title: Zinc Sulfide-Based Hybrid Exosome-Coated Nanoplatform for Targeted Treatment of Glioblastoma in an Orthotopic Mouse Glioblastoma Model

abstract: Core-hybrid shell hydroxychloroquine (HCQ) loaded zinc sulfide (ZnS) nanoparticles were synthesized, characterized and evaluated for the treatment of glioblastoma cells in vitro and in vivo. These particles, denoted as HCQ@ZnS@exo@iRGD, consist of hollow ZnS nanoparticles loading with the autophagic inhibitor of hydroxychloroquine and covered by a hybrid shell containing exosomes (exo) and phosphatidylserine derived pH- and redox-responsive pegylated iRGD peptide, a gliomablastoma-homing and penetrating peptide. The hybrid exosomes enable HCQ@ZnS with good permeability across the blood-brain barrier and targeting ability to glioblastoma cells in orthotopic mouse glioblastoma model. ZnS acts as a photosensitizer for reactive oxygen species (ROS) production to inflict damage to organelles within glioblastoma cells. Hydroxychloroquine inhibits autophagic flux, which can subsequently lead to the accumulation of impaired organelles caused by the ROS. As a result, substantial selective damage to glioblastoma cells was realized owing to the hybrid exosomes guiding the anti-tumour effects of hydroxychloroquine and ZnS under light irradiation. The results provide evidence for the utility of HCQ@ZnS@exo@iRGD as a therapeutic strategy for glioblastoma.

category: pharmacology and toxicology


title: Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

abstract:
Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntingtons disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration remain poorly understood. Herein, we investigated the ultrastructural properties and protein composition of Htt cytoplasmic and nuclear inclusions in mammalian cells and primary neurons overexpressing mutant exon1 of the Htt protein. Our findings provide novel insight into the ultrastructural properties of cytoplasmic and nuclear Htt inclusions and their mechanisms of formation. We show that Htt inclusion formation and maturation are complex processes that, although initially driven by polyQ-dependent Htt aggregation, also involve 1) polyQ and PRD domain-dependent sequestration of lipids and cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways; 2) recruitment and accumulation of remodeled or dysfunctional membranous organelles, and 3) impairment of the protein quality control and degradation machinery. We also show that nuclear and cytoplasmic Htt inclusions exhibit distinct biochemical compositions and ultrastructural properties, suggesting different mechanisms of aggregation and toxicity.

Graphical Abstract

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org.highwire.dtl.DTLVardef@295056org.highwire.dtl.DTLVardef@594664org.highwire.dtl.DTLVardef@11c5384org.highwire.dtl.DTLVardef@af0e0a_HPS_FORMAT_FIGEXP  M_FIG C_FIG Schematic depictions and original electron micrographs of cytoplasmic inclusions formed by native (tag-free) mutant Huntingtin exon1 proteins (Httex1 72Q, left) and the corresponding GFP fusion protein (Httex1 72Q-GFP, right).

category: neuroscience


title: Reversible fronto-occipitotemporal signaling complements task encoding and switching under ambiguous cues

abstract: Adaptation to changing environments involves the appropriate extraction of environmental information to achieve a behavioral goal. It remains unclear how behavioral flexibility is guided under situations where the relevant behavior is ambiguous. Using functional brain mapping of machine-learning decoders and directional functional connectivity, we show that brain-wide reversible neural signaling underpins task encoding and behavioral flexibility in ambiguously changing environments. When relevant behavior is cued ambiguously during behavioral shifting, neural coding is attenuated in distributed cortical regions, but top-down signals from the prefrontal cortex complement the coding. When behavioral shifting is cued more explicitly, modality-specialized occipitotemporal regions implement distinct neural coding about relevant behavior, and bottom-up signals from the occipitotemporal region to the prefrontal cortex supplement the behavioral shift. These results suggest that our adaptation to an ever-changing world is orchestrated by the alternation of top-down and bottom-up signaling in the fronto-occipitotemporal circuit depending on the availability of environmental information.


title: A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity Upon Viral Infection and Advanced Age

abstract: Streptococcus pneumoniae (pneumococcus) resides asymptomatically in the nasopharynx but can progress from benign colonizer to lethal pulmonary or systemic pathogen. Both viral infection and aging are risk factors for serious pneumococcal infections. Previous work established a murine model that featured the movement of pneumococcus from the nasopharynx to the lung upon nasopharyngeal inoculation with influenza A virus (IAV) but did not fully recapitulate the severe disease associated with human co-infection. We built upon this model by first establishing pneumococcal nasopharyngeal colonization, then inoculating both the nasopharynx and lungs with IAV. In young (2 months) mice, co-infection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, disease and mortality in a fraction of mice. In old mice (20-22 months), co-infection resulted in earlier and more severe disease. Aging was not associated with greater bacterial burdens but rather with more rapid pulmonary inflammation and damage. Both aging and IAV infection led to inefficient bacterial killing by neutrophils ex vivo. Conversely, aging and pneumococcal colonization also blunted IFN- production and increased pulmonary IAV burden. Thus, in this multistep model, IAV promotes pneumococcal pathogenicity by modifying bacterial behavior in the nasopharynx, diminishing neutrophil function, and enhancing bacterial growth in the lung, while pneumococci increase IAV burden likely by compromising a key antiviral response. Thus, this model provides a means to elucidate factors, such as age and co-infection, that promote the evolution of S. pneumoniae from asymptomatic colonizer to invasive pathogen, as well as to investigate consequences of this transition on antiviral defense.

category: microbiology


title: A persistent giant algal virus, with a unique morphology, encodes an unprecedented number of genes involved in energy metabolism

abstract:
Viruses have long been viewed as entities possessing extremely limited metabolic capacities. Over the last decade, however, this view has been challenged, as metabolic genes have been identified in viruses possessing large genomes and virions--the synthesis of which is energetically demanding. Here, we unveil peculiar phenotypic and genomic features of Prymnesium kappa virus RF01 (PkV RF01), a giant virus of the Mimiviridae family. We found that this virus encodes an unprecedented number of proteins involved in energy metabolism, such as all four succinate dehydrogenase (SDH) subunits (A-D) as well as key enzymes in the {beta}-oxidation pathway. The SDHA gene was transcribed upon infection, indicating that the viral SDH is actively used by the virus-- potentially to modulate its hosts energy metabolism. We detected orthologous SDHA and SDHB genes in numerous genome fragments from uncultivated marine Mimiviridae viruses, which suggests that the viral SDH is widespread in oceans. PkV RF01 was less virulent compared with other cultured prymnesioviruses, a phenomenon possibly linked to the metabolic capacity of this virus and suggestive of relatively long co-evolution with its hosts. It also has a unique morphology, compared to other characterized viruses in the Mimiviridae family. Finally, we found that PkV RF01 is the only alga-infecting Mimiviridae virus encoding two aminoacyl-tRNA synthetases and enzymes corresponding to an entire base-excision repair pathway, as seen in heterotroph-infecting Mimiviridae. These Mimiviridae encoded-enzymes were found to be monophyletic and branching at the root of the eukaryotic tree of life. This placement suggests that the last common ancestor of Mimiviridae was endowed with a large, complex genome prior to the divergence of known extant eukaryotes.

ImportanceViruses on Earth are tremendously diverse in terms of morphology, functionality, and genomic composition. Over the last decade, the conceptual gap separating viruses and cellular life has tightened because of the detection of metabolic genes in viral genomes that express complex virus phenotypes upon infection. Here, we describe Prymnesium kappa virus RF01, a large alga-infecting virus with a unique morphology, an atypical infection profile, and an unprecedented number of genes involved in energy metabolism (such as the tricarboxylic (TCA) cycle and the {beta}-oxidation pathway). Moreover, we show that the gene corresponding to one of these enzymes (the succinate dehydrogenase subunit A) is transcribed during infection and is widespread among marine viruses. This discovery provides evidence that a virus has the potential to actively regulate energy metabolism with its own gene.


title: Inference of long-range cell-cell mechanical communication from ECM remodeling fluctuations

abstract: Cells sense, manipulate and respond to their mechanical microenvironment in a plethora of physiological processes, yet the understanding of how cells transmit, receive and interpret environmental cues to communicate with distant cells is severely limited due to lack of tools to quantitatively infer the complex tangle of dynamic cell-cell interactions in complicated environments. We present a computational method to systematically infer and quantify long-range mechanical cell-cell communication through the extracellular matrix (cell-ECM-cell communication) by correlating ECM remodeling fluctuations in between communicating cells and demonstrating that these fluctuations contain sufficient information to define unique signatures that robustly distinguish between different pairs of communicating cells. We demonstrate our method with finite element simulations and live 3D imaging of fibroblasts and cancer cells embedded in fibrin gels. While previous studies relayed on the formation of a visible fibrous  band extending between cells to inform on mechanical communication, our method detected mechanical propagation even in cases where visible bands never formed. We revealed that while contractility is required, band formation is not necessary, for cell-ECM-cell communication, and that mechanical signals propagate from one cell to another even upon massive reduction in their contractility. Our method sets the stage to measure the fundamental aspects of intercellular long-range mechanical communication in physiological contexts and may provide a new functional readout for high content 3D image-based screening. The ability to infer cell-ECM-cell communication using standard confocal microscopy holds the promise for wide use and democratizing the method.

category: cell biology


title: Nanopore sequencing reveals full-length Tropomyosin 1 isoforms and their regulation by RNA binding proteins during rat heart development

abstract: Alternative splicing (AS) contributes to the diversity of the proteome by producing multiple isoforms from a single gene. Although short-read RNA sequencing methods have been the gold standard for determining AS patterns of genes, they have a difficulty in defining full length mRNA isoforms assembled using different exon combinations. Tropomyosin 1 (TPM1) is an actin binding protein required for cytoskeletal functions in non-muscle cells and for contraction in muscle cells. Tpm1 undergoes AS regulation to generate muscle versus non-muscle TPM1 protein isoforms with distinct physiological functions. It is unclear which full length Tpm1 isoforms are produced via AS and how they are regulated during heart development. To address these, we utilized nanopore long-read cDNA sequencing without gene-specific PCR amplification. In rat hearts, we identified full length Tpm1 isoforms composed of distinct exons with specific exon linkages. We showed that Tpm1 undergoes AS transitions during embryonic heart development such that muscle-specific exons are connected together generating predominantly muscle specific Tpm1 isoforms in adult hearts. We found that the RNA binding protein RBFOX2 controls AS of rat Tpm1 exon 6a, which is important for cooperative actin binding. Furthermore, RBFOX2 regulates Tpm1 AS of exon 6a antagonistically to the RNA binding protein PTBP1. In sum, we defined full length Tpm1 isoforms with different exon combinations that are tightly regulated during cardiac development and provided insights into regulation of Tpm1 AS by RNA binding proteins. Our results demonstrate that nanopore sequencing is an excellent tool to determine fulllength AS variants of muscle enriched genes.

category: molecular biology


title: Targeted downregulation of estradiol binding Na+/H+ exchanger nhx-2, mimics calorie restriction, extends reproductive longevity and ameliorates effects associated with alpha synuclein aggregation in C. elegans

abstract:
Setting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to multiple disorders including neurodegenerative diseases, cardiovascular ailments and bone disorders amongst others. The present study, employing transgenic C. elegans that expresses  human alpha synuclein, endeavors to decipher the association of reproductive senescence with age-associated neurodegenerative diseases and behavioral ageing, under normal conditions and after being probed with estradiol. We carried out RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects. These studies led us to functional characterization of the Na+/H+ exchanger; nhx-2, expressed exclusively in gut. We found that RNAi of nhx-2 not only ameliorates the effects associated with alpha-Synuclein aggregation, but it also attunes effects related to behavioral aging including that of reproductive health-span and neuroprotection via mimicking dietary restriction, as it alters food absorption from the gut. We further elucidated that these effects are Sir-2.1 driven as nhx-2 knock out did not delay reproductive senescence in knock down condition of sir-2.1. To substantiate our findings, we performed whole transcriptome analysis in nhx-2 mutant strain. Our data revealed differential expression of 61 out of 62 hallmark genes of CR described by GenDR, in knock out condition of nhx-2. As estradiol plays a central role in both reproductive health as well as neuronal health, we subjected worms to exogenous estradiol treatment and observed that it led to elevated levels of nhx-2. Studies on structural binding analysis demonstrated significant binding potential of estradiol receptor NHR-14 with nhx-2 gene and ChIP analysis revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3). These studies identify nhx-2 as an important modulator that extends reproductive longevity and ameliorates effects associated with alpha synuclein aggregation in C elegans.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/229344v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@917377org.highwire.dtl.DTLVardef@133a07dorg.highwire.dtl.DTLVardef@6d6f28org.highwire.dtl.DTLVardef@9cde9a_HPS_FORMAT_FIGEXP  M_FIG C_FIG HIGHLIGHTSO_LISilencing of sodium proton antiporter nhx-2 affords neuroprotection and ameliorates effects associated with alpha-Synuclein aggregation via mimicking dietary restriction in C. elegans.
C_LIO_LIExogenous 17-{beta}-Estradiol treatment induces the expression of nhx-2, through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3).
C_LIO_LIEffects associated with nhx-2, including prolonged reproductive span and neuroprotective effects, are SIR-2.1 driven.
C_LIO_LInhx-2 silencing decreases alpha-Synuclein aggregation, however; estradiol mediated overexpression above the endogenous levels, does not amend the aggregation any further.
C_LI


title: Dynamics of nonlinguistic statistical learning: From neural entrainment to the emergence of explicit knowledge

abstract: Humans are highly attuned to patterns in the environment. This ability to detect environmental patterns, referred to as statistical learning, plays a key role in many diverse aspects of cognition. However, the spatiotemporal neural mechanisms underlying implicit statistical learning, and how these mechanisms may relate or give rise to explicit learning, remain poorly understood. In the present study, we investigated these different aspects of statistical learning by using an auditory nonlinguistic statistical learning paradigm combined with magnetoencephalography. Twenty-four healthy volunteers were exposed to structured and random tone sequences, and statistical learning was quantified by neural entrainment. Already early during exposure, participants showed strong entrainment to the embedded tone patterns. A significant increase in entrainment over exposure was detected only in the structured condition, reflecting the trajectory of learning. While source reconstruction revealed a wide range of brain areas involved in this process, entrainment in areas around the left pre-central gyrus as well as right temporo-frontal areas significantly predicted behavioral performance. Sensor level results confirmed this relationship between neural entrainment and subsequent explicit knowledge. These results give insights into the dynamic relation between neural entrainment and explicit learning of triplet structures, suggesting that these two aspects are systematically related yet dissociable. Neural entrainment reflects robust, implicit learning of underlying patterns, whereas the emergence of explicit knowledge, likely built on the implicit encoding of structure, varies across individuals and may depend on factors such as sufficient exposure time and attention.


title: Direct Antimicrobial Resistance Prediction from clinical MALDI-TOF mass spectra using Machine Learning

abstract: Early administration of effective antimicrobial treatments is critical for the outcome of infections. Antimicrobial resistance testing enables the selection of optimal antibiotic treatments, but current culture-based techniques take up to 72 hours. We have developed a novel machine learning approach to predict antimicrobial resistance directly from MALDI-TOF mass spectra profiles of clinical samples. We trained calibrated classifiers on a newly-created publicly available database of mass spectra profiles from clinically most relevant isolates with linked antimicrobial susceptibility phenotypes. The dataset combines more than 300,000 mass spectra with more than 750,000 antimicrobial resistance phenotypes from four medical institutions. Validation against a panel of clinically important pathogens, including Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae, resulting in AUROC values of 0.8, 0.74, and 0.74 respectively, demonstrated the potential of using machine learning to substantially accelerate antimicrobial resistance determination and change of clinical management. Furthermore, a retrospective clinical case study found that implementation of this approach would have resulted in a beneficial change in the clinical treatment in 88% (8/9) of cases. MALDI-TOF mass spectra based machine learning may thus be an important new tool for antibiotic stewardship.


title: Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation

abstract: In meiosis, DNA double strand break (DSB) formation by Spo11 initiates recombination and enables chromosome segregation. Numerous factors are required for Spo11 activity, and couple the DSB machinery to the development of a meiosis-specific ?axis-tethered loop? chromosome organization. Through in vitro reconstitution and budding yeast genetics we here provide architectural insight into the DSB machinery by focussing on a foundational DSB factor, Mer2. We characterise the interaction of Mer2 with the histone reader Spp1, and show that Mer2 directly associates to nucleosomes, likely highlighting a contribution of Mer2 to tethering DSB factors to chromatin. We reveal the biochemical basis of Mer2 association with Hop1, a HORMA domain-containing chromosomal axis factor. Finally, we identify a conserved region within Mer2 crucial for DSB activity, and show that this region of Mer2 establishes an interaction with the DSB factor Mre11. In combination with previous work, we establish Mer2 as a keystone of the DSB machinery by bridging key protein complexes involved in the initiation of meiotic recombination.

category: biochemistry


title: singlecellVR: interactive visualization of single-cell data in virtual reality

abstract: Single-cell assays have transformed our ability to model heterogeneity within cell populations. As these assays have advanced in their ability to measure various aspects of molecular processes in cells, computational methods to analyze and meaningfully visualize such data have required matched innovation. Independently, Virtual Reality (VR) has recently emerged as a powerful technology to dynamically explore complex data and shows promise for adaptation to challenges in single-cell data visualization. However, adopting VR for single-cell data visualization has thus far been hindered by expensive prerequisite hardware or advanced data preprocessing skills. To address current shortcomings, we present singlecellVR, a user-friendly web application for visualizing single-cell data, designed for cheap and easily available virtual reality hardware (e.g., Google Cardboard, [~]$10). singlecellVR can visualize data from a variety of sequencing-based technologies including transcriptomic, epigenomic, and proteomic data as well as combinations thereof. Analysis modalities supported include approaches to clustering as well as trajectory inference and visualization of dynamical changes discovered through modelling RNA velocity. We provide a companion software package, scvr to streamline data conversion from the most widely-adopted single-cell analysis tools as well as a growing database of pre-analyzed datasets to which users can contribute.

category: genomics


title: RIP140 inhibits glycolysis-dependent proliferation of breast cancer cells by regulating GLUT3 expression through transcriptional crosstalk between hypoxia induced factor and p53

abstract: Cancer cells with uncontrolled proliferation preferentially depend on glycolysis to grow, even in the presence of oxygen. The transcriptional co-regulator RIP140 represses the activity of transcription factors that drive cell proliferation and metabolism and plays a role in mammary tumorigenesis. Here we use cell proliferation and metabolic assays to demonstrate that RIP140-deficiency causes a glycolysis-dependent increase in breast tumor growth. We further demonstrate that RIP140 reduces the transcription of the glucose transporter GLUT3 gene, by inhibiting the transcriptional activity of hypoxia inducible factor HIF-2 in cooperation with p53. Interestingly, RIP140 expression was significantly associated with good prognosis only for breast cancer patients with tumors expressing low GLUT3, low HIF-2 and high p53, thus confirming the mechanism of RIP140 anti-tumor activity provided by our experimental data. Overall, our work establishes RIP140 as a critical modulator of the p53/HIF cross-talk to inhibit breast cancer cell glycolysis and proliferation.

category: cancer biology


title: Quantitative sub-cellular acyl-CoA analysis reveals distinct nuclear regulation

abstract: Quantitative sub-cellular metabolomic measurements can yield crucial insights into the roles of metabolites in cellular processes, but are subject to multiple confounding factors. We developed Stable Isotope Labeling of Essential nutrients in cell Culture - Sub-cellular Fractionation (SILEC-SF), which uses isotope labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-Coenzyme A thioesters in sub-cellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing we identified the branched chain amino acid (BCAA) isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.


title: Fluency shaping increases integration of the command-to-execution and the auditory-to-motor pathways in persistent developmental stuttering

abstract: Fluency-shaping enhances the speech fluency of persons who stutter, yet underlying conditions and neuroplasticity-related mechanisms are largely unknown. While speech production-related brain activity in stuttering is well studied, it is unclear whether therapy repairs networks of altered sensorimotor integration, imprecise neural timing and sequencing, faulty error monitoring, or insufficient speech planning. Here, we tested the impact of one-year fluency-shaping therapy on resting-state fMRI connectivity within sets of brain regions subserving these speech functions. We analyzed resting-state data of 22 patients who participated in a fluency-shaping program, 18 patients not participating in therapy, and 28 fluent control participants, measured one year apart. Improved fluency was accompanied by an increased synchronization within the sensorimotor integration network. Specifically, two connections were strengthened; the left inferior frontal gyrus showed increased connectivity with the precentral gyrus at the representation of the left laryngeal motor cortex, and the left inferior frontal gyrus showed increased connectivity with the right superior temporal gyrus. Thus, therapy-associated neural remediation was based on a strengthened integration of the command-to-execution pathway together with an increased auditory-to-motor coupling. Since we investigated task-free brain activity, we assume that our findings are not biased to network activity involved in compensation but represent long-term focal neuroplasticity effects.


title: Young Infants Process Prediction Errors at the Theta Rhythm

abstract: Examining how young infants respond to unexpected events is key to our understanding of their emerging concepts about the world around them. From a predictive processing perspective, it is intriguing to investigate how the infant brain responds to unexpected events (i.e., prediction errors), because they require infants to refine their predictions about the environment. Here, to better understand prediction error processes in the infant brain, we presented 9-month-olds (N = 36) a variety of physical and social events with unexpected versus expected outcomes, while recording their electroencephalogram (EEG). We found a pronounced response in the ongoing 4 - 5 Hz theta rhythm for the processing of unexpected (in contrast to expected) events, for a prolonged time window (2 s) and across all scalp-recorded electrodes. The condition difference in the theta rhythm was not related to the condition difference in infants event-related activity to unexpected (versus expected) events in the negative central (Nc) component (.4 - .6 s), a component, which is commonly analyzed in infant violation of expectation studies using EEG. These findings constitute critical evidence that the theta rhythm is involved in the processing of prediction errors from very early in human brain development. We discuss how the theta rhythm may support infants refinement of basic concepts about the physical and social environment.


title: CAR/Nr1i3 directs T cell adaptation to bile acids in the small intestine

abstract: Bile acids (BAs) are lipid emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, BAs can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain BA homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high BA concentrations in the small intestine lamina propria (siLP). We previously reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1/ABCB1 in the siLP to prevent BA toxicity and suppress Crohns disease-like small bowel inflammation4. Here, we identify the nuclear xenobiotic receptor, constitutive androstane receptor (CAR/NR1I3), as a regulator of MDR1 expression in T cells, and safeguard against BA toxicity and inflammation in the small intestine. CAR was activated and induced large-scale transcriptional reprograming in Teff cells infiltrating the siLP, but not the colon. CAR induced expression of detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine, Il10. Accordingly, CAR-deficiency in T cells exacerbated, whereas pharmacologic CAR activation suppressed, BA-driven ileitis in T cell-reconstituted Rag-/- mice. These data suggest that CAR acts locally in small intestinal T cells to detoxify BAs and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohns disease, and provides evidence of lymphocyte sub-specialization within the small intestine.

category: immunology


title: Helicase-Like Functions in Phosphate Loop Containing Beta-Alpha Polypeptides

abstract:
The P-loop Walker A motif underlies hundreds of essential enzyme families that bind nucleotide triphosphates (NTPs) and mediate phosphoryl transfer (P-loop NTPases), including the earliest DNA/RNA helicases, translocases and recombinases. What were the primordial precursors of these enzymes? Could these large and complex proteins emerge from simple polypeptides? Previously, we showed that P-loops embedded in simple {beta} repeat proteins bind NTPs, but also, unexpectedly so, ssDNA and RNA. Here, we extend beyond the purely biophysical function of ligand binding to demonstrate rudimentary helicase-like activities. We further constructed simple 40-residue polypeptides comprising just one {beta}-(P-loop)- element. Despite their simplicity, these P-loop prototypes confer functions such as strand separation and exchange. Foremost, these polypeptides unwind dsDNA, and upon addition of NTPs, or inorganic polyphosphates, release the bound ssDNA strands to allow reformation of dsDNA. Binding kinetics and low-resolution structural analyses indicate that activity is mediated by oligomeric forms spanning from dimers to high-order assemblies. The latter are reminiscent of extant P-loop recombinases such as RecA. Overall, these P-loop prototypes comprise a plausible description of the sequence, structure and function of the earliest P-loop NTPases. They also indicate that multifunctionality and dynamic assembly were key in endowing short polypeptides with elaborate, evolutionarily relevant functions.

Significance statementIt is widely assumed that todays large and complex proteins emerged from much shorter and simpler polypeptides. Yet the nature of these early precursors remains enigmatic. We describe polypeptides that contain one of the earliest protein motifs, a phosphate-binding loop, or P-loop, embedded in a single beta-alpha element. These P-loop prototypes show intriguing characteristics of a primordial world comprised of nucleic acids and peptides. They are  generalists capable of binding different phospho-ligands, including inorganic polyphosphates and single-stranded DNA. Nonetheless, in promoting double-stranded DNA unwinding and strand-exchange they resemble modern P-loop helicases and recombinases. Our study describes a missing link in the evolution of complex proteins - simple polypeptides that tangibly relate to contemporary P-loop enzymes in sequence, structure and function.


title: Trophic niche of the invasive gregarious species Crepidula fornicata, in relation to ontogenic changes

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe slipper limpet Crepidula fornicata is a common and widespread invasive gregarious species along the European coast. Among its life-history traits, well documented ontogenic changes in behavior (i.e., motile male to sessile female) suggests a potential shift in feeding strategy across its life stages. Considering the ecological significance of this species in colonized areas, understanding how conspecifics share the trophic resource is crucial. Using fatty acids (FA) and stable isotopes (SI) as complementary trophic markers, we conducted a field survey between late winter and spring to investigate the trophic niche of three ontogenic stages of C. fornicata that bear different sexual (male/female) and motility (motile/sessile) traits. Potential trophic sources were characterized by their pigment, FA and SI compositions and discriminated well over the study period. We showed that the biofilm covering C. fornicata shells harbored a higher biomass of primary producers (i.e., chlorophytes and diatoms) than the surrounding sediment surface. Over the study period, we observed a covariation between the three ontogenic stages for both FA and SI compositions which suggest that the trophic niche of C. fornicata does not change significantly across its benthic life. During periods of low food availability, slipper limpets displayed an opportunistic suspension-feeding behaviour, relying on both fresh and detrital organic matter, likely coming from superficial sedimentary organic matter. During high food availability (i.e., spring phytoplankton bloom), all ontogenic stages largely benefited from this fresh supply of organic matter (pelagic diatoms in this case). However, the three ontogenic stages showed consistent differences in FA composition, and to a lesser extent in SI composition. These differences persist over time, as they originate more likely from ontogenic physiological changes (e.g., differential growth rates, metabolic rate or gametogenesis) rather than diet discrepancies.

category: ecology


title: Pervasive selection biases inferences of the species tree

abstract:
Despite the importance of natural selection in species evolutionary history, phylogenetic methods that take into account population-level processes typically ignore selection. The assumption of neutrality is often based on the idea that selection occurs at a minority of loci in the genome and is unlikely to compromise phylogenetic inferences significantly. However, selection might behave more pervasively, as in the case of nearly neutral evolving mutations. Genome-wide processes like GC-bias and some variation segregating at the coding regions are known to evolve in the nearly neutral range. As we are now using genome-wide data to estimate species trees, it is natural to ask whether weak but pervasive selection is likely to blur species tree inferences. We developed a polymorphism-aware phylogenetic model tailored for measuring signatures of nucleotide usage biases to test the impact of selection in the species tree. Our analyses indicate that while the inferred relationships among species are not significantly compromised, the genetic distances are systematically underestimated in a node-height dependent manner: i.e., the deeper nodes tend to be more underestimated than the shallow ones. Such biases have implications for molecular dating. We dated the evolutionary history of 30 worldwide fruit fly populations, and we found signatures of GC-bias considerably affecting the estimated divergence times (up to 23%) in the neutral model. Our findings call for the need to account for selection when quantifying divergence or dating species evolution.

Significance statementAlthough little is known about the impact of natural selection on species tree estimation, expectations are that it occurs at a minority of loci in the genome and is thus unlikely to affect the divergence process. However, growing evidence suggests that a large amount of the genomic variation evolves under weak but pervasive selection (e.g., GC-bias gene conversion). We tested the impact of unaccounted-for nearly neutral selection on species tree estimation and found that the estimated branch lengths are systematically biased. Our results highlight the need for selection-aware models in species tree estimation and molecular dating.

category: evolutionary biology


title: Parasitism and host dispersal plasticity in an aquatic model system

abstract: Dispersal is a central determinant of spatial dynamics in communities and ecosystems, and various ecological factors can shape the evolution of constitutive and plastic dispersal behaviours. One important driver of dispersal plasticity is the biotic environment. Parasites, for example, influence the internal condition of infected hosts and define external patch quality. Thus state-dependent dispersal may be determined by infection status and context-dependent dispersal by the abundance of infected hosts in the population. A prerequisite for such dispersal plasticity to evolve is a genetic basis on which natural selection can act. Using interconnected microcosms, we investigated dispersal in experimental populations of the freshwater protist Paramecium caudatum in response to the bacterial parasite Holospora undulata. For a collection of 20 natural host strains, we found substantial variation in constitutive dispersal, and to a lesser degree in dispersal plasticity. First, infection tended to increase or decrease dispersal relative to uninfected controls, depending on strain identity, potentially indicative of state-dependent dispersal plasticity. Infection additionally decreased host swimming speed compared to the uninfected counterparts. Second, for certain strains, there was a weak negative association between dispersal and infection prevalence, such that uninfected hosts tended to disperse less when infection was more frequent in the population, indicating context-dependent dispersal plasticity. Future experiments may test whether the observed differences in dispersal plasticity are sufficiently strong to react to natural selection. The evolution of dispersal plasticity as a strategy to mitigate parasite effects spatially may have important implications for epidemiological dynamics.


title: Genetics of resistance to common root rot (spot blotch), Fusarium crown rot, and sharp eyespot in wheat

abstract: Due to soil changes, high density planting, and the use of straw-returning methods, wheat common root rot (spot blotch), Fusarium crown rot (FCR), and sharp eyespot (sheath blight) have become severe threats to global wheat production. Only a few wheat genotypes show moderate resistance to these root and crown rot fungal diseases, and the genetic determinants of wheat resistance to these devastating diseases are poorly understood. This review summarizes recent results of genetic studies of wheat resistance to common root rot, Fusarium crown rot, and sharp eyespot. Wheat germplasm with relatively higher resistance are highlighted and genetic loci controlling the resistance to each disease are summarized.

category: genetics


title: Sexual dimorphism of synaptonemal complex length among populations of threespine stickleback fish

abstract: Crossover frequencies often differ substantially between sexes (i.e. heterochiasmy). Although this phenomenon is widespread throughout taxa, the mechanisms that lead to heterochiasmy remain unclear. One pattern that has emerged is that the overall length of the synaptonemal complex likely has a direct influence on the total number of crossovers in each sex. However, this has only been investigated in a handful of species. The threespine stickleback fish (Gasterosteus aculeatus) is an excellent species to explore whether synaptonemal complex length is associated with differences in the total number of crossovers, as females have much longer linkage maps than males. We used an immunocytological approach to quantify synaptonemal complex length in late pachytene female and male meiocytes in two different populations of threespine stickleback fish. Overall, the freshwater population had shorter synaptonemal complex lengths than the marine population. In both populations we observed sexual dimorphism, with females possessing longer axes. Our results support a model where chromosome axis length determines overall crossover frequency and establish the threespine stickleback as a useful species to explore the mechanistic basis of heterochiasmy as well as the genetic basis underlying variation in synaptonemal complex length.


title: The first steps toward a global pandemic: Reconstructing the demographic history of parasite host switches in its native range

abstract:
BackgroundHost switching allows parasites to expand their niches. However, successful switching may require suites of adaptations and also may decrease performance on the old host. As a result, reductions in gene flow accompany many host switches, driving speciation. Because host switches tend to be rapid, it is difficult to study them in real-time and their demographic parameters remain poorly understood. As a result, fundamental factors that control subsequent parasite evolution, such as the size of the switching population or the extent of immigration from the original host, remain largely unknown. To shed light on the host switching process, we explored how host switches occur in independent host shifts by two ectoparasitic honey bee mites (Varroa destructor and V. jacobsoni).

ResultsBoth switched to the western honey bee (Apis mellifera) after it was brought into contact with their ancestral host (Apis cerana), [~]70 and [~]12 years ago, respectively. Varroa destructor subsequently caused worldwide collapses of honey bee populations. Using whole-genome sequencing on 63 mites collected in their native ranges from both the ancestral and novel hosts, we were able to reconstruct the known temporal dynamics of the switch. We further found multiple previously undiscovered mitochondrial lineages on the novel host, along with the genetic equivalent of tens of individuals that were involved in the initial host switch. Despite being greatly reduced, some gene flow remains between mites adapted to different hosts.

ConclusionOur findings suggest that while reproductive isolation may facilitate the fixation of traits beneficial for exploitation of the new host, ongoing genetic exchange may allow genetic amelioration of inbreeding effects.


title: THE REGULATORY EFFECT OF LIGHT OVER FRUIT DEVELOPMENT AND RIPENING IS MEDIATED BY EPIGENETIC MECHANISMS

abstract: Phytochrome-mediated light and temperature perception has been shown to be a major regulator of fruit development. Furthermore, chromatin remodelling via DNA demethylation has been described as a crucial mechanism behind the fruit ripening process; however, the molecular basis underlying the triggering of this epigenetic modification remains largely unknown. Here, through integrative analyses of the methylome, siRNAome and transcriptome of tomato fruits from phyA and phyB1B2 null mutants, we report that PHYB1 and PHYB2 control genome-wide DNA methylation during fruit development from green towards ripe stages. The experimental evidence indicates that PHYB1B2 signal transduction is mediated by a gene expression network involving chromatin organization factors (DNA methylases/demethylases, histone-modifying enzymes and remodelling factors) and transcriptional regulators leading in the altered mRNA profile of photosynthetic and ripening-associated genes. This new level of understanding provides insights into the orchestration of epigenetic mechanisms in response to environmental cues affecting agronomical traits.

category: plant biology


title: Midcell localization of PBP4 of Escherichia coli is modulating the timing of divisome assembly

abstract:
Insertion of new material into the Escherichia coli peptidoglycan (PG) sacculus between the cytoplasmic membrane and the outer membrane requires a well-organized balance between synthetic and hydrolytic activities to maintain cell shape and avoid lysis. The hydrolytic enzymes outnumber the enzymes that insert new PG by far and very little is known about their specific function. Here we show that the DD-carboxy/endopeptidase PBP4 localizes in a PBP1A/LpoA and FtsEX dependent fashion at midcell during septal PG synthesis. Midcell localization of PBP4 requires its non-catalytic domain 3 of unknown function, but not the activity of PBP4 or FtsE. Microscale thermophoresis with isolated proteins shows that domain 3 is needed for the interaction with NlpI, but not PBP1A or LpoA. In vivo crosslinking experiments confirm the interaction of PBP4 with PBP1A and LpoA. We propose that PBP4 functions together with the amidases AmiA and B to create denuded glycan strands to attract the initiator of septal PG synthesis, FtsN. Consistent with this model, we found that the divisome assembly at midcell was significantly affected in cells lacking PBP4.

IMPORTANCEPeptidoglycan biosynthesis is a major target for antibacterials. The covalently closed peptidoglycan mesh, called sacculus, protects the bacterium from lysis due to its turgor. Sacculus growth is facilitated by the balanced activities of synthases and hydrolases, and disturbing this balance leads to cell lysis and bacterial death. Because of the large number and possible redundant functions of peptidoglycan hydrolases, it has been difficult to decipher their individual functions. In this paper we show that the DD-endopeptidase PBP4 localizes at midcell during septal peptidoglycan synthesis in Escherichia coli and is important for the timing of the assembly of the division machinery. This shows that inhibition of certain hydrolases could weaken the cells and might enhance antibiotic action.


title: Estimating Genetic Similarity Matrices using Phylogenies

abstract: Genetic similarity is a measure of the genetic relatedness among individuals. The standard method for computing these matrices involves the inner product of observed genetic variants. Such an approach is inaccurate or impossible if genotypes are not available, or not densely sampled, or of poor quality (for example, genetic analysis of extinct species). We provide a new method for computing genetic similarities among individuals using phylogenetic trees. Our method can supplement (or stand in for) computations based on genotypes. We provide simulations suggesting that the genetic similarity matrices computed from trees are consistent with those computed from genotypes. With our methods, quantitative analysis on genetic traits and analysis of heritability and co-heritability can be conducted directly using genetic similarity matrices and so in the absence of genotype data, or under uncertainty in the phylogenetic tree. We use simulation studies to demonstrate the advantages of our method, and we provide applications to data.


title: Host-mediated, cross-generational intraspecific competition in a herbivore species

abstract: AO_SCPLOWBSTRACTC_SCPLOWConspecific insect herbivores co-occurring on the same host plant interact both directly through interference competition and indirectly through exploitative competition, plant-mediated interactions and enemy-mediated interactions. However, the situation is less clear when the interactions between conspecific insect herbivores are separated in time within the same growing season, as it is the case for multivoltine species. We hypothesized that early season herbivory would result in reduced egg laying and reduced performance of the next generation of herbivores on previously attacked plants. We tested this hypothesis in a choice experiment with box tree moth females (Cydalima perspectalis Walker, Lepidoptera: Crambidae). These females were exposed to box trees (Buxus sempervirens L., Buxaceae) that were either undamaged or attacked by conspecific larvae earlier in the season. We then compared the performance of the next generation larvae on previously damaged vs undamaged plants. Previous herbivory had no effect on oviposition behaviour, but the weight of next generation larvae was significantly lower in previously damaged plants. There was a negative correlation between the number of egg clutches laid on plants by the first generation and the performance of the next generation larvae. Overall, our findings reveal that early season herbivory reduces the performance of conspecific individuals on the same host plant later in the growing season, and that this time-lagged intraspecific competition results from a mismatch between the oviposition preference of females and the performance of its offspring.


title: How we pay attention in naturalistic settings

abstract: Research on attentional control has largely focused on single senses and the importance of behavioural goals in controlling attention. However, everyday situations are multisensory and contain regularities, both likely influencing attention. We investigated how visual attentional capture is simultaneously impacted by top-down goals, the multisensory nature of stimuli, and the contextual factors of stimulis semantic relationship and temporal predictability. Participants performed a multisensory version of the Folk et al. (1992) spatial cueing paradigm, searching for a target of a predefined colour (e.g. a red bar) within an array preceded by a distractor. We manipulated: 1) stimulis goal-relevance via distractors colour (matching vs. mismatching the target), 2) stimulis multisensory nature (colour distractors appearing alone vs. with tones), 3) the relationship between the distractor sound and colour (arbitrary vs. semantically congruent) and 4) the temporal predictability of distractor onset. Reaction-time spatial cueing served as a behavioural measure of attentional selection. We also recorded 129-channel event-related potentials (ERPs), analysing the distractor-elicited N2pc component both canonically and using a multivariate electrical neuroimaging framework. Behaviourally, arbitrary target-matching distractors captured attention more strongly than semantically congruent ones, with no evidence for context modulating multisensory enhancements of capture. Notably, electrical neuroimaging of surface-level EEG analyses revealed context-based influences on attention to both visual and multisensory distractors, in how strongly they activated the brain and type of activated brain networks. For both processes, the context-driven brain response modulations occurred long before the N2pc time-window, with topographic (network-based) modulations at ~30ms, followed by strength-based modulations at ~100ms post-distractor onset. Our results reveal that both stimulus meaning and predictability modulate attentional selection, and they interact while doing so. Meaning, in addition to temporal predictability, is thus a second source of contextual information facilitating goal-directed behaviour. More broadly, in everyday situations, attention is controlled by an interplay between ones goals, stimulis perceptual salience, meaning and predictability. Our study calls for a revision of attentional control theories to account for the role of contextual and multisensory control.


title: How we pay attention in naturalistic visual search settings


title: Towards understanding how we pay attention in naturalistic visual search settings


title: Root electrotropism in Arabidopsis does not depend on auxin distribution but requires cytokinin biosynthesis

abstract:
An efficient foraging strategy for plant roots relies on the ability to sense multiple physical and chemical cues in soil and to reorient growth accordingly (tropism). Root tropisms range from sensing gravity (gravitropism), light (phototropism), water (hydrotropism), touch (thigmotropism) and more. Electrotropism, also known as galvanotropism, is the phenomenon of aligning growth with external electric fields and currents. Although observed in a few species since the end of the 19th century, the molecular and physical mechanism of root electrotropism remains elusive, limiting the comparison to more defined sensing pathways in plants.

Here we provide a first quantitative and molecular characterisation of root electrotropism in the model system Arabidopsis thaliana, showing that it does not depend on an asymmetric distribution of the plant hormone auxin, but that instead it requires the biosynthesis of a second hormone, cytokinin. We also show that the dose-response kinetics of the early steps of root electrotropism follows a power law analogous to the one observed in some physiological reactions in animals.

A future full molecular and quantitative characterisation of root electrotropism would represent a step forward towards a better understanding of signal integration in plants, and an independent outgroup for comparative analysis of electroreception in animals and fungi.


title: Neural repetition suppression modulates time perception: evidence from electrophysiology and pupillometry

abstract: Human time perception is malleable and subject to many biases. For example, it has repeatedly been shown that stimuli that are physically intense or that are unexpected seem to last longer. Two hypotheses have been proposed to account for such biases: one states that these temporal illusions are the result of heightened arousal which speeds up neural clock dynamics, whereas the alternative  magnitude coding account states that the magnitude of sensory responses causally modulates perceived durations. Common experimental paradigms used to study temporal biases can not dissociate between these accounts, as arousal and sensory magnitude covary and modulate each other. Here, we present two temporal discrimination experiments where flashing stimuli demarcated the start and end of a to-be-timed interval. These stimuli could either be in the same or in a different location, which led to different sensory responses due to neural repetition suppression. Crucially, changes and repetitions were fully predictable, allowing us to explore effects of sensory response magnitude without changes in arousal or surprise. Intervals with changing markers were perceived as lasting longer than those with repeating markers. We measured EEG (Experiment 1) and pupil size (Experiment 2), and found that temporal perception related to changes in event-related potentials (P2) and pupil constriction, both of which have been related to responses in the sensory cortex. Conversely, correlates of surprise and arousal (P3 amplitude and pupil dilation) were unaffected by stimulus repetitions and changes. These results demonstrate that sensory magnitude affects time perception even under constant levels of arousal.


title: Rapid Online Assessment of Reading Ability

abstract: An accurate model of the factors that contribute to individual differences in reading ability depends on data collection in large, diverse and representative samples of research participants. However, that is rarely feasible due to the constraints imposed by standardized measures of reading ability which require test administration by trained clinicians or researchers. Here we explore whether a simple, two-alternative forced choice, time limited lexical decision task (LDT), self-delivered through the web-browser, can serve as an accurate and reliable measure of reading ability. We found that performance on the LDT is highly correlated with scores on standardized measures of reading ability such as the Woodcock-Johnson Letter Word Identification test (r = 0.91, disattenuated r = 0.94). Importantly, the LDT reading ability measure is highly reliable (r = 0.97). After optimizing the list of words and pseudowords based on item response theory, we found that a short experiment with 76 trials (2-3 minutes) provides a reliable (r = 0.95) measure of reading ability. Thus, the self-administered, Rapid Online Assessment of Reading ability (ROAR) developed here overcomes the constraints of resource-intensive, in-person reading assessment, and provides an efficient and automated tool for effective online research into the mechanisms of reading (dis)ability.

category: animal behavior and cognition


title: Retracing Schwann cell developmental transitions in embryonic dissociated DRG/Schwann cell cocultures in mice

abstract: Embryonic Dissociated Dorsal Root Ganglia cultures are often used to investigate the role of novel molecular pathways or drugs in Schwann cell development and myelination. These cultures largely recapitulate the order of cellular and molecular events that occur in Schwann cells of embryonic nerves. However, the timing of Schwann cell developmental transitions, notably the transition from Schwann Cell Precursors to immature Schwann cells and then to myelinating Schwann cells, has not been estimated so far in this culture system. In this study, we determined the expression profiles of Schwann cell developmental genes during the first week of culture and then compared our data to the expression profiles of these genes in developing spinal nerves. This helped in identifying that Schwann Cell Precursors transition into immature Schwann Cells between the 5th and 7th day in vitro. Furthermore, we also investigated the transition of immature cells into pro-myelinating and myelinating Schwann cells upon the induction of myelination in vitro. Our results suggest that Schwann cell differentiation beyond the immature stage can be observed as early as 4 days post the induction of myelination in cocultures. Finally, we compared the myelinating potential of coculture-derived Schwann cell monocultures to cultures established from neonatal sciatic nerves and found that both these cultures system exhibit similar myelinating phenotypes. In effect, our results allow for a better understanding and interpretation of coculture experiments especially in studies that aim to elucidate the role of a novel actor in Schwann Cell development and myelination.


title: Multiplex-GAM: genome-wide identification of chromatin contacts yields insights not captured by Hi-C

abstract: Technologies for measuring 3D genome topology are increasingly important for studying mechanisms of gene regulation, for genome assembly and for mapping of genome rearrangements. Hi-C and other ligation-based methods have become routine but have specific biases. Here, we develop multiplex-GAM, a faster and more affordable version of Genome Architecture Mapping (GAM), a ligation-free technique to map chromatin contacts genome-wide. We perform a detailed comparison of contacts obtained by multiplex-GAM and Hi-C using mouse embryonic stem (mES) cells. We find that both methods detect similar topologically associating domains (TADs). However, when examining the strongest contacts detected by either method, we find that only one third of these are shared. The strongest contacts specifically found in GAM often involve "active" regions, including many transcribed genes and super-enhancers, whereas in Hi-C they more often contain "inactive" regions. Our work shows that active genomic regions are involved in extensive complex contacts that currently go under-estimated in genome-wide ligation-based approaches, and highlights the need for orthogonal advances in genome-wide contact mapping technologies.


title: Distinguishing between recent balancing selection and incomplete sweep using deep neural networks

abstract: 1Balancing selection is an important adaptive mechanism underpinning a wide range of phenotypes. Despite its relevance, the detection of recent balancing selection from genomic data is challenging as its signatures are qualitatively similar to those left by ongoing positive selection. In this study we developed and implemented two deep neural networks and tested their performance to predict loci under recent selection, either due to balancing selection or incomplete sweep, from population genomic data. Specifically, we generated forward-in-time simulations to train and test an artificial neural network (ANN) and a convolutional neural network (CNN). ANN received as input multiple summary statistics calculated on the locus of interest, while CNN was applied directly on the matrix of haplotypes. We found that both architectures have high accuracy to identify loci under recent selection. CNN generally outperformed ANN to distinguish between signals of balancing selection and incomplete sweep and was less affected by incorrect training data. We deployed both trained networks on neutral genomic regions in European populations and demonstrated a lower false positive rate for CNN than ANN. We finally deployed CNN within the MEFV gene region and identified several common variants predicted to be under incomplete sweep in a European population. Notably, two of these variants are functional changes and could modulate susceptibility to Familial Mediterranean Fever, possibly as a consequence of past adaptation to pathogens. In conclusion, deep neural networks were able to characterise signals of selection on intermediate-frequency variants, an analysis currently inaccessible by commonly used strategies.


title: Visuospatial attention updates the cortical representation of sound under reduced sensory uncertainty

abstract: Selective attentional biases arising from one sensory modality may manifest in another. The effects of visuospatial attention, often considered a foundation for visual object perception, are unclear in the auditory domain during audiovisual (AV) scene processing. This study investigates temporal and spatial factors that facilitate such cross-modal bias transfer at the neural level. Auditory encoding of random tone pips in AV scenes was investigated via a temporal response function model (TRF) of the participants electroencephalogram (N=30). The spatially uninformative pips were associated with spatially distributed visual contrast reversals ( flips) through asynchronous, probabilistic AV temporal onset distributions. Participants deployed visuospatial selection on these AV stimuli to perform a task. A late (~300 ms) cross-modal transfer of the unimodal attentional bias was found on the neural representation of pips. Transfer depended on the selected visual input being (i) presented during or shortly after a related sound in a relatively limited temporal window (<165 ms); and (ii) positioned across limited (1:4) visual foreground to background ratios. In addition, the magnitude of attentional enhancement was proportional to the proximity of flips to the foreground area. The results indicate that ongoing neural representations of sounds can incorporate relevant visuospatial attributes for auditory stream segregation.


title: Visuospatial attention revamps cortical processing of sound: restrict stimulus uncertainty


title: Immunomodulatory Contribution of Mast Cells to the Biomaterial Microenvironment

abstract: Bioactive immunomodulatory biomaterials have shown promise for influencing the immune response to promote tissue repair and regeneration. Macrophages and T cells have been associated with this response; however, other immune cell types have been traditionally overlooked. In this study, we investigated the role of mast cells in the regulation of the immune response to decellularized biomaterial scaffolds using a subcutaneous implant model. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a sex specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with adoptive mast cell transfer. Further investigation of the later stage immune response in male mice determined a greater sustained pro-inflammatory gene expression profile including the IL-1 cytokine family, IL-6, alarmins, and chemokines. These results highlight mast cells as another important cell type that influences the immune response to pro-regenerative biomaterials.

category: bioengineering


title: Immunomodulatory Contribution of Mast Cells to the Regenerative Biomaterial Microenvironment


title: CellPhy: accurate and fast probabilistic inference of single-cell phylogenies from scDNA-seq data

abstract: We introduce a maximum likelihood framework called CellPhy for inferring phylogenetic trees from single-cell DNA sequencing (scDNA-seq) data. CellPhy leverages a finite-site Markov genotype substitution model with 16 diploid states, akin to those typically used in statistical phylogenetics. It includes a dedicated error function for single cells that incorporates amplification/sequencing error and allelic dropout (ADO). Moreover, it can explicitly consider the uncertainty of the variant calling process by using genotype likelihoods as input. We implemented CellPhy in a widely used open-source phylogenetic inference package (RAxML-NG) that provides statistical confidence measurements on the estimated tree and scales particularly well on large scDNA-seq datasets with hundreds or thousands of cells. To benchmark CellPhy, we carried out 19,400 coalescent simulations of cell samples from exponentially-growing tumors for which the true phylogeny was known. We evolved single-cell diploid DNA genotypes along the simulated genealogies under different scenarios, including infinite- and finite-sites nucleotide mutation models, trinucleotide mutational signatures, sequencing, and amplification errors, allele dropouts, and cell doublets. Our simulations suggest that CellPhy is robust to amplification/sequencing errors and ADO and outperforms state-of-the-art methods under realistic scDNA-seq scenarios both in terms of accuracy and speed. Also, we sequenced 24 single-cell whole-genomes from a colorectal tumor. Together with three published scDNA-seq data sets, we analyzed these empirical data to illustrate how CellPhy can provide more reliable biological insights than most competing methods. CellPhy is freely available at https://github.com/amkozlov/cellphy.

category: bioinformatics


title: Dense poly(ethylene glycol) coatings maximize nanoparticle transport across lymphatic endothelial cells and accumulate in the skin draining lymph nodes

abstract: Lymphatic vessels have recently been shown to effectively deliver immune modulatory therapies to the lymph nodes, which enhances their therapeutic efficacy. Prior work has shown that lymphatics transport 10-250 nm nanoparticles from peripheral tissues to the lymph node. However, the surface chemistry required to maximize this transport is poorly understood. Here, we determined the effect of surface poly(ethylene glycol) (PEG) density and size on nanoparticle transport across lymphatic endothelial cells (LECs) by differentially PEGylated model polystyrene nanoparticles. Using an established in-vitro lymphatic transport model, we found PEGylation improved the transport of 100 and 40 nm nanoparticles across LECs 50-fold compared to the unmodified nanoparticles and that transport is maximized when the PEG is in a dense brush conformation or high grafting density (Rf/D = 4.9). We also determined that these trends are not size-dependent. PEGylating 40 nm nanoparticles improved transport efficiency across LECs 68-fold compared to unmodified nanoparticles. We also found that PEGylated 100 nm and 40 nm nanoparticles accumulate in lymph nodes within 4 hours after intradermal injection, while unmodified nanoparticles accumulated minimally. Dense PEGylation also led nanoparticles to travel the furthest distance from the injection site. Finally, we determined that nanoparticles are transported via both paracellular and transcellular mechanisms, and that PEG conformation modulates the cellular transport mechanisms. Our results suggest that PEG conformation is crucial to maximize nanoparticle transport across LECs and into lymphatic vessels, making PEG density a crucial design. Optimizing PEG density on nanoparticle formulations has the potential to enhance immunotherapeutic and vaccine outcomes.


title: Assessing Confidence in Root Placement on Phylogenies: An Empirical Study Using Non-Reversible Models for Mammals

abstract:
AO_SCPLOWBSTRACTC_SCPLOWUsing time-reversible Markov models is a very common practice in phylogenetic analysis, because although we expect many of their assumptions to be violated by empirical data, they provide high computational efficiency. However, these models lack the ability to infer the root placement of the estimated phylogeny. In order to compensate for the inability of these models to root the tree, many researchers use external information such as using outgroup taxa or additional assumptions such as molecular-clocks. In this study, we investigate the utility of non-reversible models to root empirical phylogenies and introduce a new bootstrap measure, the rootstrap, which provides information on the statistical support for any given root position.

Availability and implementationrootstrap support is implemented in IQ-TREE 2 and a tutorial is available at the iqtree webpage http://www.iqtree.org/doc/Rootstrap. In addition, a python script is available at https://github.com/suhanaser/Rootstrap. [phylogenetic inference, root estimation, bootstrap, non-reversible models]


title: The vesicular release probability sets the strength of individual Schaffer collateral synapses

abstract: Information processing in the brain is controlled by quantal release of neurotransmitters, a tightly regulated process. From ultrastructural analysis, it is known that presynaptic boutons along single axons differ in the number of vesicles docked at the active zone. It is not clear whether the probability of these vesicles to get released (pves) is homogenous or also varies between individual boutons. Here, we optically measure evoked transmitter release at individual Schaffer collateral synapses at different calcium concentrations, using the genetically encoded glutamate sensor iGluSnFR. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters N, pves, and q. We find that Schaffer collateral boutons typically release single vesicles under low pves conditions and switch to multivesicular release in high calcium saline. Analyzing the variability of quantal parameters, we conclude that under near-physiological conditions, the vesicular release probability rather than the number of readily releasable vesicles or their transmitter content determines the potency of individual boutons.


title: A Unified Framework for Lineage Tracing and Trajectory Inference

abstract: Understanding the genetic and epigenetic programs that control differentiation during development is a fundamental challenge, with broad impacts across biology and medicine. New measurement technologies like single-cell RNA-sequencing and CRISPR-based lineage tracing have opened new windows on these processes, through computational trajectory inference and lineage reconstruction. While these two mathematical problems are deeply related, they been approached from separate directions: methods for trajectory inference are not typically designed to leverage information from lineage tracing and vice versa. We present a novel, unified framework for lineage tracing and trajectory inference. Specifically, we develop a method for reconstructing developmental trajectories from time courses with snapshots of both cell states and lineages, leveraging mathematical tools from graphical models and optimal transport. We find that lineage data helps disentangle complex state transitions with increased accuracy using fewer measured time points. Moreover, integrating lineage tracing with trajectory inference in this way enables accurate reconstruction of developmental pathways that are impossible to recover with state-based methods alone.

category: developmental biology


title: Timing of neurogenesis through sequential accumulation of miR-9 due to additive expression of multiple alleles

abstract: MicroRNAs (miRs) have important quantitative roles in tuning dynamical gene expression. Hes/Her transcription factor dynamics are sensitive to the increasing amount of miR-9 in the cell, transitioning from noisy high-level expression to oscillatory expression and then to downregulation. However, the mechanism by which miR-9 is quantitatively controlled is not known. In vertebrates, several distinct genomic loci produce the same mature miR-9, but the functional significance of multiple primary transcripts remains unknown. Here, we show that the amount of mature miR-9 increases during zebrafish neurogenesis in a sharp stepwise manner. We characterize the spatiotemporal profile of 7 distinct pri-mir-9s and show that they are sequentially expressed during hindbrain neurogenesis. Quantitative analysis of expression at the single-cell level, shows that expression of late-onset pri-mir-9-1 is added on, rather than replacing the expression of early onset pri-mir-9-4 and 9-5. Mutating the late-onset pri-mir-9-1 with CRISPR/Cas9 prevents the developmental increase of mature miR-9 and reduces late neuronal differentiation. Finally, we use mathematical modelling to explore possible benefits of a stepwise increase of miR-9 over a linear increase. We find that an adaptive network containing Her6 can be insensitive to a linear increase in miR-9 and show that such adaptation can be overcome by step-wise increases of miR-9. In conclusion, our work suggests that a sharp stepwise increase of mature miR-9 is contributed by sequential temporal activation of distinct loci. This may be a strategy to overcome adaptation and facilitate a transition to a new state of Her6 dynamics or level.


title: Model-based genotype and ancestry estimation for potential hybrids with mixed-ploidy

abstract: Non-random mating among individuals can lead to spatial clustering of genetically similar individuals and population stratification. This deviation from panmixia is commonly observed in natural populations. Consequently, individuals can have parentage in single populations or involving hybridization between differentiated populations. Accounting for this mixture and structure is important when mapping the genetics of traits and learning about the formative evolutionary processes that shape genetic variation among individuals and populations. Stratified genetic relatedness among individuals is commonly quantified using estimates of ancestry that are derived from a statistical model. Development of these models for polyploid and mixed-ploidy individuals and populations has lagged behind those for diploids. Here, we extend and test a hierarchical Bayesian model, called entropy, which can use low-depth sequence data to estimate genotype and ancestry parameters in autopolyploid and mixed-ploidy individuals (including sex chromosomes and autosomes within individuals). Our analysis of simulated data illustrated the trade-off between sequencing depth and genome coverage and found lower error associated with low depth sequencing across a larger fraction of the genome than with high depth sequencing across a smaller fraction of the genome. The model has high accuracy and sensitivity as verified with simulated data and through analysis of admixture among populations of diploid and tetraploid Arabidopsis arenosa.


title: A structured observation distribution for generative biological sequence prediction and forecasting

abstract: Generative probabilistic modeling of biological sequences has widespread existing and potential application across biology and biomedicine, from evolutionary biology to epidemiology to protein design. Many standard sequence analysis methods preprocess data using a multiple sequence alignment (MSA) algorithm, one of the most widely used computational methods in all of science. However, as we show in this article, training generative probabilistic models with MSA preprocessing leads to statistical pathologies in the context of sequence prediction and forecasting. To address these problems, we propose a principled drop-in alternative to MSA preprocessing in the form of a structured observation distribution (the ``MuE" distribution). The MuE is a latent alignment model in which not only the alignment variable but also the regressor sequence can be latent. We prove theoretically that the MuE distribution comprehensively generalizes popular methods for inferring biological sequence alignments, and provide a precise characterization of how such biological models have differed from natural language latent alignment models. We show empirically that models that use the MuE as an observation distribution outperform comparable methods across a variety of datasets, and apply MuE models to a novel problem for generative probabilistic sequence models: forecasting pathogen evolution.


title: SLO2.1 and NALCN form a functional complex to modulate myometrial cell excitability

abstract: Depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential is necessary for the transition of the uterus from a quiescent state to a contractile state. The molecular mechanisms involved in this transition are not completely understood. Here, we report a novel coupled system between the Na+-activated K+ channel (SLO2.1) and the non-selective Na+ leak channel (NALCN) which determines the MSMC membrane potential. We show that SLO2.1 currents are activated by an inward Na+ leak current carried by the NALCN channel leading to MSMC hyperpolarization. These results show an unanticipated role for the Na+ leak currents in activating a negative feedback system countering the excitable effects of Na+ currents. This is a novel role for the NALCN channel in which Na+ acts as an intracellular signaling molecule. In fact, we report here that the net effect of Na+ entry through NALCN channels is a hyperpolarization of the MSMCs plasma membrane because of the activation of SLO2.1 K channel. Importantly, we also report that a decrease in NALCN/SLO2.1 activity triggers both Ca2+ entries through VDCCs, promoting myometrial contraction. Consistently, with a functional coupling, our data show that NALCN and SLO2.1 are in proximity to one another in human MSMCs. We propose that the spatial arrangement of SLO2.1 and NALCN permits these channels to functionally interact in order to regulate human MSMC membrane potential and cell excitability to modulate uterine contractile activity.


title: A novel sodium signaling complex regulates uterine activity


title: Integrated tapered fibertrode for simultaneous control and readout of neural activity over small brain volumes with reduced light-induced artefacts

abstract: Recognizing the neural patterns underlying different brain functions is essential to achieve a more comprehensive view on how small sets of neurons organize in complex 3D networks to determine different behaviours. In this framework, optogenetic techniques have been successfully proven as a powerful tool to control brain functions achieving millisecond temporal resolution and cell-type specificity, by combining the use of light-gated opsins and ad-hoc light delivery optoelectronic devices. However, targeting small brain volumes with simultaneous electrical recording results in the introduction of photoelectric artefacts, in particular when light emission and recoding sites are very close one to each other. In this work we take advantage of the photonic properties of tapered fibers to present a fully integrated fibertrode to target small brain volumes with abated photoelectric noise. The device hosts a light emitting window just below a recording pad, and exploits the angled light emission from the window to achieve simultaneous activation and electrical readout of small groups of cells with no photoelectric artifacts in vivo. Despite the highly non-planar surface of the fiber taper, windows size, shape and electrodes impedance can be modulated by controlling the fabrication parameters during focused ion beam milling and deposition, thus resulting in a versatile, integrated and customizable optogenetic tool for neurobiology studies in closed-loop configuration over small brain volumes.


title: Src activates retrograde membrane traffic through phosphorylation of GBF1

abstract: The Src tyrosine kinase controls cancer-critical protein glycosylation through Golgi to ER relocation of GALNTs enzymes. How Src induces this trafficking event is unknown. Golgi to ER transport depends on the GTP Exchange factor (GEF) GBF1 and small GTPase Arf1. Here we show that Src induces the formation of tubular transport carriers containing GALNTs through promotion of a GBF1-Arf1 complex. The complex is initiated by phosphorylation on GBF1 on 10 tyrosine residues; two of them, Y876 and Y898 are located near the C-terminus of the Sec7 GEF domain. Their phosphorylation promotes partial melting of the Sec7 domain, favoring binding to the GTPase. Perturbation of these rearrangements prevent GALNTs relocation. In sum, Src promotes GALNTs relocation by favoring binding of GBF1 to Arf1. Regulation of a GEF-Arf axis by tyrosine phosphorylation appears to be a highly conserved and wide-spread mechanism.


title: Esrrb is a cell cycle dependent priming factor balancing between pluripotency and differentiation

abstract: Cell cycle and differentiation decisions are tightly linked; however, the underlying principles that drive these decisions are not fully understood. Here, we combined cell-cycle reporter system and single-cell RNA-seq profiling to study the transcriptomes of mouse embryonic stem cells (ESCs) in the context of cell cycle states and differentiation. By applying retinoic acid, a multi-linage differentiation assay, on G1 and G2/M pre-sorted ESCs, we show that only G2/M ESCs were capable of differentiating into extraembryonic endoderm cells (XENs), whereas cells in the G1 phase predominantly produce Epiblast Stem Cells. We identified ESRRB, a key pluripotency factor that is upregulated during G2/M phase, as a central driver of XEN differentiation. Furthermore, enhancer chromatin states based on WT and Esrrb-KO ESCs show association of ESRRB with XEN poised enhancers. Cells engineered to overexpress Esrrb during G1 allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. In addition, Embryonic bodies (EBs) are not affected by deletion of ESRRB but trigger apoptosis upon attempts to apply direct XEN differentiation. Taken together, this study reveals an important functional link between Esrrb and cell-cycle states during the exit from pluripotency. Finally, the experimental scheme of single cell RNA-seq in the context of cell cycle can be further expanded into other cellular systems to better understand differentiation decisions and cancer models.


title: BioCRNpyler: Compiling Chemical Reaction Networks from Biomolecular Parts in Diverse Contexts

abstract:
Biochemical interactions in systems and synthetic biology are often modeled with chemical reaction networks (CRNs). CRNs provide a principled modeling environment capable of expressing a huge range of biochemical processes. In this paper, we present a software toolbox, written in Python, that compiles high-level design specifications represented using a modular library of biochemical parts, mechanisms, and contexts to CRN implementations. This compilation process offers four advantages. First, the building of the actual CRN representation is automatic and outputs Systems Biology Markup Language (SBML) models compatible with numerous simulators. Second, a library of modular biochemical components allows for different architectures and implementations of biochemical circuits to be represented succinctly with design choices propagated throughout the underlying CRN automatically. This prevents the often occurring mismatch between high-level designs and model dynamics. Third, high-level design specification can be embedded into diverse biomolecular environments, such as cell-free extracts and in vivo milieus. Finally, our software toolbox has a parameter database, which allows users to rapidly prototype large models using very few parameters which can be customized later. By using BioCRNpyler, users ranging from expert modelers to novice script-writers can easily build, manage, and explore sophisticated biochemical models using diverse biochemical implementations, environments, and modeling assumptions.

Author summaryThis paper describes a new software package BioCRNpyler (pronounced "Biocompiler") designed to support rapid development and exploration of mathematical models of biochemical networks and circuits by computational biologists, systems biologists, and synthetic biologists. BioCRNpyler allows its users to generate large complex models using very few lines of code in a way that is modular. To do this, BioCRNpyler uses a powerful new representation of biochemical circuits which defines their parts, underlying biochemical mechanisms, and chemical context independently. BioCRNpyler was developed as a Python scripting language designed to be accessible to beginning users as well as easily extendable and customizable for advanced users. Ultimately, we see Biocrnpyler being used to accelerate computer automated design of biochemical circuits and model driven hypothesis generation in biology.

category: synthetic biology


title: Centrosomal P4.1-associated protein (CPAP) positively regulates endocytic vesicular transport and lysosome targeting of EGFR

abstract: Centrosomal P4.1-associated protein (CPAP) plays a critical role in restricting the centriole length in human cells. Here, we report a novel, positive regulatory role for CPAP in endocytic vesicular transport (EVT) and lysosome targeting of internalized-cell surface receptor EGFR. We observed that higher CPAP levels cause an increase in the abundance of multi-vesicular body (MVB) and EGFR is detectable in CPAP-overexpression induced puncta. While the surface levels, and total and phosphorylated cellular levels of EGFR are higher under CPAP deficiency, ligandengagement induced internalization of this receptor is not impacted by CPAP levels. Furthermore, routing of EGFR into early endosomes is not influenced by CPAP. However, most importantly, we found that CPAP is required for targeting ligand-activated, internalized EGFR to lysosome. Transport of ligand-bound EGFR from early endosome to late endosome/MVB and lysosome is severely diminished in CPAP-depleted cells. Moreover, CPAP depleted cells showed diminished ability to form MVB structures upon EGFR activation. These observations show a positive regulatory role for CPAP in early endosome to late endosome transport and lysosome targeting of ligand-bound EGFR-like cell surface receptors. Overall, identification of this regulatory role for CPAP in endocytic trafficking of EGFR provides new insights in understanding the cellular functions of CPAP.


title: Permutation tests for hypothesis testing with animal social data: problems and potential solutions

abstract:
O_LIPermutation tests are widely used to test null hypotheses with animal social network data, but suffer from high rates of type I and II error when the permutations do not properly simulate the intended null hypothesis.
C_LIO_LITwo common types of permutations each have limitations. Pre-network (or datastream) permutations can be used to control "nuisance effects" like spatial, temporal, or sampling biases, but only when the null hypothesis assumes random social structure. Node (or node-label) permutation tests can test null hypotheses that include nonrandom social structure, but only when nuisance effects do not shape the observed network.
C_LIO_LIWe demonstrate one possible solution addressing these limitations: using pre-network permutations to adjust the values for each node or edge before conducting a node permutation test. We conduct a range of simulations to estimate error rates caused by confounding effects of social or non-social structure in the raw data.
C_LIO_LIRegressions on simulated datasets suggest that this "double permutation" approach is less likely to produce elevated error rates relative to using only node permutations, pre-network permutations, or node permutations with simple covariates, which all exhibit elevated type I errors under at least one set of simulated conditions. For example, in scenarios where type I error rates from pre-network permutation tests exceed 30%, the error rates from double permutation remain at 5%.
C_LIO_LIThe double permutation procedure provides one potential solution to issues arising from elevated type I and type II error rates when testing null hypotheses with social network data. We also discuss alternative approaches that can provide robust inference, including fitting mixed effects models, restricted node permutations, testing multiple null hypotheses, and splitting large datasets to generate replicated networks. Finally, we highlight ways that uncertainty can be explicitly considered and carried through the analysis.
C_LI


title: Data-driven causal analysis of observational time series in ecology

abstract: Complex ecosystems are challenging to understand as they often defy manipulative experiments for practical or ethical reasons. In response, several fields have developed parallel approaches to infer causal relations from observational time series. Yet these methods are easy to misunderstand and often controversial. Here, we provide an accessible and critical review of three statistical causal inference approaches popular in ecological time series analysis: pairwise correlation, Granger causality, and state space reconstruction. For each, we ask what a method tests for, what causal statement it might imply, and when it could lead us astray. We devise new ways of visualizing key concepts, describe some novel pathologies of causal inference methods, and point out how so-called "model-free" causality tests are not assumption-free. We hope that our synthesis will facilitate thoughtful application of causal inference approaches and encourage explicit statements of assumptions.


title: RNAlign2D, a novel RNA structural alignment tool based on pseudo-amino acid substitution matrix

abstract:
BackgroundThe functions of RNA molecules are mainly determined by their secondary structures. These functions can also be predicted using bioinformatic tools that enable the alignment of multiple RNAs to determine functional domains and/or classify RNA molecules into RNA families. However, the existing multiple RNA alignment tools, which use structural information, are slow in aligning long molecules and/or a large number of molecules. Therefore, a more rapid tool for multiple RNA alignment may improve the classification of known RNAs and help to reveal the functions of newly discovered RNAs.

ResultsHere, we introduce an extremely fast Python-based tool called RNAlign2D. It converts RNA sequences to pseudo-amino acid sequences, which incorporate structural information, and uses a customizable scoring matrix to align these RNA molecules via the multiple protein sequence alignment tool MUSCLE.

ConclusionsRNAlign2D produces accurate RNA alignments in a very short time. The pseudo-amino acid substitution matrix approach utilized in RNAlign2D is applicable for virtually all protein aligners.


title: Climate risk to European fisheries and coastal communities

abstract:
With the majority of the global human population living in coastal regions, correctly characterising the climate risk that ocean-dependent communities and businesses are exposed to is key to prioritising the finite resources available to support adaptation. We apply a climate risk analysis across the European fisheries sector for the first time to identify the most at-risk fishing fleets and coastal regions and then link the two analyses together. We employ a novel approach combining biological traits with physiological metrics to differentiate climate hazards between 556 populations of fish and use these to assess the relative climate risk for 380 fishing fleets and 105 coastal regions in Europe. Countries in southeast Europe as well as the UK have the highest risks to both fishing fleets and coastal regions overall while, in other countries, the risk-profile is greater at either the fleet level or at the regional level. European fisheries face a diversity of challenges posed by climate change and climate adaptation, therefore, needs to be tailored to each country, region and fleets specific situation. Our analysis supports this process by highlighting where and what adaptation measures might be needed and informing where policy and business responses could have the greatest impact.

Significance StatementWe present a novel climate risk analysis for i) 105 ocean-dependent communities and ii) 380 fishing fleets in Europe. Our unique approach provides a perspective over the climate risks in this diverse and populous continent that is unprecedented in both its breadth and detail. We show that countries in southeast Europe as well as the UK have the highest climate risk overall, both in terms of fishing fleets and coastal communities. Substantial variation in climate risk is seen even within countries, emphasizing that climate adaptation interventions need to be tailored to the specific characteristics of the fleet or community. A focus on sustainable fisheries management and diversification of fish portfolios can reduce climate risks across the board.


title: Change in liana density over 30 years in a Bornean rain forest supports the escape hypothesis

abstract: Liana dynamics may influence tree dynamics and vice versa. Only long-term studies can perhaps disentangle them. In two permanent plots of lowland dipterocarp forest at Danum a liana census in 1988 was repeated in 2018. The primary forest was still in a late stage of recovery from an inferred large and natural disturbance in the past. Mean number of lianas per tree decreased by 22 and 34% in plots 1 and 2, and in different ways. By 2018 there were relatively more trees with few lianas and relatively fewer trees with many lianas than in 1988. The redistribution was strongest for overstorey trees of the Dipterocarpaceae (more with no lianas by 2018) and understorey trees of the Euphorbiaceae (many losing high loads in especially plot 2). Proportion of trees with lianas increased overall by 3.5%. Number of lianas per tree showed a quadratic relationship with tree size: maximal for large trees, fewer for smaller and very large trees. Tree survival and stem growth rate were significantly negatively related to the number of lianas after accounting for spatial autocorrelation. Monte Carlo random subsampling of trees in 1988 and 2018, to achieve statistical independence, established significance of change. Dipterocarps and euphorbs clearly differed in their liana dynamics between plots. Regression models had different forms for the two plots, which reflected a complicated structural-spatial variability in host-liana dynamics. Analysis of the abundant tree species individually, highlighted a group of emergent dipterocarps with low liana counts decreasing with time. Building on an earlier hypothesis for this forest type and site, these very large trees appear to have been losing their lianas by branch shedding, as they moved into and out of the main canopy. They were evidently  escaping from the parasite. The process may in part explain the characteristically very uneven forest canopy at Danum. Change in liana density was therefore contingent on both forest history and site succession, and on plot-level structure and tree dynamics. Liana promotion in the intermittent ENSO dry periods was seemingly being offset by closing of the forest and dominance by dipterocarps in late seral stages.


title: Homeostatic cerebellar compensation of age-related changes of vestibulo-ocular reflex adaptation: a computational epidemiology study

abstract: The vestibulo-ocular reflex (VOR) stabilizes vision during head motion. Age-related changes of vestibular neuroanatomical properties predict a linear decay of VOR function. Nonetheless, human epidemiological data show a stable VOR function across the life span. In this study, we model cerebellum-dependent VOR adaptation to relate structural and functional changes throughout aging. We consider three neurosynaptic factors that may codetermine VOR adaptation during aging: the electrical coupling of inferior olive neurons, the intrinsic plasticity of Purkinje cell (PC) synapses, and long-term spike timing-dependent plasticity at parallel fiber - PC synapses and mossy fiber - medial vestibular nuclei synapses. Our cross-sectional aging analyses suggest that long-term plasticity acts as a global homeostatic mechanism that underpins the stable temporal profile of VOR function. The results also suggest that the intrinsic plasticity of PC synapses operates as a local homeostatic mechanism that further sustains the VOR at older ages. Importantly, the computational epidemiology approach presented in this study allows discrepancies among human cross-sectional studies to be understood in terms of interindividual variability in older individuals. Finally, our longitudinal aging simulations show that the amount of residual fibers coding for the peak and trough of the VOR cycle constitutes a predictive hallmark of VOR trajectories over a lifetime.

category: neuroscience