title: Metabarcoding, direct stomach observation and stable isotope analysis reveal a highly diverse diet for the invasive green crab in Atlantic Patagonia

abstract: The European green crab Carcinus maenas and its sister species C. aestuarii are highly invasive species causing damage to coastal ecosystems and contributing to severe economic losses worldwide. C. maenas was first detected at the Atlantic Patagonian coast in 2001. In this work, we studied the diet of the green crab in a recently invaded location in Golfo Nuevo, using three complementary techniques: direct stomach observation, metabarcoding of gut content and stable isotope analysis. Direct stomach observation and metabarcoding showed that green crabs have a broad omnivorous diet, ingesting most of the phyla present in the study area. Gut content metabarcoding allowed a detailed description of algal diversity and revealed other taxa that went unnoticed in the visual stomach analysis. Stable isotope analysis showed that the major contribution to the crabs diet was from the phytoplankton chain (by bivalve consumption) and not directly from algae. This study approach combining three complementary techniques also allowed us to detect some differences in the diet between sexes, which suggests that male and female crabs are not as ecologically equivalent as previously thought. Besides, we detected sequences corresponding to C. aestuarii suggesting that the green crab Patagonian population is a hybrid of both sister species. These findings are key to understanding the impacts green crabs can have on the local ecosystem.

category: ecology


title: Extraction of accurate cytoskeletal actin velocity distributions from noisy measurements

abstract: Dynamic remodeling of the actin cytoskeleton is essential for many cellular processes. Tracking the movement of individual actin filaments can in principle shed light on how this complex behavior arises at the molecular level. However, the information that can be extracted from these measurements is often limited by low signal-to-noise ratios. We developed a Bayesian statistical approach to estimate true, underlying velocity distributions from the tracks of individual actin-associated fluorophores with quantified localization uncertainties. We found that filamentous (F)-actin velocity distributions in fibroblasts and endothelial cells were well described by a statistical jump process, in which filaments exist in mechanical equilibria punctuated by abrupt, jump-like movements. A model with exponentially distributed jump length- and time-scales recapitulated actin filament velocity distributions measured for the cell cortex, integrin-based adhesions, and stress fibers, suggesting that a common physical model can potentially describe actin filament dynamics in a variety of cellular contexts.

category: biophysics


title: Regular aerobic exercise is positively associated with hippocampal structure and function in young and middle-aged adults

abstract: Regular exercise has numerous benefits for brain health, including the structure and function of the hippocampus. The hippocampus plays a critical role in memory function, and is altered in a number of psychiatric disorders associated with memory impairments (e.g. depression and schizophrenia), as well as healthy ageing. While many studies have focussed on how regular exercise may improve hippocampal integrity in older individuals, less is known about these effects in young to middle-aged adults. Therefore, we assessed the associations of regular exercise and cardiorespiratory fitness with hippocampal structure and function in these age groups. We recruited 40 healthy young to middle-aged adults, comprised of two groups (n = 20) who self-reported either high or low levels of exercise, according to World Health Organisation guidelines. We assessed cardiorespiratory fitness using a graded exercise test (VO2max) and hippocampal structure via manual tracing of T1-weighted magnetic resonance images. We also assessed hippocampal function using magnetic resonance spectroscopy to derive estimates of NAA concentration and hippocampal-dependent associative memory and pattern separation tasks. We observed evidence of increased N-acetyl-aspartate concentration and associative memory performance in individuals engaging in high levels of exercise. However, no differences in hippocampal volume or pattern separation capacity were observed between groups. Cardiorespiratory fitness was positively associated with hippocampal volume (left, right, and bilateral), N-acetyl-aspartate concentration, and pattern separation. However, no association was observed between cardiorespiratory fitness and associative memory. Therefore, we provide evidence that higher levels of exercise and cardiorespiratory fitness are associated with improved hippocampal structure and function. Exercise may provide a low-risk, effective method of improving hippocampal integrity in an early-to-mid-life stage.

category: neuroscience


title: SEMplMe: A tool for integrating DNA methylation effects in transcription factor binding affinity predictions

abstract:
MotivationAberrant DNA methylation in transcription factor binding sites has been shown to lead to anomalous gene regulation that is strongly associated with human disease. However, the majority of methylation-sensitive positions within transcription factor binding sites remain unknown. Here we introduce SEMplMe, a computational tool to generate predictions of the effect of methylation on transcription factor binding strength in every position within a transcription factors motif.

ResultsSEMplMe uses ChIP-seq and whole genome bisulfite sequencing to predict effects of methylation within binding sites. SEMplMe validates known methylation sensitive and insensitive positions within a binding motif, identifies cell type specific transcription factor binding driven by methylation, and outperforms SELEX-based predictions for CTCF. These predictions can be used to identify aberrant sites of DNA methylation contributing to human disease.

Availability and ImplementationSEMplMe is available from https://github.com/Boyle-Lab/SEMplMe.

Contactapboyle@umich.edu

Supplementary InformationSupplementary data are available at Bioinformatics online.

category: bioinformatics


title: MethylSPWNet and MethylCapsNet: Biologically Motivated Organization of DNAm Neural Network, Inspired by Capsule Networks

abstract: DNA methylation (DNAm) alterations have been heavily implicated in carcinogenesis and the pathophysiology of diseases through upstream regulation of gene expression. DNAm deep-learning approaches are able to capture features associated with aging, cell type, and disease progression, but lack incorporation of prior biological knowledge. Here, we present modular, user-friendly deep learning methodology and software, MethylCapsNet and MethylSPWNet, that group CpGs into biologically relevant capsules - such as gene promoter context, CpG island relationship, or user-defined groupings - and relate them to diagnostic and prognostic outcomes. We demonstrate these models utility on 3,897 individuals in the classification of central nervous system (CNS) tumors. MethylCapsNet and MethylSPWNet provide an opportunity to increase DNAm deep learning analyses interpretability by enabling a flexible organization of DNAm data into biologically relevant capsules.


title: ERAP2 increases the abundance of a peptide submotif highly selective for the Birdshot Uveitis-associated HLA-A29

abstract: Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labelled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.

category: immunology


title: ResistoXplorer: a web-based tool for visual, statistical and exploratory data analysis of resistome data

abstract: The study of resistomes using whole metagenomic sequencing enables high throughput identification of resistance genes in complex microbial communities, such as the human microbiome. Over recent years, sophisticated and diverse pipelines have been established to facilitate raw data processing and annotation. Despite the progress, there are no easy-to-use tools for comprehensive visual, statistical, and functional analysis of resistome data. Thus, exploration of the resulting large complex datasets remains a key bottleneck requiring robust computational resources and technical expertise, which creates a significant hurdle for advancements in the field. Here, we introduce ResistoXplorer, a user-friendly tool that integrates recent advancements in statistics and visualization, coupled with extensive functional annotations and phenotype collection, to enable high-throughput analysis of common outputs generated from metagenomic resistome studies. ResistoXplorer contains three modules- the  Antimicrobial Resistance Gene Table module offers various options for composition profiling, functional profiling and comparative analysis of resistome data; the  Integration module supports integrative exploratory analysis of resistome and microbiome abundance profiles derived from metagenomic samples; finally, the  Antimicrobial Resistance Gene List module enables users to intuitively explore the associations between antimicrobial resistance genes and the microbial hosts using network visual analytics to gain biological insights. ResistoXplorer is publicly available at http://www.resistoxplorer.no.

category: microbiology


title: Implicit anticipation of probabilistic regularities: Larger CNV emerges for unpredictable events

abstract: Anticipation of upcoming events plays a crucial role in automatic behaviors. It is, however, still unclear whether the event-related brain potential (ERP) markers of anticipation could track the implicit acquisition of probabilistic regularities that can be considered as building blocks of automatic behaviors. Therefore, in a four-choice reaction time (RT) task performed by young adults (N = 36), the contingent negative variation (CNV) as an ERP marker of anticipation was measured from the onset of a cue stimulus until the presentation of a target stimulus. Due to the probability structure of the task, target stimuli were either predictable or unpredictable, but this was unknown to participants. The cue did not contain predictive information on the upcoming target. Results showed that the CNV amplitude during response preparation was larger before the unpredictable than before the predictable target stimuli. In addition, although RTs increased, the P3 amplitude decreased for the unpredictable as compared with the predictable target stimuli, possibly due to the stronger response preparation that preceded stimulus presentation. These results suggest that enhanced attentional resources are allocated to the implicit anticipation and processing of unpredictable events. This might originate from the formation of internal models on the probabilistic regularities of the stimulus stream, which primarily facilitates the processing of predictable events. Overall, we provide ERP evidence that supports the role of implicit anticipation and predictive processes in the acquisition of probabilistic regularities.


title: Adolescent female rats undergo full systems consolidation of an aversive memory, while males of the same age fail to discriminate contexts

abstract: Generalization is an adaptive process that allows animals to deal with threatening circumstances similar to prior experiences. Systems consolidation is a time-dependent process in which memory loses it precision concomitantly with reorganizational changes in the brain structures that support memory retrieval. In this, memory becomes progressively independent from the hippocampus and more reliant on cortical structures. Generalization, however, may take place much faster in adult animals depending on the presence of sex hormones. Notwithstanding its relevance, there are few studies on sex differences in memory modulation. Here, a contextual fear discrimination task was used to investigate the onset of memory generalization and hippocampus-independence in adolescent male and female rats (P42-49). Subjects were tested 2, 7, 14, 21 or 28 days after training, with females showing memory generalization from day 21 on, whereas males surprisingly unable to discriminate contexts at any time. Ovariectomized females, however, displayed an early onset of generalization. Consistently, pre-test pharmacological blocking of dorsal hippocampus was able to impair memory retrieval in females, but not in males, which indicate that precise memory is dependent on the hippocampus. To our notice, this is the first report of a memory systems consolidation process - expressed in its two dimensions, neuroanatomical and qualitative - in adolescent female rats, and one that can also be accelerated by the reduction of sex hormones through ovariectomy. It is also unprecedented that despite adolescent male rats being able to remember fear learning, they did not discriminate contexts with any precision.


title: Cdc42 reactivation at growth sites is regulated by local cell-cycle-dependent loss of its GAP Rga4

abstract: In fission yeast, polarized cell growth stops during division and resumes after cell separation. We uncoupled these sequential events by delaying cytokinesis with a temporary Latrunculin A treatment. Mitotic cells recovering from treatment initiate end growth without cell separation, displaying a polar elongation sans separation (PrESS) phenotype. PrESS cell ends reactivate Cdc42, a major regulator of polarized growth, before cell separation, but at a fixed time after anaphase B. A candidate screen implicates Rga4, a negative regulator of Cdc42, in this process. We show that Rga4 appears punctate at the cell sides during G2, but is diffuse during mitosis, extending to the ends. While the Morphogenesis Orb6 (MOR) pathway is known to promote cell separation and growth by activating protein synthesis, we find that for polarized growth, removal of Rga4 from the ends is also necessary. Therefore, we propose that growth resumes after division once the MOR pathway is activated and the ends lose Rga4 in a cell-cycle-dependent manner.

category: cell biology


title: Calcium-vesicles perform active diffusion in the sea urchin embryo during larval biomineralization

abstract:
Biomineralization is the process by which organisms use minerals to harden their tissues and provide them with physical support. Biomineralizing cells concentrate the mineral in vesicles that they secret into a dedicated compartment where crystallization occurs. The dynamics of vesicle motion and the molecular mechanisms that control it, are not well understood. Sea urchin larval skeletogenesis provides an excellent platform for investigating the kinetics of mineral-bearing vesicles. Here we used lattice light-sheet microscopy to study the three-dimensional (3D) dynamics of calcium-bearing vesicles in the cells of normal sea urchin embryos and of embryos where skeletogenesis is blocked through the inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR). We developed computational tools for displaying 3D-volumetric movies and for automatically quantifying vesicle dynamics. Our findings imply that calcium vesicles perform an active diffusion motion in both, calcifying (skeletogenic) and non-calcifying (ectodermal) cells of the embryo. The diffusion coefficient and vesicle speed are larger in the mesenchymal skeletogenic cells compared to the epithelial ectodermal cells. These differences are possibly due to the distinct mechanical properties of the two tissues, demonstrated by the enhanced f-actin accumulation and myosinII activity in the ectodermal cells compared to the skeletogenic cells. Vesicle motion is not directed toward the biomineralization compartment, but the vesicles slow down when they approach it, and probably bind for mineral deposition. VEGFR inhibition leads to an increase of vesicle volume but hardly changes vesicle kinetics and doesnt affect f-actin accumulation and myosinII activity. Thus, calcium vesicles perform an active diffusion motion in the cell of the sea urchin embryo, with diffusion length and speed that inversely correlate with the strength of the actomyosin network. Overall, our studies provide an unprecedented view of calcium vesicle 3D-dynamics and point toward cytoskeleton remodeling as an important effector of the motion of mineral-bearing vesicles.

Authors summaryBiomineralization is a widespread, fundamental process by which organisms use minerals to harden their tissues. Mineral-bearing vesicles were observed in biomineralizing cells and play an essential role in biomineralization, yet little is known about their three-dimensional (3D) dynamics. Here we quantify 3D-vesicle-dynamics during calcite skeleton formation in sea urchin larvae, using lattice-light-sheet microscopy. We discover that calcium vesicles perform a diffusive motion in both calcifying and non-calcifying cells of the embryo. The diffusion coefficient and vesicle speed are higher in the mesenchymal skeletogenic cells compared to the epithelial ectodermal cells. This difference is possibly due to the higher rigidity of the ectodermal cells as demonstrated by the enhanced signal of f-actin and myosinII activity in these cells compared to the skeletogenic cells. The motion of the vesicles in the skeletogenic cells, is not directed toward the biomineralization compartment but the vesicles slow down near it, possibly to deposit their content. Blocking skeletogenesis through the inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR), increases vesicle volume but doesnt change the diffusion mode and the cytoskeleton markers in the cells. Our studies reveal the active diffusive motion of mineral bearing vesicles that is apparently defined by the mechanical properties of the cells.

Calcium-vesicle diffusion in biomineralization

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category: developmental biology


title: Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

abstract: Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to induce mosaic inactivation of zebrafish ccm2 resulting in a novel lethal multi-cavernous lesion in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic those that mediate intussusceptive angiogenesis; however, in contrast to the normal process, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resultant aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires the flow-regulated transcription factor KLF2; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe a zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.


title: simATAC: A single-cell ATAC-seq simulation framework

abstract: Single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) identifies regulated chromatin accessibility modules at the single-cell resolution. Robust evaluation is critical to the development of scATAC-seq pipelines, which calls for reproducible datasets for benchmarking. We hereby present the simATAC framework, an R package that generates scATAC-seq count matrices that highly resemble real scATAC-seq datasets in library size, sparsity, and chromatin accessibility signals. simATAC deploys statistical models derived from analyzing 90 real scATAC-seq cell groups. simATAC provides a robust and systematic approach to generate in silico scATAC-seq samples with known cell labels for assessing analytical pipelines.


title: Sub-optimal Discontinuous Current-Clamp switching rates lead to deceptive mouse neuronal firing

abstract:
AO_SCPLOWBSTRACTC_SCPLOWIntracellular recordings using sharp microelectrodes often rely on a technique called Discontinuous Current-Clamp to accurately record the membrane potential while injecting current through the same microelectrode. It is well known that a poor choice of DCC switching rate can lead to under-or over-estimation of the cell potential, however, its effect on the cell firing is rarely discussed. Here, we show that sub-optimal switching rates lead to an overestimation of cell excitability. We performed intracellular recordings of mouse spinal motoneurons and recorded their firing in response to pulses and ramps of current in Bridge and DCC mode at various switching rates. We demonstrate that using an incorrect (too low) DCC frequency leads not only to an underestimation of the input resistance, but also, paradoxically, to an artificial overestimation of the firing of these cells: neurons fire at lower current, and at higher frequencies than at higher DCC rates, or than the same neuron recorded in Bridge mode. These effects are dependent on the membrane time constant of the recorded cell, and special care needs to be taken in large cells with very short time constants. Our work highlights the importance of choosing an appropriate DCC switching rate to obtain not only accurate membrane potential readings but also an accurate representation of the firing of the cell.

SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWDiscontinuous Current-Clamp is a technique often used during intracellular recordings in vivo. However, incorrect usage of this technique can lead to incorrect interpretations. Poor choice of the DCC switching rate can lead to under- or over-estimation of the cell potential. In addition, we show here that sub-optimal switching rates lead to an overestimation of the cell excitability.


title: Evolution of multicellularity and unicellularity in yeast S. cerevisiae to study reversibility of evolutionary trajectories.

abstract: Adaptive trajectories of populations have been focus of number of studies. However, adaptive trajectories have not been studied in the context of reverse evolution. By reverse evolution, we mean a scenario where selection is reversed. In this work, we use evolution (and reversal from) of multicellularity in S. cerevisiae as a model to answer this question. When selected for fast-settling variants, multicellularity evolves rapidly in the organism. On reversing selection, unicellularity evolves from the multicellular clusters. However, the dynamic trajectories of the two processes are different. In this context, evolution is not reversed dynamically at a phenotypic level. The phenotypic reversal is not driven by reversal of the original mutations during the forward evolution. Overall, our results show that the dynamics of molecular and phenotypic trajectories of evolution are distinct, and reversal of selection leads to unique trajectories of phenotypic reversal.

category: evolutionary biology


title: Variation and variability in Drosophila grooming behavior

abstract: Behavioral differences can be observed between species or populations (variation) or between individuals in a genetically similar population (variability). Here, we investigate genetic differences as a possible source of variation and variability in Drosophila grooming. Grooming confers survival and social benefits. Grooming features of five Drosophila species exposed to a dust irritant were analyzed. Aspects of grooming behavior, such as anterior to posterior progression, were conserved between and within species. However, significant differences in activity levels, proportion of time spent in different cleaning movements, and grooming syntax were identified between species. All species tested showed individual variability in the order and duration of action sequences. Genetic diversity was not found to correlate with grooming variability within a species: melanogaster flies bred to increase or decrease genetic heterogeneity exhibited similar variability in grooming syntax. Individual flies observed on consecutive days also showed grooming sequence variability. Standardization of sensory input using optogenetics reduced but did not eliminate this variability. In aggregate, these data suggest that sequence variability may be a conserved feature of grooming behavior itself. These results also demonstrate that large genetic differences result in distinguishable grooming phenotypes (variation), but that genetic heterogeneity within a population does not necessarily correspond to an increase in the range of grooming behavior (variability).

category: animal behavior and cognition


title: A model of uniform cortical composition predicts the scaling laws of the mammalian cerebrum

abstract:
The size of the mammalian cerebrum spans more than 5 orders of magnitude. The smallest cerebrums have a smooth (lissencephalic) cortical surface, which gets increasingly folded (gyrencephalic) with cerebral size. Further, the proportion of white-to-gray matter volume increases with the total volume. These scaling relations have unusually little variation. It remains an open question, why this is so. Here, we show that almost all variance is explained by assuming a homogeneous composition of the cortex across mammals. On the basis of this assumption we derive quantitative computational models. The first model predicts the cortical surface area from the gray and white matter volume. A single free parameter, for the height of cortical columns {lambda} = 2.9mm, r2 = 0.996). The second model predicts the white matter volume as a function of the gray volume and the cerebral size (two parameters, [Formula], [Formula]). The models are validated by predicting the effective cortical thickness and the folding parameter{kappa} . The results accurately predict the human intraspecific variation of the surface relations. We find a reduced {lambda} for cetaceans. Preterm human infants do not follow the model. We also find deviations of gray and white matter volume for large cerebrums. Overall, the models thus show how the regular architecture of the cortex shapes the cerebrum.

Significance statementThe mammalian cerebrum shows a vast distribution in size, from 10 mm3 to over 5 liters. Across this range highly regular scaling relations have been found, e.g., for volume of grey and white matter and cortical surface. Despite considerable efforts, these scaling relations are still not understood. Here, we develop a model, assuming that cortex and the white matter have a uniform composition across mammals of every size, and independent of phylogeny. On the basis of this simple assumption we could accurately predict the scaling relations. The results show that humans are in the normal scaling range from birth age. Cetaceans are the only clade to show a reduced cortical thickness parameter.


title: A comparative study of stress responses elicited by misfolded proteins targeted by bipartite or matrix-targeting signal sequences to yeast mitochondria

abstract: The double-membrane-bound architecture of mitochondria, essential for ATP production, sub-divides the organelle into inter-membrane space (IMS) and matrix. IMS and matrix possess contrasting oxido-reductive environments and distinct protein quality control (PQC) machineries resulting different protein folding environments. To understand the nature of stress response elicited by equivalent proteotoxic stress to sub-mitochondrial compartments, we fused well-described bipartite or matrix-targeting signal sequences to misfolding and aggregation-prone stressor proteins to target and impart stress to yeast mitochondrial IMS or matrix. We show, mitochondrial proteotoxicity leads to growth arrest of yeast cells of varying degrees depending on nature of stressor proteins and the intra-mitochondrial location of stress. Next, using transcriptomics and proteomics, we report a comprehensive stress response elicited by two types of targeting signal-fused stressor proteins. Among global responses by mitochondria-targeted stressors by both types of signal sequences, an adaptive response of abrogated mitochondrial respiration and concomitant upregulation of glycolysis is uncovered. Beyond shared stress responses, specific signatures due to stress within mitochondrial sub-compartments are also revealed. We report that bipartite signal sequence-fused stressor proteins eliciting stress to IMS, leads to specific upregulation of IMS-chaperones and TOM complex components. In contrast, matrix-targeted stressors lead to specific upregulation of matrix-chaperones and cytosolic PQC components. Finally, by systematic genetic interaction using deletion strains of differentially upregulated genes, we found prominent modulatory role of TOM complex components during IMS-stress response. In contrast, VMS1 markedly modulates the stress response originated from matrix.


title: Role of Sugar Stereochemistry on Structural and Free Energy Landscape of Double-Stranded Nucleic Acids

abstract: The conformational landscape of 29-mer long four stereo variants of furanosal nucleic acids and their C2 deoxy counterparts were explored using molecular dynamics and well-tempered metadynamics simulations. The ribose containing double-stranded nucleic acids exhibit helical structure, however inversion of C3 and/or C2 stereocentre of ribose results in structural modification. The free energy surfaces relative to the average twist angle and end-to-end distances suggests that the configuration at the C3 position plays a pivotal role in determining the helicity. The C3 stereocentre acts as toggle-switch for helix to non-helical structures in double-stranded nucleic acids. Thus, the ribose containing double-stranded nucleic acids result in well-organized helical structures, while those containing xylose and lyxose show a variety of structures, which include (circular) ladder configurations. Based on the present set of results, it can be inferred that ribose containing double-stranded nucleic acids form well-defined helical structures in contrast to their C2 and C3 epimers.


title: Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

abstract:
BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

METHODSWe conducted the largest to date genome-wide genotype-by-sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.

RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05).

CONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

category: genetics


title: MultiGWAS: An integrative tool for Genome Wide Association Studies (GWAS) in tetraploid organisms

abstract: SummaryThe Genome-Wide Association Studies (GWAS) are essential to determine the genetic bases of either ecological or economic phenotypic variation across individuals within populations of the model and non-model organisms. For this research question, the GWAS replication testing different parameters and models to validate the results reproducibility is common. However, straightforward methodologies that manage both replication and tetraploid data are still missing. To solve this problem, we designed the MultiGWAS, a tool that does GWAS for diploid and tetraploid organisms by executing in parallel four software, two designed for polyploid data (GWASpoly and SHEsis) and two for diploids data (GAPIT and TASSEL). MultiGWAS has several advantages. It runs either in the command line or in a graphical interface; it manages different genotype formats, including VCF. Moreover, it allows control for population structure, relatedness, and several quality control checks on genotype data. Besides, MultiGWAS can test for additive and dominant gene action models, and through a proprietary scoring function, select the best model to report its associations. Finally, it generates several reports that facilitate identifying false associations from both the significant and the best-ranked association SNP among the four software. We tested MultiGWAS with public tetraploid potato data for tuber shape and several simulated data under both additive and dominant models. These tests demonstrated that MultiGWAS is better at detecting reliable associations than using each of the four software individually. Moreover, the parallel analysis of polyploid and diploid software that only offers Multi-GWAS demonstrates its utility in understanding the best genetic model behind the SNP association in tetraploid organisms. Therefore, MultiG-WAS probed to be an excellent alternative for wrapping GWAS replication in diploid and tetraploid organisms in a single analysis environment.


title: Aspartate-phobia of thermophiles as a reaction to deleterious chemical transformations

abstract: Prokaryotes growing at high temperatures have a high proportion of charged residues in their proteins to stabilize their 3D structure. By mining 175 disparate bacterial and archaeal proteomes we found that, against the general trend for charged residues, the frequency of aspartic acid residues decreases strongly as natural growth temperature increases. In search of the explanation, we hypothesized that the reason for such unusual correlation is the deleterious consequences of spontaneous chemical transformations of aspartate at high temperatures. Our subsequent statistical analysis supported this hypothesis. First, knowing that these chemical modifications are higher in the unfolded polypeptide chains, we observed the most pronounced decrease of Asp frequency with temperature within intrinsically disordered regions. Second, it is known that the reaction rate of the chemical transformations of Asp is highest with the smallest downstream residue Gly and noticeably reduced for bulky residues. In agreement with this, the frequency of Gly residues downstream of Asp decreases with optimal growth temperature, while the frequency of bulky residues significantly increases. Thus, our analysis suggests that organisms have likely adapted to high temperatures by minimizing the harmful consequences of spontaneous chemical transformations of Asp residues.


title: Improved online event detection and differentiation by a simple gradient-based nonlinear transformation: Implications for the biomedical signal and image analysis

abstract: Despite recent success in advanced signal analysis technologies, simple and universal methods are still of interest in a variety of applications. Wearable devices including biomedical monitoring and diagnostic systems suitable for long-term operation are prominent examples, where simple online signal analysis and early event detection algorithms are required. Here we suggest a simple and universal approach to the online detection of events represented by abrupt bursts in long-term observational data series. We show that simple gradient-based transformations obtained as a product of the signal and its derivative lead to the improved accuracy of the online detection of any significant bursts in the observational data series irrespective of their particular shapes. We provide explicit analytical expressions characterizing the performance of the suggested approach in comparison with the conventional solutions optimized for particular theoretical scenarios and widely utilized in various signal analysis applications. Moreover, we estimate the accuracy of the gradient-based approach in the exact positioning of single ECG cycles, where it outperforms the conventional Pan-Tompkins algorithm in its original formulation, while exhibiting comparable detection effectiveness. Finally, we show that our approach is also applicable to the comparative analysis of lanes in electrophoretic gel images widely used in life sciences and molecular diagnostics like restriction fragment length polymorphism (RFLP) and variable number tandem repeats (VNTR) methods. A simple software tool for the semi-automated electrophoretic gel image analysis based on the proposed gradient based methodology is freely available online at https://bitbucket.org/rogex/sds-page-image-analyzer/downloads/.

category: physiology


title: Revisiting Cryptococcus extracellular vesicles properties and their use as vaccine platforms

abstract: Whereas extracellular vesicle (EV) research has become commonplace in different biomedical fields, this field of research is still in its infancy in mycology. Here we provide a robust set of data regarding the structural and compositional aspects of EVs isolated from the fungal pathogenic species Cryptococcus neoformans, C. deneoformans and C. deuterogattii. Using cutting-edge methodological approaches including cryogenic electron microscopy and cryogenic electron tomography, proteomics, and flow cytometry, we revisited cryptococcal EV features and suggest a new EV structural model, in which the vesicular lipid bilayer is covered by mannoprotein-based fibrillar decoration, bearing the capsule polysaccharide as its outer layer. About 10% of the EV population is devoid of fibrillar decoration, adding another aspect to EV diversity. By analyzing EV protein cargo from the three species, we characterized the typical Cryptococcus EV proteome. It contains several membrane-bound protein families, including some Tsh proteins bearing a SUR7/PalI motif. The presence of known protective antigens on the surface of Cryptococcus EVs, resembling the morphology of encapsulated virus structures, suggested their potential as a vaccine. Indeed, mice immunized with EVs obtained from an acapsular C. neoformans mutant strain rendered a strong antibody response in mice and significantly prolonged their survival upon C. neoformans infection.


title: Placental and fetal characteristics of the Ohia mouse line recapitulate outcomes in human hypoplastic left heart syndrome

abstract: Congenital heart defects (CHDs) are the most common birth defect worldwide. The morbidity and mortality associated with these defects is compounded by increased frequency of fetal growth abnormalities. In the Ohia mouse model of hypoplastic left heart syndrome (HLHS), the double homozygous genotype is embryonically lethal at mid-pregnancy; a time in which optimal establishment of the placenta is crucial to fetal survival. We aimed to characterize placental and fetal growth and development in the double heterozygous genotype (Sap130m/+Pcdha9m/+) to determine whether the genetic mutations associated with HLHS in the Ohia mouse also affect the placenta. The frequency of fetuses with reduced weight near term was shifted in the Sap130m/+Pcdha9m/+ fetuses compared to wildtype. This shift in fetal weight distribution in the Sap130m/+Pcdha9m/+ fetuses was associated with reduced labyrinth region area (P<0.001) and reduced fetal capillary density (P<0.001) in the placentas. Positive correlations were observed between fetal weight and placenta mRNA expression of several nutrient transporters in the Sap130m/+Pcdha9m/+ fetuses but not observed in the wildtype. Increased protein expression of Slc7a5 (P<0.05) and Slc7a8 (P<0.05) was also found in the placenta of Sap130m/+Pcdha9m/+ fetuses. This data shows, despite a potential compensatory mechanism to increase nutrient transport, abhorrent placental vascularization leads to inadequate fetal growth in the Ohia mouse model. Such differences are similar to findings in studies of human placentas and highlights the importance of this mouse model in continuing to understand the developmental links and disruptions to the heart-placenta axis.


title: Pancreatic α and β cells are globally phase-locked

abstract: The Ca2+ modulated pulsatile secretion of glucagon and insulin by pancreatic  and {beta} cells plays a key role in glucose homeostasis. However, how  and {beta} cells coordinate via paracrine interaction to produce various Ca2+ oscillation patterns is still elusive. Using a microfluidic device and transgenic mice in which  and {beta} cells were labeled with different colors, we were able to record islet Ca2+ signals at single cell level for long times. Upon glucose stimulation, we observed heterogeneous Ca2+ oscillation patterns intrinsic to each islet. After a transient period, the oscillations of  and {beta} cells were globally phase-locked, i.e., the two types of cells in an islet each oscillate synchronously but with a phase shift between the two. While the activation of  cells displayed a fixed time delay of ~20 s to that of {beta} cells, {beta} cells activated with a tunable delay after the  cells. As a result, the tunable phase shift between  and {beta} cells set the islet oscillation period and pattern. Furthermore, we demonstrated that the phase shift can be modulated by glucagon. A mathematical model of islet Ca2+ oscillation taking into consideration of the paracrine interaction was constructed, which quantitatively agreed with the experimental data. Our study highlights the importance of cell-cell interaction to generate stable but tunable islet oscillation patterns.

category: systems biology


title: Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection

abstract: Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.


title: Disentangling Semantic Composition and Semantic Association in the Left Temporal Lobe

abstract:
Although composing two words into a complex representation (e.g., "coffee cake") is conceptually different from forming associations between a pair of words (e.g., "coffee, cake"), the brain regions supporting semantic composition have also been implicated for associative encoding. Here, we adopted a two-word magnetoencephalography (MEG) paradigm which varies compositionality ("French/Korean cheese" vs. "France/Korea cheese") and strength of association ("France/French cheese" vs. "Korea/Korean cheese") between the two words. We collected MEG data while 42 English speakers (24 females) viewed the two words successively in the scanner, and we applied both univariate regression analyses and multivariate pattern classification to the source estimates of the two words. We show that the left anterior and middle temporal lobe (LATL; LMTL) are distinctively modulated by semantic composition and semantic association. Specifically, the LATL is mostly sensitive to high-association compositional phrases, while the LMTL responds more to low-association compositional phrases. Pattern-based directed connectivity analyses further revealed a continuous information flow from the anterior to the middle temporal region, suggesting that the integration of adjective and noun properties originated earlier in the LATL is consistently delivered to the LMTL when the complex meaning is newly encountered. Taken together, our findings shed light into a functional dissociation within the left temporal lobe for compositional and distributional semantic processing.

Significance StatementPrior studies on semantic composition and associative encoding have been conducted independently within the subfields of language and memory, and they typically adopt similar two-word experimental paradigms. However, no direct comparison has been made on the neural substrates of the two processes. The current study relates the two streams of literature, and appeals to audiences in both subfields within cognitive neuroscience. Disentangling the neural computations for semantic composition and association also offers insight into modeling compositional and distributional semantics, which has been the subject of much discussion in Natural Language Processing and cognitive science.


abstract:
Modern spatial transcriptomics methods can target thousands of different types of RNA transcripts in a single slice of tissue. Many biological applications demand a high spatial density of transcripts relative to the imaging resolution, leading to partial mixing of transcript rolonies in many voxels; unfortunately, current analysis methods do not perform robustly in this highly-mixed setting. Here we develop a new analysis approach, BARcode DEmixing through Non-negative Spatial Regression (BarDensr): we start with a generative model of the physical process that leads to the observed image data and then apply sparse convex optimization methods to estimate the underlying (demixed) rolony densities. We apply Bar-Densr to simulated and real data and find that it achieves state of the art signal recovery, particularly in densely-labeled regions or data with low spatial resolution. Finally, BarDensr is fast and parallelizable. We provide open-source code as well as an implementation for the  NeuroCAAS cloud platform.

Author SummarySpatial transcriptomics technologies allow us to simultaneously detect multiple molecular targets in the context of intact tissues. These experiments yield images that answer two questions: which kinds of molecules are present, and where are they located in the tissue? In many experiments (e.g., mapping RNA expression in fine neuronal processes), it is desirable to increase the signal density relative to the imaging resolution. This may lead to mixing of signals from multiple RNA molecules into single imaging voxels; thus we need to demix the signals from these images. Here we introduce BarDensr, a new computational method to perform this demixing. The method is based on a forward model of the imaging process, followed by a convex optimization approach to approximately  invert mixing induced during imaging. This new approach leads to significantly improved performance in demixing imaging data with dense expression and/or low spatial resolution.

category: genomics


title: Enhancers regulate polyadenylation site cleavage and control 3'UTR isoform expression

abstract: Multi-UTR genes are widely transcribed but show cell type-specific 3'UTR isoform expression. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate mRNA isoform expression. Deletion of an endogenous enhancer of a multi-UTR gene did not impair transcript production but prevented a switch in 3'UTR isoform expression. Also, the same enhancers are able to increase transcript production in the context of single-UTR gene promoters, but they increase 3' end processing activity when paired with multi-UTR gene promoters. We show that transcription factors regulate processing activity of weak polyadenylation sites to control cell type-specific alternative 3'UTR isoform expression of widely expressed genes.

category: biochemistry


title: Enhancers regulate 3' end processing activityto control expression of alternative 3'UTR isoforms


title: The anti-sigma factor MucA is required for viability in Pseudomonas aeruginosa

abstract: During decades-long infections in the cystic fibrosis (CF) airway, Pseudomonas aeruginosa undergoes selection. One bacterial genetic adaptation often observed in CF isolates is mucA mutations. MucA inhibits the sigma factor AlgU. Mutations in mucA lead to AlgU misregulation, resulting in a mucoid phenotype that is associated with poor CF disease outcomes. Due to its ability to be mutated, mucA is assumed to be dispensable for bacterial viability. Here we show that, paradoxically, a portion of mucA is essential in P. aeruginosa. We demonstrate that mucA is no longer required in a strain lacking algU, that mucA alleles encoding for proteins that do not bind to AlgU are insufficient for viability, and that mucA is no longer essential in mutant strains containing AlgU variants with reduced sigma factor activity. Furthermore, we found that overexpression of algU prevents cell growth in the absence of MucA, and that this phenotype can be rescued by overproduction of RpoD, the housekeeping sigma factor. Together, these results suggest that in the absence of MucA, the inability to regulate AlgU activity results in the loss of bacterial viability. Finally, we speculate that essentiality of anti-sigma factors that regulate envelope function may be a widespread phenomenon in bacteria.


title: How accurately can we assess zoonotic risk?

abstract: The authors have withdrawn their manuscript as a website associated with a zoonotic risk prediction tool mentioned here was not public. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author


title: NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

abstract:
Amyloid fibril formation of -synuclein (S) is associated with multiple neurodegenerative diseases, including Parkinsons Disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of S fibrils, which leads to seeding of endogenous intrinsically disordered monomer via templated elongation and secondary nucleation. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we probe weak interactions of intrinsically disordered acetylated-S (Ac-S) monomers with seeding-competent Ac-S fibrils and seeding-incompetent off-pathway oligomers to identify Ac-S monomer residues at the binding interface. Under conditions that favor fibril elongation, we determine that the first 11 N-terminal residues on the monomer form a common binding site for both fibrils and off-pathway oligomers. Additionally, the presence of off-pathway oligomers within a fibril seeding environment suppresses seeded amyloid formation, as observed through thioflavin-T fluorescence experiments. This highlights that off-pathway S oligomers can act as an auto-inhibitor against S fibril elongation. Based on these data taken together with previous results, we propose a model in which Ac-S monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N-terminus and the intrinsically disordered flanking regions (IDR) on the fibril surface. We suggest that this monomer recruitment may play a role in the elongation of amyloid fibrils and highlight the potential of the IDRs of the fibril as important therapeutic targets against seeded amyloid formation.

SignificanceCell-to-cell spreading of S fibrils leads to amyloid seeding of endogenous monomer. Detailed atomic-level mechanistic understanding of the fibril seeding process of S is essential for design of therapeutic approaches against Parkinsons disease. In light of its complexity, this process remains ill-defined at the molecular level. Using relaxation-based solution NMR experiments, we mapped a common N-terminal binding interface of the Ac-S intrinsically disordered monomer with Ac-S fibrils and off-pathway oligomers to elucidate critical monomer-aggregate interactions during seeded aggregation and in equilibrium with mature aggregates. From this work, we propose a new paradigm, in which Ac-S monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N-terminus and the flanking IDRs on the fibril surface.


title: Effects of Peripheral Haptic Feedback on Intracortical Brain-Computer Interface Control and Associated Sensory Responses in Motor Cortex

abstract: Intracortical brain-computer interfaces (iBCIs) provide people with paralysis a means to control devices with signals decoded from brain activity. Despite recent impressive advances, these devices still cannot approach able-bodied levels of control. To achieve naturalistic control and improved performance of neural prostheses, iBCIs will likely need to include proprioceptive feedback. With the goal of providing proprioceptive feedback via mechanical haptic stimulation, we aim to understand how haptic stimulation affects motor cortical neurons and ultimately, iBCI control. We provided skin shear haptic stimulation as a substitute for proprioception to the back of the neck of a person with tetraplegia. The neck location was determined via assessment of touch sensitivity using a monofilament test kit. The participant was able to correctly report skin shear at the back of the neck in 8 unique directions with 65% accuracy. We found motor cortical units that exhibited sensory responses to shear stimuli, some of which were strongly tuned to the stimuli and well modeled by cosine-shaped functions. We also demonstrated online iBCI cursor control with continuous skin-shear feedback driven by decoded command signals. Cursor control performance increased slightly but significantly when the participant was given haptic feedback, compared to the purely visual feedback condition.


title: The Role of Colony Temperature in the Entrainment of Circadian Rhythms of Honey Bee Foragers

abstract: Honey bees utilize their circadian rhythms to accurately predict the time of day. This ability allows foragers to remember the specific timing of food availability and its location for several days. Previous studies have provided strong evidence toward light/dark cycles being the primary Zeitgeber for honey bees. Work in our laboratory described large individual variation in the endogenous period length of honey bee foragers from the same colony and differences in the endogenous rhythms under different constant temperatures. In this study, we further this work by examining temperature inside the honey bee colony. By placing temperature and light data loggers at different locations inside the colony we measured temperature at various locations within the colony. We observed significant oscillations of temperature inside the hive, that show seasonal patterns. We then simulated the observed temperature oscillations in the laboratory and found that using the temperature cycle as a Zeitgeber, foragers present large individual differences in the phase of locomotor rhythms with respect to temperature. Moreover, foragers successfully synchronize their locomotor rhythms to these simulated temperature cycles. Advancing the cycle by six hours, resulted in changes in the phase of activity in some foragers in the assay. The results shown in this study highlight the importance of temperature as a potential Zeitgeber in the field. Future studies will examine the possible functional and evolutionary role of the observed phase differences of circadian rhythms.


title: UFold: Fast and Accurate RNA Secondary Structure Prediction with Deep Learning

abstract:
MotivationFor many RNA molecules, the secondary structure is essential for the correct function of the RNA. Predicting RNA secondary structure from nucleotide sequences is a long-standing problem in genomics, but the prediction performance has reached a plateau over time. Traditional RNA secondary structure prediction algorithms are primarily based on thermodynamic models through free energy minimization, which imposes strong prior assumptions and is slow to run.

ResultsHere we propose a deep learning-based method, called UFold, for RNA secondary structure prediction, trained directly on annotated data without any thermodynamic assumptions. UFold improves substantially upon previous models, with approximately 10~30% improvement over traditional thermodynamic models and 14% improvement over other learning-based methods. It achieves an F1 score of 0.91 on base pair prediction accuracy on an RNA structure prediction benchmark dataset. UFold is also fast with an inference time about 160ms per sequence up to 1600bp length. We provide an online web server that implements UFold for RNA structure prediction and is made freely available.

AvailabilityAn online web server running UFold is available at https://ufold.ics.uci.edu. Code is available at https://github.com/uci-cbcl/UFold.

Contactxhx@uci.edu


title: Conformational Reorganisation of Apolipoprotein E Triggered by Phospholipid Assembly

abstract:
Apolipoprotein E (ApoE), a major determinant protein for lipid-metabolism, actively participates in lipid transport in central nervous system via high-affinity interaction with lipoprotein receptor LDLR. Prior evidences indicate that the phospholipids first need to assemble around apoE, before the protein can recognise its receptor. However, despite multiple attempts via spectroscopic and biochemical investigations, it is unclear what are the impact of lipid assembly on globular structure of apoE. Here, using a combination of all-atom and coarse-grained molecular dynamics simulations, we demonstrate that, an otherwise compact tertiary fold of monomeric apoE3 spontaneously unwraps in an aqueous phospholipid solution in two distinct stages. Interestingly, these structural reorganizations are triggered by an initial localised binding of lipid molecules to the C-terminal domain of the protein, which induce a rapid separation of C-terminal domain of apoE3 from the rest of its tertiary fold. This is followed by a slow lipid-induced inter-helix separation event within the N-terminal domain of the protein, as seen in an extensively long coarse-grained simulation. Remarkably, the resultant complex takes the shape of an  open conformation of lipid-stabilised unwrapped protein, which intriguingly coincides with an earlier proposal by small-angle X-ray scattering (SAXS) experiment. The lipid-binding activity and the lipid-induced protein conformation are found to be robust across a monomeric mutant and wild-type sequence of apoE3. The  open complex derived in coarse-grained simulation retains its structural morphology after reverse-mapping to all-atom representation. Collectively, the investigation puts forward a plausible structure of currently elusive conformationally activated state of apoE3, which is primed for recognition by lipoprotein receptor and can be exploited for eventual lipid transport.

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title: Oxylipin metabolism is controlled by mitochondrial b-oxidation during bacterial inflammation.

abstract: Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial {beta}-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin {beta}-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-{gamma}. Last, dampening oxylipin levels by {beta}-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial {beta}-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.


title: Assessing Study Reproducibility through MMRI: A Novel Approach for Large-scale High-throughput Association Studies

abstract: Magnetic Resonance Imaging (MRI) technology has been increasingly used in large-scale association studies. Reproducibility of statistically significant findings generated by MRI-based association studies, especially structural MRI (sMRI) and functional MRI (fMRI), has been recently heavily debated. However, there is still a lack of overall reproducibility assessment for MRI-based association studies. It is also crucial to elucidate the relationship between overall reproducibility and sample size in an experimental design. In this study, we proposed an overall reproducibility index for large-scale high-throughput MRI-based association studies. We performed the overall reproducibility assessments for several recent large sMRI/fMRI databases and observed satisfactory overall reproducibility. Furthermore, we performed the sample size evaluation for the purpose of achieving a desirable overall reproducibility. Additionally, we evaluated the overall reproducibility of GMV changes for UKB vs. PPMI and UKB vs. HCP. We demonstrated that both sample size and some experimental factors play important roles in the overall reproducibility for different experiments. In summary, a systematic assessment of overall reproducibility is fundamental and crucial in the current large-scale high-throughput MRI-based research.


title: Assessing Overall Reproducibility for Large-scale High-throughput MRI-based Association Studies


title: Musical Rhythm across Western Genres arises from Hierarchical Temporal Modulation Structures that match the Structures found in Infant- and Child-Directed Speech

abstract: Statistical learning by the human brain plays a core role in the development of cognitive systems like language and music. Both music and speech have structured inherent rhythms, however the acoustic sources of these rhythms are debated. Theoretically, rhythm structures in both systems may be related to a novel set of acoustic statistics embedded in the amplitude envelope, statistics originally revealed by modelling childrens nursery rhymes. Here we apply similar modelling to explore whether the amplitude modulation (AM) timescales underlying rhythm in music match those in child-directed speech (CDS). Utilising AM-driven phase hierarchy modelling previously applied to infant-directed speech (IDS), adult-directed speech (ADS) and CDS, we test whether the physical stimulus characteristics that yield speech rhythm in IDS and CDS describe rhythm in music. Two models were applied. One utilized a low-dimensional representation of the auditory signal adjusted for known mechanisms of the human cochlear, and the second utilized probabilistic amplitude demodulation, estimating the modulator (envelope) and carriers using Bayesian inference. Both models revealed a similar hierarchically-nested temporal modulation structure across Western musical genres and instruments. Core bands of AM and spectral patterning matched prior analyses of IDS and CDS, and music showed strong phase dependence between slower bands of AMs, again matching IDS and CDS. This phase dependence is critical to the perception of rhythm. Control analyses modelling other natural sounds (wind, rain, storms, rivers) did not show similar temporal modulation structures and phase dependencies. We conclude that acoustic rhythm in language and music has a shared statistical basis.


title: The Temporal Statistics of Musical Rhythm across Western Genres: An Amplitude Modulation Phase Hierarchy Model


title: The Effect of Task on Object Processing revealed by EEG decoding

abstract: Recent studies showed that task demand affects object representations in higher-level visual areas and beyond, but not so much in earlier areas. There are, however, limitations in those studies including the relatively weak manipulation of task due to the use of familiar real-life objects, the low temporal resolution in fMRI, and the emphasis on the amount and not the source of information carried by brain activations. In the current study, observers categorized images of artificial objects in one of two orthogonal dimensions, shape and texture, while their brain activity was recorded with electroencephalogram (EEG). Results showed that object processing along the texture dimension was affected by task demand starting from a relatively late time (320-370ms time window) after image onset. The findings are consistent with the view that task exerts an effect on the later phases of object processing.


title: Automated improvement of stickleback reference genome assemblies with Lep-Anchor software

abstract: We describe an integrative approach to improve contiguity and haploidy of a reference genome assembly and demonstrate its impact with practical examples. With two novel features of Lep-Anchor software and a combination of dense linkage maps, overlap detection and bridging long reads we generated an improved assembly of the nine-spined stickleback (Pungitius pungitius) reference genome. We were able to remove a significant number of haplotypic contigs, detect more genetic variation and improve the contiguity of the genome, especially that of X chromosome. However, improved scaffolding cannot correct for mosaicism of erroneously assembled contigs, demonstrated by a de novo assembly of a 1.7 Mbp inversion. Qualitatively similar gains were obtained with the genome of three-spined stickleback (Gasterosteus aculeatus). Since the utility of genome-wide sequencing data in biological research depends heavily on the quality of the reference genome, the improved and fully automated approach described here should be helpful in refining reference genome assemblies.


title: Structure of long-range direct and indirect spinocerebellar pathways as well as local spinal circuits mediating proprioception.

abstract:
Proprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways are wired. Defining the anatomy of secondary neurons in the spinal cord that integrate and relay proprioceptive and potentially cutaneous information from the periphery to the cerebellum is fundamental to understanding how proprioceptive circuits function. Here, we use genetic tools in both male and female mice to define the unique anatomical trajectories of long-range direct and indirect spinocerebellar pathways as well as local intersegmental spinal circuits. We find that Clarkes column (CC) neurons, a major contributor to the direct spinocerebellar pathway, has mossy fiber terminals that diversify extensively in the cerebellar cortex with axons terminating bilaterally, but with no significant axon collaterals within the spinal cord, medulla, or cerebellar nuclei. By contrast, we find that two of the indirect pathways, the spino-lateral reticular nucleus (spino-LRt) and spino-olivary pathways, are in part, derived from cervical Atoh1-lineage neurons, while thoracolumbar Atoh1-lineage neurons project mostly locally within the spinal cord. Notably, while cervical and thoracolumbar Atoh1-lineage neurons connect locally with motor neurons, no CC to motor neuron connections were detected. Silencing of caudal Atoh1- lineage neurons results in a subtle motor impairment consistent with a defect in local proprioceptive circuitry. Altogether, we define anatomical differences between long-range direct, indirect, and local proprioceptive subcircuits that likely mediate different components of proprioceptive-motor behaviors.

Significance StatementWe define the anatomy of long-range direct and indirect spinocerebellar pathways as well as local spinal proprioceptive circuits. We observe that mossy fiber axon terminals of Clarkes column (CC) neurons diversify proprioceptive information across granule cells in multiple lobules on both ipsilateral and contralateral sides sending no significant collaterals within the spinal cord, medulla, or cerebellar nuclei. Strikingly, we find that cervical spinal cord Atoh1-lineage neurons form mainly the indirect spino- lateral reticular nucleus and spino-olivary tracts and thoracolumbar Atoh1-lineage neurons project locally within the spinal cord while only a few Atoh1-lineage neurons form a direct spinocerebellar tract. Altogether, we define the development, anatomical projections, and some behavioral consequences of silencing spinal proprioceptive pathways.


title: Atypical genomic cortical patterning in autism with poor early language outcome

abstract:
Cortical regional identities develop through anterior-posterior (A-P) and dorsal-ventral (D-V) prenatal genomic patterning gradients. Here we find that A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) is intact in typically developing and autistic toddlers with good language outcome, but is absent in autistic toddlers with poor early language outcome. Genes driving this effect are prominent in midgestational A-P and D-V gene expression gradients and prenatal cell types driving SA and CT variation (e.g., progenitor cells versus excitatory neurons). These genes are also important for vocal learning, human-specific evolution, and prenatal co-expression networks enriched for high-penetrance autism risk genes. Autism with poor early language outcome may be linked to atypical genomic cortical patterning starting in prenatal periods and which impacts later development of regional functional specialization and circuit formation.

One Sentence SummaryGenomic patterning of the cortex is atypical in autistic toddlers with poor early language outcome.


title: The relationship between hippocampal-dependent task performance and hippocampal grey matter myelination and iron content

abstract: Individual differences in scene imagination, autobiographical memory recall, future thinking and spatial navigation have long been linked with hippocampal structure in healthy people, although evidence for such relationships is, in fact, mixed. Extant studies have predominantly concentrated on hippocampal volume. However, it is now possible to use quantitative neuroimaging techniques to model different properties of tissue microstructure in vivo such as myelination and iron. Previous work has linked such measures with cognitive task performance, particularly in older adults. Here we investigated whether performance on scene imagination, autobiographical memory, future thinking and spatial navigation tasks was associated with hippocampal grey matter myelination or iron content in young, healthy adult participants. MRI data were collected using a multi-parameter mapping protocol (0.8mm isotropic voxels) from a large sample of 217 people with widely-varying cognitive task scores. We found little evidence that hippocampal grey matter myelination or iron content was related to task performance. This was the case using different analysis methods (voxel-based quantification, partial correlations), when whole brain, hippocampal regions of interest, and posterior:anterior hippocampal ratios were examined, and across different participant sub-groups (divided by gender, task performance). Variations in hippocampal grey matter myelin and iron levels may not, therefore, help to explain individual differences in performance on hippocampal-dependent tasks, at least in young, healthy individuals.


title: A toolkit for studying Varroa genomics and transcriptomics: Preservation, extraction, and sequencing library preparation

abstract:
BackgroundThe honey bee parasite, Varroa destructor, is a leading cause of honey bee population declines. In addition to being an obligate ectoparasitic mite, Varroa carries several viruses that infect honey bees and act as the proximal cause of colony collapses. Nevertheless, until recently, studies of Varroa have been limited by the paucity of genomic tools. Lab- and field-based methods exploiting such methods are still nascent. This study developed a set of methods for preserving Varroa DNA and RNA from the field to the lab and processing them into sequencing libraries. We performed preservation experiments in which Varroa mites were immersed in TRIzol, RNAlater, and absolute ethanol for preservation periods up to 21 days post-treatment to assess DNA and RNA integrity.

ResultsFor both DNA and RNA, mites preserved in TRIzol and RNAlater at room temperature degraded within 10 days post-treatment. Mites preserved in ethanol at room temperature and 4{degrees}C remained intact through 21 days. Varroa mite DNA and RNA libraries were created and sequenced for ethanol preserved samples, 15 and 21 days post-treatment. All DNA sequences mapped to the V. destructor genome at above 95% on average, while RNA sequences mapped to V. destructor, but also sometimes to high levels of the deformed-wing virus and to various organisms.

ConclusionEthanolic preservation of field-collected mites is inexpensive and simple, and allows them to be shipped and processed successfully in the lab for a wide variety of sequencing applications. It appears to preserve RNA from both Varroa and at least some of the viruses it vectors.


title: Fitting side-chain NMR relaxation data using molecular simulations

abstract: Proteins display a wealth of dynamical motions that can be probed using both experiments and simulations. We present an approach to integrate side chain NMR relaxation measurements with molecular dynamics simulations to study the structure and dynamics of these motions. The approach, which we term ABSURDer (Average Block Selection Using Relaxation Data with Entropy Restraints) can be used to find a set of trajectories that are in agreement with relaxation measurements. We apply the method to deuterium relaxation measurements in T4 lysozyme, and show how it can be used to integrate the accuracy of the NMR measurements with the molecular models of protein dynamics afforded by the simulations. We show how fitting of dynamic quantities leads to improved agreement with static properties, and highlight areas needed for further improvements of the approach.


title: Infection and transmission of SARS-CoV-2 depends on heparan sulfate proteoglycans

abstract: The current pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans, and transmitted the virus to ACE2-positive cells. Moreover, human primary nasal cells were infected by SARS-CoV-2 and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.


title: Seeding of outbreaks of COVID-19 by contaminated fresh and frozen food

abstract: The authors have withdrawn this manuscript because some aspects of the published work were completed prior to regulatory approval. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.


title: Mechanism of negative membrane curvature generationby I-BAR domains

abstract: The membrane sculpting ability of BAR domains has been attributed to the intrinsic curvature of their banana-shaped dimeric structure. However, there is often a mismatch between this intrinsic curvature and the diameter of the membrane tubules generated. I-BAR domains have been especially mysterious: they are almost flat but generate high negative membrane curvature. Here, we use atomistic implicit-solvent computer modeling to show that the membrane bending of the IRSP53 I-BAR domain is dictated by its higher oligomeric structure, whose curvature is completely unrelated to the intrinsic curvature of the dimer. Two other I-BARs gave similar results, whereas a flat F-BAR sheet developed a concave membrane binding interface, consistent with its observed positive membrane curvature generation. Laterally interacting helical spirals of I-BAR dimers on tube interiors are stable and have an enhanced binding energy that is sufficient for membrane bending to experimentally observed tubule diameters at a reasonable surface density.


title: Task-Dependent Electrophysiological Signatures ofTemporal Discrimination

abstract: Studies investigating the neural mechanisms of time perception often measure brain activity while participants perform a temporal task. However, several of these studies are based exclusively on tasks in which time is relevant, making it hard to dissociate activity related to decisions about time from other task-related patterns. In the present study, human participants performed a temporal or color discrimination task of visual stimuli. Participants were informed which magnitude they would have to judge before or after presenting the two stimuli (S1 and S2) in different blocks. Our behavioral results showed, as expected, that performance was better when participants knew beforehand which magnitude they would judge. Electrophysiological data (EEG) was analyzed using Linear Discriminant Contrasts (LDC) and a Representational Similarity Analysis (RSA) approach to investigate whether and when information about time and color was encoded. During the presentation of S1, we did not find consistent differences in EEG activity as a function of the task. On the other hand, during S2, we found that temporal and color information was encoded in a task-relevant manner. Taken together, our results suggest that task goals strongly modulate decision-related information in EEG activity.


title: Post-interval EEG activity is related to task-goals in temporal discrimination


title: Nucleotide substitutions during speciation may explain substitution rate variation

abstract: Although molecular mechanisms associated with the generation of mutations are highly conserved across taxa, there is widespread variation in mutation rates between evolutionary lineages. When phylogenies are reconstructed based on nucleotide sequences, such variation is typically accounted for by the assumption of a relaxed molecular clock, which is just a statistical distribution of mutation rates without much underlying biological mechanism. Here, we propose that variation in accumulated mutations may be partly explained by an elevated mutation rate during speciation. Using simulations, we show how shifting mutations from branches to speciation events impacts inference of branching times in phylogenetic reconstruction. Furthermore, the resulting nucleotide alignments are better described by a relaxed than by a strict molecular clock. Thus, elevated mutation rates during speciation potentially explain part of the variation in substitution rates that is observed across the tree of life.


title: Multigenerational downregulation of insulin/IGF-1 signalling in adulthood improves lineage survival, reproduction, and fitness in C. elegans

abstract: Adulthood-only downregulation of insulin/IGF-1 signalling (IIS), an evolutionarily conserved pathway regulating resource allocation between somatic maintenance and reproduction, increases lifespan without fecundity cost in the nematode, Caenorhabditis elegans. However, long-term multi- generational effects of reduced IIS remain unexplored, and it has been proposed that inter- and trans-generational effects of reduced IIS can have adverse effects on offspring fitness. To test this hypothesis, we ran a mutation accumulation (MA) experiment and downregulated IIS in half of the 400 MA lines by silencing daf-2 gene expression using RNA interference (RNAi) across 40 generations. Contrary to the prediction, adulthood-only daf-2 RNAi reduced extinction of MA lines both under UV-induced and spontaneous mutation accumulation suggesting net benefit of multi-generational downregulation of IIS. Fitness of the surviving UV-induced MA lines was higher under daf-2 RNAi. Reduced IIS increased inter-generational F1 offspring fitness under UV stress but had no quantifiable trans-generational effects. Functional hrde-1 was required for both the benefits of multi-generational daf-2 RNAi and for inter- generational effects. Overall, we did not find any life-history costs of multi- generational reduction of IIS and the benefits became more apparent under stress. Our results thus suggest that multi-generational adulthood-only reduction of IIS via daf-2 RNAi has net beneficial effect on fitness. We discuss the challenges these findings pose for the evolutionary theory of ageing, suggest possible solutions and how future research may address them.


title: A toolkit to generate inducible and interconvertible Drosophila overexpression transgenes

abstract: The existence of three independent binary systems for conditional gene expression (Gal4/UAS; LexA/LexAop; QF/QUAST) has greatly expanded versatile genetic analyses in the fruit fly Drosophila melanogaster; however, the experimental application of these tools is limited by the need to generate multiple collections of non-interchangeable transgenic fly strains for each inducible gene expression system. To address this practical limitation, we developed a modular vector that contains the regulatory elements from all three binary systems, enabling Gal4-, LexA- or QF-dependent expression of transgenes. Our methods also incorporate DNA elements that facilitate independent site-specific recombination and elimination of regulatory UAS, LexAop or QUAST modules with spatial and temporal control, thus offering unprecedented possibilities and logistical advantages for in vivo genetic modulation and efficient interconversion of overexpression transgenic fly lines.


title: A computationally designed fluorescent biosensor for D-serine

abstract: Solute-binding proteins (SBPs) have evolved to balance the demands of ligand affinity, thermostability and conformational change to accomplish diverse functions in small molecule transport, sensing and chemotaxis. Although the ligand-induced conformational changes that occur in SBPs make them useful components in biosensors, they are challenging targets for protein engineering and design. Here we have engineered a D-alanine-specific SBP into a fluorescent biosensor with specificity for the signaling molecule D-serine (D-serFS). This was achieved through binding site and remote mutations that improved affinity (KD = 6.7 {+/-} 0.5 M), specificity (40-fold increase vs. glycine), thermostability (Tm = 79 {degrees}C) and dynamic range (~14%). This sensor allowed measurement of physiologically relevant changes in D-serine concentration using two-photon excitation fluorescence microscopy in rat brain hippocampal slices. This work illustrates the functional trade-offs between protein dynamics, ligand affinity and thermostability, and how these must be balanced to achieve desirable activities in the engineering of complex, dynamic proteins.


title: Safety and data quality of EEG recorded simultaneously with multi-band fMRI

abstract:
PurposeSimultaneously recorded electroencephalography and functional magnetic resonance imaging (EEG-fMRI) is highly informative yet technically challenging. Until recently, there has been little information about EEG data quality and safety when used with newer multi-band (MB) fMRI sequences. Here, we measure the relative heating of a MB protocol compared with a standard single-band (SB) protocol considered to be safe. We also evaluated EEG quality recorded concurrently with the MB protocol on humans.

Materials and MethodsWe compared radiofrequency (RF)-related heating at multiple electrodes and magnetic field magnitude, B1+RMS, of a MB fMRI sequence with whole-brain coverage (TR = 440 ms, MB factor = 4) against a previously recommended, safe SB sequence using a phantom outfitted with a 64-channel EEG cap. Next, 9 human subjects underwent eyes-closed resting state EEG-fMRI using the MB sequence. Additionally, in three of the subjects resting state EEG was recorded also during the SB sequence and in an fMRI-free condition to directly compare EEG data quality across scanning conditions. EEG data quality was assessed by the ability to remove gradient and cardioballistic artifacts along with a clean spectrogram.

ResultsThe heating induced by the MB sequence was lower than that of the SB sequence by a factor of 0.73 {+/-} 0.38. This is consistent with an expected heating ratio of 0.64, calculated from the square of the ratio of B1+RMS values of the sequences. In the resting state EEG data, gradient and cardioballistic artifacts were successfully removed using traditional template subtraction. All subjects showed an individual alpha peak in the spectrogram with a posterior topography characteristic of eyes-closed EEG. The success of artifact rejection for the MB sequence was comparable to that in traditional SB sequences.

ConclusionsOur study shows that B1+RMS is a useful indication of the relative heating of fMRI protocols. This observation indicates that simultaneous EEG-fMRI recordings using this MB sequence can be safe in terms of RF-related heating, and that EEG data recorded using this sequence is of acceptable quality after traditional artifact removal techniques.


title: Tau, XMAP215/Msps and Eb1 co-operate interdependently to regulate microtubule polymerisation and bundle formation in axons

abstract:
The formation and maintenance of microtubules requires their polymerisation, but little is known about how this polymerisation is regulated in cells. Focussing on the essential microtubule bundles in axons of Drosophila and Xenopus neurons, we show that the plus-end scaffold Eb1, the polymerase XMAP215/Msps and the lattice-binder Tau co-operate interdependently to promote microtubule polymerisation and bundle organisation during axon development and maintenance. Eb1 and XMAP215/Msps promote each others localisation at polymerising microtubule plus-ends. Tau outcompetes Eb1-binding along microtubule lattices, thus preventing depletion of Eb1 tip pools. The three factors genetically interact and show shared mutant phenotypes: reductions in axon growth, comet size, comet number and comet velocity, as well as prominent deterioration of parallel microtubule bundles into disorganised curled conformations. This microtubule curling is caused by Eb1 plus-end depletion which impairs spectraplakin-mediated guidance of extending microtubules into parallel bundles. Our demonstration that Eb1, XMAP215/Msps and Tau co-operate during the regulation of microtubule polymerisation and bundle organisation, offers new conceptual explanations for developmental and degenerative axon pathologies and how to treat them.

Summary statementEb1, XMAP215 and tau co-operate interdependently in axons to promote the polymerisation of microtubules and their organisation into the parallel bundles required for axonal transport.


title: Classification of Sex and Alzheimers Disease via Brain Imaging-Based Deep Learning on 85,721 Samples

abstract: Beyond detecting brain lesions or tumors, comparatively little success has been attained in identifying brain disorders such as Alzheimers disease (AD), based on magnetic resonance imaging (MRI). Many machine learning algorithms to detect AD have been trained using limited training data, meaning they often generalize poorly when applied to scans from previously unseen populations. Here we aimed to build a practical brain imaging-based AD diagnostic classifier using deep learning/transfer learning on dataset of unprecedented size and diversity. We pooled MRI data from more than 217 sites/scanners to constitute the largest brain MRI sample to date (85,721 scans from 50,876 participants). Next, we applied a state-of-the-art deep convolutional neural network, Inception-ResNet-V2, to build a sex classifier with high generalization capability. The sex classifier achieved 94.9% accuracy and served as a base model in transfer learning for the objective diagnosis of AD. After transfer learning, the model fine-tuned for AD classification achieved 91.3% accuracy in leave-sites-out cross-validation on the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset and 94.2%/87.9% accuracy for direct tests on two unseen independent datasets (AIBL/OASIS). When this AD classifier was tested on brain images from unseen mild cognitive impairment (MCI) patients, MCI patients who finally converted to AD were 3 times more likely to be predicted as AD than MCI patients who did not convert (65.2% vs 20.6%). Predicted scores from the AD classifier showed significant correlations with illness severity. In sum, the proposed AD classifier could offer a medical-grade biomarker that could be integrated into AD diagnostic practice. Our trained model, code and preprocessed data are freely available to the research community.


title: A Practical Alzheimer Disease Classifier via Brain Imaging-Based Deep Learning on 85,721 Samples


title: MTCL2 promotes asymmetric microtubule organizationby crosslinking microtubules on the Golgi membrane

abstract: The Golgi complex plays an active role in organizing asymmetric microtubule arrays essential for polarized vesicle transport. The coiled-coil protein MTCL1 stabilizes microtubules nucleated from the Golgi membrane. Here, we report an MTCL1 paralog, MTCL2, which preferentially acts on the perinuclear microtubules accumulated around the Golgi. MTCL2 associates with the Golgi membrane through the N-terminal coiled- coil region and directly binds microtubules through the conserved C-terminal domain without promoting microtubule stabilization. Knockdown of MTCL2 significantly impaired microtubule accumulation around the Golgi as well as the compactness of the Golgi ribbon assembly structure. Given that MTCL2 forms parallel oligomers through homo-interaction of the central coiled-coil motifs, our results indicate that MTCL2 promotes asymmetric microtubule organization by crosslinking microtubules on the Golgi membrane. Results of in vitro wound healing assays further suggest that this function of MTCL2 enables integration of the centrosomal and Golgi-associated microtubules on the Golgi membrane, supporting directional migration. Additionally, the results demonstrated the involvement of CLASPs and giantin in mediating the Golgi association of MTCL2.


title: The genetic architecture and genomic context of glyphosate resistance in Amaranthus tuberculatus

abstract: Much of what we know about the genetic basis of herbicide resistance has come from detailed investigations of monogenic adaptation at known target-sites, despite the increasingly recognized importance of polygenic resistance. Little work has been done to characterize the broader genomic basis of herbicide resistance, including the number and distribution of genes involved, their effect sizes, allele frequencies, and signatures of selection. In this work, we implemented genome-wide association (GWA) and population genomic approaches to examine the genetic architecture of glyphosate resistance in the problematic agricultural weed, Amaranthus tuberculatus. A GWA was able to correctly identify the gene targeted by glyphosate, but when we statistically controlled for two target-site genetic mechanisms, we found an additional 250 genes across all 16 chromosomes associated with non-target site resistance (NTSR). The encoded proteins had functions that have been linked to non-target site resistance (NTSR), the most significant of which is response to chemicals, but also showed pleiotropic roles in reproduction and growth. The architecture of NTSR was enriched for large effect sizes and low allele frequencies, suggesting the role of pleiotropic constraints on its evolution. The enrichment of rare alleles also suggested that the genetic architecture of NTSR may be population-specific and heterogeneous across the range. Despite their rarity, we found signals of recent positive selection on NTSR-alleles by both window- and haplotype-based statistics, and an enrichment of amino-acid changing variants. In our samples, genome-wide SNPs explain a comparable amount of the total variation in glyphosate resistance to monogenic mechanisms, even in a collection of individuals where 80% of resistant individuals have large-effect TSR mutations, indicating an underappreciated polygenic contribution to the evolution of herbicide resistance in weed populations.


title: TMS bursts can modulate local and networks oscillations during lower-limb movement in elderly subjects

abstract:
IntroductionLower-limb motor functions involve processing information via both motor and cognitive control networks. Measuring oscillations is a key element in communication within and between cortical networks during high order motor functions. Increased midfrontal theta oscillations are related to improved lower-limb motor performances in patients with movement disorders. Non-invasive neuromodulation approaches have not been explored extensively to understand the oscillatory mechanism of lower-limb motor functions. This study aims to examine the effects of repetitive transcranial magnetic stimulation (rTMS) on local and network EEG oscillations in healthy elderly subjects.

MethodsEleven healthy elder subjects (67-73 years) were recruited via advertisements, and underwent both active and sham stimulation procedures in a random, counterbalanced design. TMS bursts ({theta}-TMS; 4 pulses/sec) were applied over the midfrontal lead (vertex) before a GO-Cue pedaling task, and signals were analyzed using time-frequency methods.

ResultsTMS bursts increase the theta activity in the local (p=0.02), as well as the associated network during the lower-limb pedaling task (p = 0.02). Furthermore, after task-related TMS burst sessions, increased resting-state alpha activity was observed in the midfrontal region (p= 0.01).

ConclusionOur study suggests the ability of midfrontal TMS bursts to directly modulate local and network oscillations in a frequency manner during lower-limb motor task. TMS burst-induced modulation may provide insights into the functional roles of oscillatory activity during lower-limb movement in normal and disease conditions.