following a Type-I migration strategy. Values of{delta} 2H indicated that breeding range of TS migrants extended farther north than IP and IR migrants. The breeding season was longer for IP migrants whose{delta} 13C and{delta} 15N values declined and increased, respectively, with time of capture.

Average species dietary NB did not differ among migratory groups, but TS migrants displayed wider breeding origin niches, suggesting that long-distant migration is linked to broader ecological niches. Isotope origin NB well reflected species geographic range extent, while dietary NB did not correlate with literature accounts of species diet. We found no relationship between species breeding NB and population trends in Europe, implying that conditions in the wintering grounds could be more important for the long-term persistence of species.

We demonstrate that isotopic measurements of passerines migrating through a bottleneck represents a unique opportunity to investigate large-scale life-history phenomena relevant to conservation.

category: ecology


title: Modeling microbial diversity across different soil ecosystems and environmental covariate selections in tropical SE Asian landscape

abstract: Microbes play essential roles in the ecology of various environments and structure. Diversity of soil microbial communities is an important scientific interest in tropical landscape including in South East Asia. Soil environment in SE Asia is diverse and this influences the microbial diversity. Soil microbes in this study were collected using DNA isolation protocols and the whole microbial community structure of sampled soil was analyzed through next generation sequencing. Soil microbial identification was conducted by amplifying the 16S rRNA gene. Soils were sampled from 4 different environments in Sumatra and Kalimantan ecosystems representing plantation, swamp, peatland, and coastal ecosystems. Measured soil covariates including soil organic carbon C analyzed based on the Walkley-Black method and Kjeldahl method for N. Model of microbes in soil ecosystems were based on Akaike model selection (AIC) by testing the influence of soil covariates on soil microbial phylum. The microbial community was found to be comprising of a total number of 11 phyla. In soil of coastal ecosystem, microbial diversity at phylum level were dominated by Proteobacteria (82.3%), Actinobacteria (9.41%), Acidobacteria (4.7%), and the lowest was Bacteroidetes and Chloroflexi (0.58%). In plantation soil, the microbial abundance order was Firmicutes (41.6%) > Actinobacteria (29.7%) > Acidobacteria (20.0%) > Gemmatimonadetes (5.94%). The soil microbial abundance order in swamp was Proteobacteria (42.2%) > Acidobacteria (20.04%) > Bacteroidetes > (10.46%) > Actinobacteria (9.24%). In soil of peatland ecosystem, taxonomic assignments of microbial at the phylum level were dominated by Firmicutes (66.18%), Proteobacteria(16.94%), and Actinobacteria (16.87%). According to the values of AIC, Firmicutes was a microbial phylum that has high abundance in soil ecosystems influenced by pH covariates with AIC values of -6.54. Other soil covariates show less influence on Firmicutes with AIC values of -5.06. The combination model also show that pH cofactor was the important determinants with AIC values of -0.54 for Firmicutes (pH+C) and Firmicutes (pH+N) models. While AIC value for combination model of Firmicutes (C+N) only equals to 0.14.


title: From musk to body odor: decoding olfaction through genetic variation

abstract: The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1003 Han Chinese and validated results for six of these odors in an ethnically diverse population (n=364). In both populations, we replicated three previously reported associations ({beta}-ionone/OR5A, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first OR shown to drive specific anosmia to a musk compound. We also found that the derived alleles of the SNPs reportedly associated with odor perception tend to reduce odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept.

category: genetics


title: A massively parallel reporter assay reveals focused and broadly encoded RNA localization signals in neurons

abstract:
Asymmetric subcellular localization of mRNA is a common cellular phenomenon that is thought to contribute to spatial gene regulation. In highly polar neurons, subcellular transcript localization and translation are thought to enhance cellular efficiency and timely responses to external cues. Although mRNA localization has been observed in many tissues and numerous examples of the functional importance of this process exist, we still lack a systematic understanding of how the transcript sorting machinery works in a sequence-specific manner.

Here, we addressed these gaps by combining subcellular transcriptomics and rationally designed sequence libraries. We developed a massively parallel reporter assay (MPRA) for mRNA localization and tested ~50,000 sequences for their ability to drive RNA localization to neurites of neuronal cell lines. By scanning the 3UTR of >300 genes we identified many previously unknown localization regions and mapped the localization potential of endogenous sequences. Our data suggest two ways the localization potential can be encoded in the 3UTR: focused localization motifs and broadly encoded localization potential based on small contributions.

We identified sequence motifs enriched in dendritically localized transcripts and tested the potential of these motifs to affect the localization behavior of an mRNA. This assay revealed sequence elements with the ability to bias localization towards neurite as well as soma. Depletion of RNA binding proteins predicted or experimentally shown to bind these motifs abolished the effect on localization, suggesting that these motifs act by recruiting specific RNA-binding proteins.

Based on our dataset we developed machine learning models that accurately predict the localization behavior of novel sequences. Testing this predictor on native mRNA sequencing data showed good agreement between predicted and observed localization potential, suggesting that the rules uncovered by our MPRA also apply to the localization of native transcripts.

Applying similar systematic high-throughput approaches to other cell types will open the door for a comparative perspective on RNA localization across tissues and reveal the commonalities and differences of this crucial regulatory mechanism.

category: genomics


title: Activation of proneuronal transcription factor Ascl1 in maternal liver ensures a healthy pregnancy

abstract:
Background & AimsMaternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice.

MethodsTo investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from mid-gestation until term.

ResultsAs a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 exhibited aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and elevated release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta displayed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 exhibited robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments.

ConclusionIn summary, we demonstrate that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies reveal Ascl1 as a novel and critical regulator of the physiology of pregnancy.

SynopsisHow the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression of Ascl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring.

Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

category: physiology


title: Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma.

abstract:
Failure of CNS neurons to mount a significant intrinsic growth response after trauma results in chronic functional deficits after spinal cord injury. Approaches to identify novel axon growth activators include transcriptional and repressor screening of embryonic cortical and retinal ganglion neurons in vitro. These high throughput approaches have identified several candidates; however, their inability to comprehensively model the adult CNS has resulted in their exploitation in vivo failing to stimulate significant anatomical and functional gains. To identify novel cell autonomous axon growth activators while maintaining CNS complexity, we screened intact adult corticospinal neurons (CSNs) undergoing functional plasticity after unilateral pyramidotomy. RNA-seq of intact sprouting corticospinal tract (CST) axons showed an enrichment of genes in the 3-phosphoinositide degradation pathways, including six 5-phosphatases. We explored whether Inositol Polyphosphate-5-phosphatase K (Inpp5k) could enhance CST axon growth in clinical models of CNS trauma. Overexpression of Inpp5k in intact adult CSNs enhanced sprouting of intact CST terminals into the denervated cervical cord after pyramidotomy and cortical stroke lesion. Inpp5k overexpression also stimulated sprouting of CST axons in the cervical cord after acute and chronic severe thoracic spinal contusion. We show that Inpp5k stimulates axon growth by elevating the density of active cofilin in the cytosol of labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. This study identifies Inpp5k as a novel CST growth activator and underscores the veracity of using in vivo transcriptional screening to identify the next generation of cell autonomous factors capable of repairing the damaged CNS.

SIGNIFICANCE STATEMENTNeurological recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post trauma. In vitro screening strategies exploit the intrinsically high growth capacity of embryonic CNS neurons to identify novel axon growth activators. While promising candidates have been shown to stimulate axon growth in vivo, concomitant functional recovery remains incomplete. Using transcriptional profiling of intact adult corticospinal tract neurons undergoing functional plasticity, we identified Inpp5k as a novel axon growth activator capable of stimulating CST axon growth after pyramidotomy, stroke and acute and chronic contusion injuries. These data support using in vivo screening approaches to identify novel axon growth activators.


title: Influenca: a gamified assessment of value-based decision-making for longitudinal studies

abstract: Reinforcement learning is a core facet of motivation and alterations have been associated with various mental disorders. To build better models of individual learning, repeated measurement of value-based decision-making is crucial. However, the focus on lab-based assessment of reward learning has limited the number of measurements and the test-retest reliability of many decision-related parameters is therefore unknown. Here, we developed an open-source cross-platform application Influenca that provides a novel reward learning task complemented by ecological momentary assessment (EMA) for repeated assessment over weeks. In this task, players have to identify the most effective medication by selecting the best option after integrating offered points with changing probabilities (according to random Gaussian walks). Participants can complete up to 31 levels with 150 trials each. To encourage replay on their preferred device, in-game screens provide feedback on the progress. Using an initial validation sample of 127 players (2904 runs), we found that reinforcement learning parameters such as the learning rate and reward sensitivity show low to medium intra-class correlations (ICC: 0.22-0.52), indicating substantial within- and between-subject variance. Notably, state items showed comparable ICCs as reinforcement learning parameters. To conclude, our innovative and openly customizable app framework provides a gamified task that optimizes repeated assessments of reward learning to better quantify intra- and inter-individual differences in value-based decision-making over time.


title: Perceived and mentally rotated contents are differentially represented in cortical depth of V1

abstract: Primary visual cortex (V1) in humans is known to represent both veridically perceived external input and internally-generated contents underlying imagery and mental rotation. However, it is unknown how the brain keeps these contents separate thus avoiding a mixture of the perceived and the imagined which could lead to potentially detrimental consequences. Inspired by neuroanatomical studies showing that feedforward and feedback connections in V1 terminate in different cortical layers, we hypothesized that this anatomical compartmentalization underlies functional segregation of external and internally-generated visual contents, respectively. We used high-resolution layer-specific fMRI to test this hypothesis in a mental rotation task. We found that rotated contents were predominant at outer cortical depth bins (i.e. superficial and deep). At the same time perceived contents were represented stronger at the middle cortical bin. These results identify how through cortical depth compartmentalization V1 functionally segregates rather than confuses external from internally-generated visual contents. These results indicate that feedforward and feedback manifest in distinct subdivisions of the early visual cortex, thereby reflecting a general strategy for implementing multiple cognitive functions within a single brain region.


title: Numerical uncertainty can critically affect simulations of mechanistic models in neuroscience

abstract: Understanding neural computation on the mechanistic level requires models of neurons and neuronal networks. To analyze such models one typically has to solve coupled ordinary differential equations (ODEs), which describe the dynamics of the underlying neural system. These ODEs are solved numerically with deterministic ODE solvers that yield single solutions with either no, or only a global scalar bound on precision. It can therefore be challenging to estimate the effect of numerical uncertainty on quantities of interest, such as spike-times and the number of spikes. To overcome this problem, we propose to use recently developed sampling-based probabilistic solvers, which are able to quantify such numerical uncertainties. They neither require detailed insights into the kinetics of the models, nor are they difficult to implement. We show that numerical uncertainty can affect the outcome of typical neuroscience simulations, e.g. jittering spikes by milliseconds or even adding or removing individual spikes from simulations altogether, and demonstrate that probabilistic solvers reveal these numerical uncertainties with only moderate computational overhead.


title: Probabilistic solvers enable a straight-forward exploration of numerical uncertainty in neuroscience models


title: Sleep Loss Impacts the Interconnected Brain-Body-Mood Regulation of Cardiovascular Function in Humans

abstract: Poor sleep is associated with hypertension, a major risk factor for cardiovascular disease1,2. However, the mechanism(s) through which sleep loss impacts blood pressure remain largely unknown, including the inter-related brain and peripheral body systems that regulate vascular function3. In a repeated-measures experimental study of 66 healthy adult participants, we demonstrate four core findings addressing this question. First, a night of sleep loss significantly increased blood pressure--both systolic and diastolic, yet this change in vascular tone was independent of any increase in heart rate. Second, sleep loss compromised functional brain connectivity within regions that regulate vascular tone. Third, sleep-loss related changes in brain connectivity and vascular tone were significantly inter-dependent, with changes in brain nodes explaining the shift towards hypertension. Fourth, sleep-loss related changes in mood, specifically reductions in positive and amplification in negative states, each demonstrated an interaction with the impairments in brain connectivity and blood pressure. Together, these findings support an embodied framework in which sleep loss confers increased risk of cardiovascular disease through interactions between brain homeostatic control, mood-state and blood pressure.


title: Cognitive impairment and metabolite profile alterations in the hippocampus and cortex of male and female mice exposed to a fat and sugar-rich diet are normalized by diet reversal

abstract: Diabetes impacts on brain metabolism, structure and function. Alterations in brain metabolism have been observed in obesity and diabetes models induced by exposure to diets rich in saturated fat and/or sugar, and have been linked to memory impairment. However, it remains to be determined whether brain dysfunction induced by obesogenic diets results from permanent brain alterations. We tested the hypothesis that an obesogenic diet (high-fat and high-sucrose diet; HFHSD) causes reversible changes in hippocampus and cortex metabolism and alterations in behavior. To test this hypothesis, mice were exposed to HFHSD for 24 weeks or for 16 weeks followed by 8 weeks of diet normalization. Development of the metabolic syndrome, changes in behavior, and brain metabolite profiles by 1H magnetic resonance spectroscopy (MRS) were assessed longitudinally. Control mice were fed an ingredient-matched low-fat and low-sugar diet. Mice fed a HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in male than female mice. Relative to controls, both male and female HFHSD-fed mice showed increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working spatial memory as evaluated by spontaneous alternation in a Y-maze. Alterations in the metabolite profiles were observed both in the hippocampus and cortex, but were more distinct in the former. HFHSD-induced metabolic changes included altered levels of lactate, glutamate, GABA, glutathione, taurine, N-acetylaspartate, creatine and choline. Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered upon diet normalization for 8 weeks. We conclude that cortical and hippocampal derangements induced by long-term HFHSD consumption are reversible rather than being the result of permanent tissue damage.


title: Adjuvant and immunomodulatory potential of Natural Killer T (NKT) activation by NKTT320

abstract:
Invariant natural killer T-lymphocytes (iNKT) are unique immunomodulatory innate T-cells with an invariant TCR recognizing glycolipids presented on MHC class-I-like CD1d molecules. Activated iNKT rapidly secrete pro-and anti-inflammatory cytokines, potentiate innate and adaptive immunity, and modulate inflammation. Here, we report the effects of in vivo iNKT activation by a novel humanized monoclonal antibody, NKTT320, that binds to the invariant region of the iNKT TCR. NKTT320 led to rapid iNKT activation, increased polyfunctionality, and elevation of multiple plasma analytes within 24 hours of administration. Flow cytometry and RNA-Seq confirmed downstream activation of multiple immune subsets, enrichment of JAK/STAT and PI3K/AKT pathway genes, and upregulation of inflammation-modulating genes CMKLR1, ARG2 and NLRP12. NKTT320 also induced iNKT trafficking to adipose tissue and did not cause iNKT anergy. Our data indicate that NKTT320 has a sustained effect on in vivo iNKT activation, potentiation of innate and adaptive immunity, and resolution of inflammation, which supports its future use as an immunotherapeutic and vaccine adjuvant.

SummaryiNKTs are known immunomodulatory cells whose activation is a potential target for immunotherapies and use as an adjuvant. Here we report the potential utility of in vivo iNKT activation using the novel humanized monoclonal antibody NKTT320 for this purpose.


title: Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes

abstract: Alternative splicing (AS) is a key mechanism underlying cellular differentiation and a driver of complexity in mammalian neuronal tissues. However, understanding of which isoforms are differentially used or expressed and how this affects cellular differentiation remains unclear. Long read sequencing allows full-length transcript recovery and quantification, enabling transcript-level analysis of AS processes and how these change with cell state. Here, we utilise Oxford Nanopore Technologies sequencing to produce a custom annotation of a well-studied human neuroblastoma cell line and to characterise isoform expression and usage across differentiation. We identify many previously unannotated features, including a novel transcript of the voltage-gated calcium channel subunit gene, CACNA2D2. We show differential expression and usage of transcripts during differentiation, and identify a putative molecular regulator underlying this state change. Our work highlights the potential of long read sequencing to uncover previously unknown transcript diversity and mechanisms influencing alternative splicing.


title: Antarctic Teleosts With and Without Haemoglobin Behaviourally Mitigate Deleterious Effects of Acute Environmental Warming

abstract: Recent studies forecast that many ectothermic animals, especially aquatic stenotherms, may not be able to thrive or even survive predicted climate change. These projections, however, generally do not call much attention to the role of behaviour, an essential thermoregulatory mechanism of many ectotherms. Here we characterize species-specific locomotor and respiratory responses to acute ambient warming in two highly stenothermic Antarctic Notothenioid fishes, one of which (Chaenocephalus aceratus) lacks haemoglobin and appears to be less tolerant to thermal stress as compared to the other (Notothenia coriiceps), which expresses haemoglobin. At the onset of ambient warming, both species perform distinct locomotor manoeuvres that appear to include avoidance reactions. In response to unavoidable progressive hyperthermia, fishes demonstrate a range of species-specific manoeuvres, all of which appear to provide some mitigation of the deleterious effects of obligatory thermoconformation and to compensate for increasing metabolic demand by enhancing the efficacy of branchial respiration. As temperature continues to rise, Chaenocephalus aceratus supplements these behaviours with intensive pectoral fin fanning which may facilitate cutaneous respiration through its scaleless integument, and Notothenia coriiceps manifests respiratory-locomotor coupling during repetitive startle-like manoeuvres which may further augment gill ventilation. The latter behaviours, found only in Notothenia coriiceps, have highly stereotyped appearance resembling Fixed Action Pattern sequences. Altogether, this behavioural flexibility could contribute to the reduction of the detrimental effects of acute thermal stress within a limited thermal range. In an ecologically relevant setting, this may enable efficient thermoregulation of fishes by habitat selection, thus facilitating their resilience in persistent environmental change.

category: animal behavior and cognition


title: Sexual deprivation modulates social interaction and reproductive physiology

abstract: In highly polyandrous species, where females mate with multiple males within a single fertility period, there is typically a high level of sperm competition. To cope with this challenge, males apply various behavioral and physiological strategies to maximize their paternity rates. Previous studies in Drosophila melanogaster established a link between the composition of the social environment and the reproductive success of individual male flies. While most studies until now focused on the adaptive responses of male flies to the presence of rival males, little is known about whether the outcomes of sexual interactions with female partners affect male-male social interactions in a competitive environment such as the social group. Here we show that repeated failures to mate promote a coordinated physiological and behavioral responses that can serve to increase paternity chances over mating rivals. We exposed male flies to sexual deprivation or successful mating and analyzed the behavioral repertoires of individuals within groups and the structure of their emerging social networks. We discovered that failures to mate and successful mating generate distinct emergent group interactions and structures, where sexually deprived males form low density social networks and actively minimize their encounters with other group members, while increasing their aggressive behavior. In addition, sexually deprived male flies elevate the production of seminal fluid proteins (known to facilitate post-mating responses in females) and extend mating duration upon mating with receptive females, altogether leading to reduced re-mating rates. Our results demonstrate the existence of a flexible mating strategy that may provide a short-term fitness advantage over competing rivals and pave the path for using simple model organisms to dissect the neurobiology of social plasticity as coping strategy to living in a highly dynamic environment as the social domain.


title: Panache: a Web Browser-Based Viewer for Linearized Pangenomes

abstract:
MotivationPangenomics evolved since its first applications on bacteria, extending from the study of genes for a given population to the study of all of its sequences available. While multiple methods are being developed to construct pangenomes in eukaryotic species there is still a gap for efficient and user-friendly visualization tools. Emerging graph representations comes with their own challenges, and linearity remains a suitable option for user-friendliness.

ResultsWe introduce Panache, a tool for the visualization and exploration of linear representations of gene-based and sequence-based pangenomes. It uses a layout similar to genome browsers to display presence absence variations and additional tracks along a linear axis with a pangenomics perspective.

AvailabilityPanache is available at github.com/SouthGreenPlatform/panache under the MIT License.

Contacteloi.durant@ird.fr, m.rouard@cgiar.org


title: Activin B Promotes the Initiation and Progression of Liver Fibrosis

abstract:
Background & AimsLiver fibrosis is a pivotal pathology in multiple hepatic disease indications, profoundly characterizing disease severity and outcomes. The role of activin B, a TGF{beta} superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis.

MethodsLiver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4)-induced liver fibrosis. The direct effects of activin B and A on hepatocytes and hepatic stellate cells (HSCs) were evaluated in vitro.

ResultsAs a result, hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. We found that neutralizing activin B largely prevented, as well as remarkably regressed, CCl4-induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B directly promotes hepatocyte death, induces a profibrotic expression profile in HSCs, and stimulates HSCs to form a septa structure. In addition, activin B and A interdependently upregulated the transcription of profibrotic factors including connective tissue growth factor and TGF{beta}1 in injured livers.

ConclusionsWe demonstrate that activin B, cooperating with activin A, directly acts on multiple liver cell populations, and drives the initiation and progression of liver fibrosis. Our finding inspires the development of a novel therapy of chronic liver diseases.


title: Plant detection and counting from high-resolution RGB images acquired from UAVs: comparison between deep-learning and handcrafted methods with application to maize, sugar beet, and sunflower crops

abstract:
Progresses in agronomy rely on accurate measurement of the experimentations conducted to improve the yield component. Measurement of the plant density is required for a number of applications since it drives part of the crop fate. The standard manual measurements in the field could be efficiently replaced by high-throughput techniques based on high-spatial resolution images taken from UAVs. This study compares several automated detection of individual plants in the images from which the plant density can be estimated. It is based on a large dataset of high resolution Red/Green/Blue (RGB) images acquired from Unmanned Aerial Vehicules (UAVs) during several years and experiments over maize, sugar beet and sunflower crops at early stages. A total of 16247 plants have been labelled interactively on the images. Performances of handcrafted method (HC) were compared to those of deep learning (DL). The HC method consists in segmenting the image into green and background pixels, identifying rows, then objects corresponding to plants thanks to knowledge of the sowing pattern as prior information. The DL method is based on the Faster Region with Convolutional Neural Network (Faster RCNN) model trained over 2/3 of the images selected to represent a good balance between plant development stage and sessions. One model is trained for each crop.

Results show that simple DL methods generally outperforms simple HC, particularly for maize and sunflower crops. A significant level of variability of plant detection performances is observed between the several experiments. This was explained by the variability of image acquisition conditions including illumination, plant development stage, background complexity and weed infestation. The image quality determines part of the performances for HC methods which makes the segmentation step more difficult. Performances of DL methods are limited mainly by the presence of weeds. A hybrid method (HY) was proposed to eliminate weeds between the rows using the rules developed for the HC method. HY improves slightly DL performances in the case of high weed infestation. When few images corresponding to the conditions of the testing dataset were complementing the training dataset for DL, a drastic increase of performances for all the crops is observed, with relative RMSE below 5% for the estimation of the plant density.

category: plant biology


title: A pan-cancer analysis of matrisome proteins reveals CTHRC1and LOXL2 as major ECM regulators across cancers

abstract:
The extracellular matrix as part of the tumor microenvironment can regulate cancer cell growth and progression. Using TCGA data from 30 cancer types, the top 5% of matrisome genes with amplifications or deletions that affect survival in cancers were identified. Eight of these genes show altered expression in ~50% or more cancers affecting survival in ~20% or more. Among them SNED1 is the most downregulated and CTHRC1 and LOXL2 most upregulated. Differential gene expression analysis of SNED-1 did not identify any genes it regulates across cancers, while CTHRC1 and LOXL2 affected 19 and 5 genes respectively in 3 or more cancers. STRING analysis of these genes classified them as  extracellular, involved prominently in ECM organization. Their correlation and co-occurrence in context of their effect on survival and staging of the disease identified MMP13, POSTN and SFRP4 along with COL11A1, COL10A1, COL1A1, ADAMTS12 and PPAPDC1A as possible interactors of CTHRC1 and LOXL2 in cancers. These are implicated in collagen organization, making it vital to matrisome regulation of cancers. Clinical Proteomic Tumor Analysis Consortium data confirms the changes in expression of these genes along with CTHRC1 and LOXL2 in breast and lung cancer, further supporting their implication as vital pan-cancer matrisome mediators.

HighlightsO_LICTHRC1 and LOXL2 are prominently upregulated pan-cancer matrisome genes.
C_LIO_LIHigh CTHRC1 and LOXL2 expression is associated with disease progression and poor survival in cancers.
C_LIO_LICTHRC1 with POSTN, MMP13 and SFRP4 and LOXL2 with COL11A1, COL10A1, COL1A1, ADAMTS12 and PPAPDC1A drive matrisome regulation of cancers.
C_LIO_LICTHRC1 and LOXL2 could prominently drive collagen organization and function across cancers.
C_LI


title: Handedness and midsagittal corpus callosum morphology: A systematic meta-analytic evaluation.

abstract: Following a series of seminal studies in the 1980s, left or mixed hand preference is widely considered to be associated with a larger corpus callosum, influencing the interpretation of findings and various theories related to inter-hemispheric processing, brain lateralisation, and hand preference. Recent reviews of the literature, however, report inconsistencies in the literature and cast doubt on the existence of such an association. The aim of the present study was to systematically evaluate and meta-analytically integrate the available data on the effect of hand preference on corpus-callosum morphology. For this purpose, articles were identified via a search in PubMed and Web of Science databases. Studies reporting findings relating handedness (assessed as hand preference) and corpus-callosum morphology in healthy participants were considered eligible. On the basis of a total of k = 25 identified studies, random-effects meta-analyses were conducted considering four different group comparisons found in the literature. That is, studies comparing participants of (a) predominantly right- (dRH) and left-hand preference (dLH), (b) consistent right (cRH) and non-cRH preference, (c) cRH with mixed-hand preference (MH), and (d) cRH with consistent left-hand hand preference (cLH). For none of these meta-analyses did we find a significant effect of hand preference, and narrow confidence intervals suggest that the existence of substantial population effect sizes can be excluded. For example, considering the comparison of dRH and dLH, (summarizing k = 14 studies incorporating 1910 dRH and 646 dLH participants) the estimated mean effect size was g = 0.016 (95% confidence interval: -0.12 to 0.15). Thus, the common practice of assuming an increase in callosal connectivity based on hand preference is likely invalid.


title: Robust linear modelling in ElectroEncephaloGraphy can be obtained using single weights reflecting each single trials' dynamics

abstract:
Being able to remove or weigh down the influence of outlier data is desirable for any statistical models. While Magnetic and ElectroEncephaloGraphic (MEEG) data are often averaged across trials per condition, it is becoming common practice to use information from all trials to build statistical linear models. Individual trials can, however, have considerable weight and thus bias inferential results (effect sizes as well as thresholded t/F/p maps). Here, rather than looking for univariate outliers, defined independently at each measurement point, we apply the principal component projection (PCP) method at each channel, deriving a single weight per trial at each channel independently. Using both synthetic data and open EEG data, we show (1) that PCP is efficient at detecting a large variety of outlying trials; (2) how PCP-based weights can be implemented in the context of the general linear model (GLM) with accurate control of type 1 family-wise error rate; and (3) that our PCP-based Weighted Least Square (WLS) approach increases the statistical power of group analyses as well as a much slower Iterative Reweighted Least Squares (IRLS), although the weighting scheme is markedly different. Together, our results show that WLS based on PCP weights derived from whole trial profiles is an efficient method to weigh down the influence of outlier EEG data in linear models.

Data availabilityall data used are publicly available (CC0), all code (simulations and data analyzes) is also available online in the LIMO MEEG GitHub repository (MIT license).


title: ElectroEncephaloGraphy robust linear modelling using weights reflecting single trials' dynamics


title: ElectroEncephaloGraphy robust statistical linear modelling using a single weight per trial


title: Mapping differences in mammalian distributions and diversity using environmental DNA from rivers

abstract:
AimFinding more efficient ways to monitor, and estimate the diversity of, mammalian communities is a major step towards their management and conservation. Environmental DNA (eDNA) from river water has recently been shown to be a viable method for biomonitoring mammalian communities. Yet, most of the studies to date have focused on the potential for eDNA to detect individual species, with little focus on describing patterns of community diversity and structure. In this study, we focus on the sampling effort required to reliably map the diversity and distribution of semi-aquatic and terrestrial mammals and allow inferences of community structure surrounding rivers.

LocationSoutheastern England

MethodsWe used eDNA metabarcoding on water samples collected along two rivers and a beaver enclosure over two days, targeting terrestrial and semi-aquatic mammals. Mammalian community diversity and composition was assessed based on species richness and {beta}-diversity. Differences between river communities were calculated and partitioned into nestedness and turnover, and the sampling effort required to rapidly detect semi-aquatic and terrestrial species was evaluated based on species accumulation curves and occupancy modelling.

ResultseDNA metabarcoding efficiently detected 25 wild mammal species from five orders in two days of sampling, representing the vast majority (82%) of the species expected in the area. The required sampling effort varied between orders, with common species (generally rodents, deer and lagomorph species) more readily detected, with carnivores detected less frequently. Measures of species richness differed between rivers (both overall and within each mammalian order) and patterns of {beta}-diversity revealed the importance of species replacement in sites within each river, against a pattern of species loss between the two rivers.

Main conclusionseDNA metabarcoding demonstrated its capability to rapidly detect mammal species, allowing inferences of community composition that will better inform future sampling strategies for this Class. Importantly, this study highlights the potential use of eDNA data for investigating mammalian community dynamics over different spatial scales.


title: Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity.

abstract: Nutrient availability varies seasonally and spatially in the wild. The resulting nutrient limitation or restricted access to nutrients pose a major challenge for every organism. While many animals, such as hibernating animals, evolved strategies to overcome periods of nutrient scarcity, the cellular mechanisms of these strategies are poorly understood. Cave environments represent an extreme example of nutrient deprived environments since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability. Here, we used Astyanax mexicanus, which includes river-dwelling surface fish and cave adapted cavefish populations to study the genetic adaptation to nutrient limitations. We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue. Moreover, the lipid metabolism regulator, Peroxisome proliferator-activated receptor {gamma} (Ppar{gamma}), is upregulated at both transcript and protein levels in cavefish livers. Chromatin Immunoprecipitation sequencing (ChIP seq) showed that Ppar{gamma} binds cavefish promoter regions of genes to a higher extent than surface fish. Finally, we identified two possible regulatory mechanisms of Ppar{gamma} in cavefish: higher amounts of ligands of the nuclear receptor, and nonsense mutations in per2, a known repressor of Ppar{gamma}. Taken together, our study reveals that upregulated Ppar{gamma} promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient limited environments.

category: evolutionary biology


title: The nature of intraspecific genome size variation in taxonomically complex eyebrights

abstract:
O_LIGenome size (GS) is a key trait related to morphology, life history, and evolvability. Although GS is, by definition, affected by presence/absence variants (PAVs), which are ubiquitous in population sequencing studies, GS is often treated as an intrinsic property of a species. Here, we studied intra- and interspecific GS variation in taxonomically complex British eyebrights (Euphrasia).
C_LIO_LIWe generated GS data for 192 individuals of diploid and tetraploid Euphrasia and analysed GS variation in relation to ploidy, taxonomy, population affiliation, and geography. We further compared the genomic repeat content of 30 samples.
C_LIO_LIWe found considerable genuine intraspecific GS variation, and observed isolation-by-distance for GS in outcrossing diploids. Tetraploid Euphrasia showed contrasting patterns, with GS increasing with latitude in outcrossing Euphrasia arctica, but little GS variation in the highly selfing Euphrasia micrantha. Interspecific differences in GS genomic repeat percentages were small.
C_LIO_LIWe show the utility of treating GS as the outcome of polygenic variation. Like other types of genetic variation, such as single nucleotide polymorphisms, GS variation may be increased through hybridisation and population subdivision. In addition to selection on associated traits, GS is predicted to be affected indirectly by selection due to pleiotropy of the underlying PAVs.
C_LI


title: Simultaneous profiling of multiple chromatin proteins in the same cells

abstract: Methods derived from CUT&RUN and CUT&Tag enable genome-wide mapping of the localization of proteins on chromatin from as few as one cell. These and other mapping approaches focus on one protein at a time, preventing direct measurements of colocalization of different chromatin proteins in the same cells and requiring prioritization of targets where samples are limiting. Here we describe multi-CUT&Tag, an adaptation of CUT&Tag that overcomes these hurdles by using antibody-specific barcodes to simultaneously map multiple proteins in the same cells. Highly specific multi-CUT&Tag maps of histone marks and RNA Polymerase II uncovered sites of co-localization in the same cells, active and repressed genes, and candidate cis-regulatory elements. Single-cell multi-CUT&Tag profiling facilitated identification of distinct cell types from a mixed population and characterization of cell type-specific chromatin architecture. In sum, multi-CUT&Tag increases the information content per cell of epigenomic maps, facilitating direct analysis of the interplay of different proteins on chromatin.


title: Pparg drives luminal differentiation and luminal tumor formation in the urothelium

abstract: Pparg, a nuclear receptor, is downregulated in basal subtype bladder cancers that tend to be muscle invasive and amplified in luminal subtype bladder cancers that tend to be non-muscle invasive. Bladder cancers derive from the urothelium, one of the most quiescent epithelia in the body which is composed of basal, intermediate, and superficial cells. We find that expression of an activated form of Pparg (VP16;Pparg) in basal progenitors induces formation of superficial cells in situ, that exit the cell cycle, and do not form tumors. Expression in basal progenitors that have been activated by mild injury however, results in luminal tumor formation. We find that tumors are immune deserted, which may be linked to downregulation of Nf-kb, a Pparg target. Interestingly, some luminal tumors begin to shift to basal subtype tumors with time, downregulating Pparg and other luminal markers. Our findings have important implications for treatment and diagnosis bladder cancer.


title: Concurrent assessment of motor unit firing properties and fascicle length changes with high-density surface electromyography ultrasound-transparent electrodes

abstract:
The integration of electromyography (EMG) and ultrasound imaging has provided important information about the mechanisms of muscle activation and contraction. Unfortunately, EMG does not allow an accurate assessment of the interplay between the neural drive received by muscles, changes in fascicle length (FL) and the force/torque produced. We aimed to assess the relationship between modulations in tibialis anterior (TA) motor unit (MU) firing rate, FL and dorsiflexion torque (DT) using ultrasound-transparent high-density EMG electrodes. EMG and ultrasound images were recorded simultaneously from TA, using a 32-electrode silicon matrix, while performing isometric dorsiflexion, at diverse ankle joint positions (0{degrees} and 30{degrees} plantar flexion) and torques (20% and 40% of maximum). EMG signals were decomposed into individual MUs and changes in FL were assessed with a fascicle-tracking algorithm. MU firings were converted into a cumulative spike train (CST) that was cross-correlated with DT (CST-DT) and FL (CST-FL). High cross-correlations were found for CST-FL, 0.60 (range: 0.31-0.85) and CST-DT 0.71 (range: 0.31-0.88). Cross-correlation lags revealed that the delay between CST-FL (~75ms) was significantly smaller than CST-DT (~150ms, p<0.001). These delays affected the interpretation of MU recruitment/de-recruitment thresholds, with FL showing similar lengths for both recruitment and de-recruitment. This study is the first to demonstrate that changes in TA FL are closely related to both modulations in MU firing frequency and DT. These relationships allow assessment of the interplay between neural drive, muscle contraction and resultant torque, thereby providing a better understanding of the mechanisms responsible for the generation of muscle force.

NEW AND NOTEWORTHYBy employing ultrasound-transparent high-density surface EMG electrodes, we show that modulations in tibialis anterior motor unit discharge rate were closely related to both changes in its fascicle length and resultant torque. These relationships allowed quantifying delays between neural drive and muscle shortening as well as muscle shortening and torque during submaximal isometric contractions, providing an accurate estimation of the time required to generate muscle force and subsequent production of torque via the tendon.


title: Modulations in motor unit discharge are related to changes in fascicle length during isometric contractions


title: The metabolic cost of overcoming air resistive forces in distance running

abstract: We lack a mechanistic understanding of the relationship between aerodynamic drag forces and metabolic power during running. Further, the energetic and time savings possible from reducing aerodynamic drag (drafting) are still unclear due to the different methods previously assumed for converting from force reductions to metabolic power savings. Here, we quantified how small horizontal impeding forces (equivalent to aerodynamic forces) affect metabolic power and ground reaction forces over a range of velocities in competitive runners. In three sessions, 12 runners completed six 5-minute trials with 5 minutes of recovery in-between. We tested one velocity per session (12, 14 and 16 km/h), at three horizontal impeding force conditions (0, 4 and 8 N). On average, metabolic power increased by 6.13% per 1% body weight of horizontal impeding force but varied considerably between individuals. With greater horizontal impeding force, braking impulses decreased while propulsive impulses increased (p < 0.001). Across running velocities, the changes in braking and propulsive impulses with greater impeding force were correlated (r = -0.97; p < 0.001), but were not related to individual changes in metabolic power. We estimate that at [~]2-hour marathon pace, overcoming air resistive force comprises 8.52% of the gross metabolic power on average.


title: Vivarium: an interface and engine for integrative multiscale modeling in computational biology

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSMotivationC_ST_ABSThis paper introduces Vivarium - software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models, and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of biology by combining heterogeneous datasets and diverse modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists.

ResultsVivarium is a Pythonic software for building integrative multiscale models. It provides an interface that makes individual models into modules that can be wired together in large composite models, parallelized across multiple CPUs, and run with Vivariums simulation engine. Vivariums utility is demonstrated by building composite models that combine several modeling frameworks: agent based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics, and spatial diffusion. This demonstrates just the beginning of what is possible - future efforts can integrate many more types of models and at many more biological scales.

AvailabilityThe models, simulation pipelines, and notebooks developed for this paper are available at the vivarium-notebooks repository: https://github.com/vivarium-collective/vivarium-notebooks. Vivarium-core is available at https://github.com/vivarium-collective/vivarium-core, and has been released on PyPI. The Vivarium Collective (https://vivarium-collective.github.io) is a repository of freely-available Vivarium processes and composites, including the processes used in Section 3. Supplementary materials provide with an extensive methodology section, with several code listings that demonstrate the basic interfaces.

category: systems biology


title: Quantification of volumetric morphometry and optical property in the cortex of human cerebellum at micrometer resolution

abstract:
The surface of the human cerebellar cortex is much more tightly folded than the cerebral cortex. Volumetric analysis of cerebellar morphometry in magnetic resonance imaging studies suffers from insufficient resolution, and therefore has had limited impact on disease assessment. Automatic serial polarization-sensitive optical coherence tomography (as-PSOCT) is an emerging technique that offers the advantages of microscopic resolution and volumetric reconstruction of large-scale samples. In this study, we reconstructed multiple cubic centimeters of ex vivo human cerebellum tissue using as-PSOCT. The morphometric and optical properties of the cerebellar cortex across five subjects were quantified. While the molecular and granular layers exhibited similar mean thickness in the five subjects, the thickness varied greatly between the crown of the folium and the depth of the fissure in the granular layer within subjects. Layer-specific optical property remained homogenous within individual subjects but showed higher cross-subject variability than layer thickness. High-resolution volumetric morphometry and optical property maps of human cerebellar cortex revealed by as-PSOCT have great potential to advance our understanding of cerebellar function and diseases.

HighlightsWe reconstructed cubic centimeters of human cerebellar samples at micrometer resolution in five subjects.

Thickness of the granular layer varies greatly between the crowns and depths of cerebellar fissures.

Cross-subject variability is higher in optical property than cortical morphology.

Our results suggest homogenous cell and myelin density in the cortical layers of human cerebellum despite the highly convoluted folding patterns.


title: APRANK: computational prioritization of antigenic proteins and peptides from complete pathogen proteomes

abstract: Availability of highly parallelized immunoassays has renewed interest in the discovery of serology biomarkers for infectious diseases. Protein and peptide microarrays now provide a rapid, high-throughput platform for immunological testing and validation of potential antigens and B-cell epitopes. However, there is still a need for tools to prioritize and select relevant probes when designing these arrays. In this work we describe a computational method called APRANK (Antigenic Protein and Peptide Ranker) which integrates multiple molecular features to prioritize antigenic targets in a given pathogen proteome. These features include subcellular localization, presence of repetitive motifs, natively disordered regions, secondary structure, transmembrane spans and predicted interaction with the immune system. We applied this method to prioritize potentially antigenic proteins and peptides in a number of bacteria and protozoa causing human diseases: Borrelia burgdorferi (Lyme disease), Brucella melitensis (Brucellosis), Coxiella burnetii (Q fever), Escherichia coli (Gastroenteritis), Francisella tularensis (Tularemia), Leishmania braziliensis (Leishmaniasis), Leptospira interrogans (Leptospirosis), Mycobacterium leprae (Leprae), Mycobacterium tuberculosis (Tuberculosis), Plasmodium falciparum (Malaria), Porphyromonas gingivalis (Periodontal disease), Staphylococcus aureus (Bacteremia), Streptococcus pyogenes (Group A Streptococcal infections), Toxoplasma gondii (Toxoplasmosis) and Trypanosoma cruzi (Chagas Disease). We have tested this integrative method using non-parametric ROC-curves and made an unbiased validation using an independent data set. We found that APRANK is successful in predicting antigenicity for all pathogen species tested, facilitating the production of antigen-enriched protein subsets. We make APRANK available to facilitate the identification of novel diagnostic antigens in infectious diseases.


title: Identification and Characterization of Human Activation-Induced ChAT+CD4+ T Cells

abstract: Vasodilation is a cornerstone of inflammation physiology. By regulating vasodilation and tissue entry of T cells, CD4+ T lymphocytes expressing choline acetyltransferase (ChAT), a key enzyme for biosynthesis of the vasorelaxant acetylcholine (ACh), critically link immunity with vascular biology in mice. However, the characterization of primary human ChAT+ T cells remained elusive. Here, we identified human ChAT+ T cells and report that ChAT mRNA was induced by activation. Functional studies demonstrated that T cell-derived ACh increased muscarinic ACh-receptor dependent NO-synthase activity and vasorelaxation. Further, single-cell RNA-sequencing revealed ChAT+CD4+ T cells in blood from patients with severe circulatory failure and a high relative frequency of ChAT+CD4+ T cells correlated with better 30-day survival in this cohort. Our findings provide the first insights into ChAT biology in primary human T cells, linking ChAT+ T cells with vasorelaxation as well as survival in a cohort of critically ill patients.


title: A Stable Nano-Vaccine for the Targeted Delivery of Tumor-Associated Glycopeptide Antigens

abstract: We have developed a novel antigen delivery system based on polysaccharide-coated gold nanoparticles (AuNPs) targeted to antigen presenting cells (APCs) expressing Dectin-1. AuNPs were synthesized de-novo using yeast-derived {beta}-1,3-glucans (B13Gs) as the reductant and passivating agent in a microwave-catalyzed procedure yielding highly uniform and serum-stable particles. These were further functionalized with both peptides and glycopeptides from the tandem repeat sequence of mucin 4 (MUC4), a glycoprotein overexpressed in pancreatic tumors. The glycosylated sequence contained the Thomsen-Friedenreich disaccharide, a pan-carcinoma, Tumor-Associated Carbohydrate Antigen (TACA), which has been a traditional target for antitumor vaccine design. These motifs were prepared with a cathepsin B protease cleavage site (Gly-Phe-Leu-Gly), loaded on the B13Gs-coated particles and these constructs were examined for Dectin-1 binding, APC processing and presentation in a model in vitro system and for immune responses in mice. We showed that these particles elicit strong in vivo immune responses through the production of both high-titer antibodies and priming of antigen-recognizing T-cells. Further examination showed that a favorable antitumor balance of expressed cytokines was generated, with limited expression of immunosuppressive Il-10. This system is modular in that any range of antigens can be conjugated to our particles and efficiently delivered to APCs expressing Dectin-1.


title: Synovial Gene Signatures Associated with the Development of Rheumatoid Arthritis in At Risk Individuals: a Prospective Study

abstract:
BackgroundPrevious work has shown subtle infiltration of synovial T cells in the absence of overt synovial inflammation in individuals at risk of developing rheumatoid arthritis (RA).

ObjectiveTo study the molecular changes in synovium preceding arthritis development in at risk individuals.

Materials and methodsWe included sixty-seven individuals with arthralgia who were IgM rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positive and without any evidence of arthritis. All individuals underwent mini-arthroscopic synovial tissue sampling of a knee joint at baseline and were followed prospectively. An explorative genome-wide transcriptional profiling study was performed on synovial tissue using Agilent arrays (discovery cohort). Survival analysis was used to identify transcripts associated with arthritis after follow up. Expression levels of differentially expressed genes were validated using quantitative real-time PCR (qPCR). Immunohistochemistry was used to study gene candidates at the protein level in situ.

ResultsIn the discovery cohort, 6 of the 13 at risk individuals developed RA after a median follow-up time of 20 months (IQR 2 - 44; pre-RA). The 7 individuals who did not develop RA had a median follow-up time of 85 months (IQR 69 - 86). Using a False Discovery Rate of <5% we found increased expression of 3,151 transcripts correlating with a higher risk of arthritis development, whereas increased expression of 2,437 transcripts correlated with a lower risk. Gene set enrichment analysis revealed that synovial biopsies of pre-RA individuals display higher expression of genes involved in several immune response-related pathways compared with biopsies of individuals who did not develop RA. In contrast, lower expression was observed for genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism. Two-way hierarchical cluster analysis of 27 genes measured by qPCR classified the synovial biopsies of 61 individuals into two groups, where pre-RA individuals (n=16) showed a preference to cluster together. Synovial tissue from pre-RA individuals were more likely to show podoplanin positive cells and lower lipid staining compared with synovial tissue from individuals who did not develop RA.

ConclusionMolecular changes can be detected in synovial tissues before clinical onset of arthritis. Alterations in the immune response genes and lipid metabolism are associated with development of arthritis.


title: A northern range extension of a Canadian species of special concern, Dielis pilipes (Hymenoptera: Scoliidae), in the Okanagan Valley of British Columbia

abstract: The only known Canadian records of the yellow scarab hunter wasp, Dielis pilipes (Saussure) (Hymenoptera: Scoliidae), are from the southern Okanagan and Similkameen valleys of British Columbia. We report a 25-km northern range extension of the species into the Ponderosa Pine Biogeoclimatic Ecosystem Classification zone, collected in an unmanaged agricultural field in Summerland, British Columbia. This finding is of conservation importance and has implications for natural biological control of ten-lined June beetles, Polyphylla decemlineata (Say) and P. crinita LeConte (Coleoptera: Scarabaeidae), incidental agricultural pests in the Okanagan.


title: A northern range extension of a Canadian species of Special Concern, Dielis pilipes (Hymenoptera: Scoliidae), in the Okanagan Valley of British Columbia


title: Genetic resistance to yellow rust infection of the wheat ear is controlled by genes controlling foliar resistance and flowering time

abstract:
Yellow rust (YR), or stripe rust, is a fungal infection of wheat (Triticum aestivum L.) caused by the pathogen Puccinia striiformis Westend f. sp. tritici (Pst). While much research has focused on YR infection of wheat leaves, we are not aware of reports investigating the genetic control of YR resistance in other wheat structures, such as the ears. Here we use an eight-founder population to undertake genetic analysis of glume YR infection in wheat ears. Five quantitative trait loci (QTL) were identified, each explaining between ~3-7% of the phenotypic variation. Of these, three (QYrg.niab-2D.2, QYrg.niab-4D.1 and QYrg.niab-5A.1) co-located with QTL for leaf YR resistance previously identified in the same population, with evidence suggesting QYrg.niab-5A.1 may correspond to the adult plant resistance locus Yr34 which originates from T. monococcum ssp. monococcum and that resistance at QYrg.niab-2D.2 may be conferred by chromosomal introgression from a wheat relative. Additional leaf YR resistance QTL previously identified in the population were not detected as controlling glume resistance, with the remaining two glume YR QTL linked to genetic loci controlling flowering time. The first of these, QYrg.niab-2D.1, mapped to the major flowering time locus Photoperiod-D1 (Ppd-D1), with the early-flowering allele from the MAGIC founder Soissons conferring reduced glume YR resistance. The second, QYrg.niab-4A.1, was identified in one trial only, and was located close to a flowering time QTL. This indicates earlier flowering results in increased glume YR susceptibility, likely due to exposure of tissues during environmental conditions more favourable for Pst infection. Collectively, our results provide first insights into the genetic control of YR resistance in glumes, controlled by subsets of QTL for leaf YR resistance and flowering time. This work provides specific genetic targets for the control of YR resistance in both the leaves and the glumes, and may be especially relevant in Pst-prone agricultural environments where earlier flowering is favoured.

Core ideasO_LIPuccinia striiformis Westend f. sp. tritici (Pst) causes yellow rust (YR) in wheat leaves and ears.
C_LIO_LIWe present the first reports for the genetic control of YR on the wheat ear.
C_LIO_LIEar YR infection is controlled by subsets of QTL controlling leaf resistance and flowering time.
C_LIO_LIThe findings are relevant to wheat breeding for Pst-prone environments.
C_LI


title: Circulating miRNA diversity, origin and response to changing metabolic and reproductive states, new insights from the rainbow trout

abstract: Circulating miRNAs (c-miRNAs) are found in most, if not all, biological fluids and are becoming well established biomarkers of many human pathologies. The aim of the present study was to investigate the potential of c-miRNAs as biomarkers of reproductive and metabolic states in fish, a question that has received little attention. Plasma was collected throughout the reproductive cycle from rainbow trout females subjected to two different feeding levels to trigger contrasting metabolic states; ovarian fluid was sample at ovulation. Fluid samples were subjected to small RNA-seq analysis followed by quantitative PCR validation for a subset of promising c-miRNA biomarkers. A comprehensive miRNA repertoire, which was lacking in trout, was first established to allow subsequent analysis. We first showed that biological fluids miRNAomes are complex and encompass a high proportion of the overall species miRNAome. While sharing a high proportion of common miRNAs, plasma and ovarian fluid miRNAomes exhibited strong fluid-specific signatures. We further showed that the plasma miRNAome exhibited major significant changes depending on metabolic and reproductive state. We subsequently identified three (miR-1-1/2-3p, miR-133-a-1/2-3p and miR-206-3p) evolutionarily conserved muscle-specific miRNA that accumulate in the plasma in response to high feeding rates, making these myomiRs strong candidate biomarkers of active myogenesis. We also identified miR-202-5p as a candidate biomarker for reproductive success that could be used to predict ovulation and/or egg quality. These highly promising results reveal the high potential of c-miRNAs as physiologically relevant biomarkers and pave the way for the use of c-miRNAs for non-invasive phenotyping in various fish species.


title: Medial Prefrontal Cortex controlling the immobility of rats in the forced swimming test: a systematic review and meta-analysis.

abstract: The medial prefrontal cortex (mPFC) belong to the neural circuitry responsible for the behavioral responses to antidepressants in humans or animals. In the forced swimming (FST), a predictive test for antidepressants in laboratory rodents, inhibition, or stimulation of mPFC may produce antidepressant-like, unlike or no behavioral effect at all. Controversial findings may result from the variety of subregions of mPFC controlling behaviour of rats in the FST. The aim in the present study was to estimate the contribution of subregions of the mPFC to the control of rat behavior in the FST. For an unbiased view and well-powered analysis of the mentioned effects, a systematic review at Medline (Pubmed) followed by a meta-analysis was performed. Compared to other subdivisions, inhibition of prelimbic or infralimbic mPFC caused a significant drop of immobility time in the FST, which is an antidepressant-like effect. Summarizing, prelimbic or infralimbic cortices seem more relevant than other subregions to the control of immobility in the FST underlying the effects of antidepressants on mood and behaviour.


title: Deep Generative Design with 3D Pharmacophoric Constraints

abstract: Generative models have increasingly been proposed as a solution to the molecular design problem. However, it has proved challenging to control the design process or incorporate prior knowledge, limiting their practical use in drug discovery. In particular, generative methods have made limited use of three-dimensional (3D) structural information even though this is critical to binding. This work describes a method to incorporate such information and demonstrates the benefit of doing so. We combine an existing graph-based deep generative model, DeLinker, with a convolutional neural network to utilise physically-meaningful 3D representations of molecules and target pharmacophores. We apply our model, DEVELOP, to both linker and R-group design, demonstrating its suitability for both hit-to-lead and lead optimisation. The 3D pharmacophoric information results in improved generation and allows greater control of the design process. In multiple large-scale evaluations, we show that including 3D pharmacophoric constraints results in substantial improvements in the quality of generated molecules. On a challenging test set derived from PDBbind, our model improves the proportion of generated molecules with high 3D similarity to the original molecule by over 300%. In addition, DEVELOP recovers 10 x more of the original molecules compared to the base-line DeLinker method. Our approach is general-purpose, readily modifiable to alternate 3D representations, and can be incorporated into other generative frameworks. Code is available at https://github.com/oxpig/DEVELOP.