title: A role for a micron-scale supramolecular myosin array in adherens junction cytoskeletal assembly

abstract:
Epithelial cells assemble specialized actomyosin structures at E-Cadherin-based cell-cell junctions, and the force exerted drives cell shape change during morphogenesis. The mechanisms used to build this supramolecular actomyosin structure remain unclear. We used ZO-knockdown MDCK cells, which assemble a robust, polarized and highly organized actomyosin cytoskeleton at the zonula adherens, and combined genetic and pharmacological approaches with super-resolution microscopy to define molecular machines required. To our surprise, inhibiting individual actin assembly pathways (Arp2/3, formins or Ena/VASP) did not prevent or delay assembly of this polarized actomyosin structure. Instead, as junctions matured, micrometer-scale supramolecular myosin arrays assembled, with aligned stacks of myosin filaments adjacent to the apical membrane, while associated actin filaments remained disorganized. This suggested these myosin arrays might bundle actin at mature junctions. Consistent with this, inhibiting ROCK or myosin ATPase disrupted myosin localization/organization, and prevented actin bundling and polarization. These results suggest a novel mechanism by which myosin self-assembly helps drive actin organization to facilitate cell shape change.

SummaryWe explored mechanisms epithelial cells use to assemble supramolecular actomyosin structures at E-Cadherin-based cell-cell junctions. Our data suggest individual actin assembly pathways are not essential. Instead, microscopy and pharmacological inhibition suggest micrometer-scale supramolecular myosin arrays help bundle actin at mature junctions.

category: cell biology


title: Reconstructing human early embryogenesis in vitro with pluripotent stem cells

abstract: Understanding human development is of fundamental biological and clinical importance. Yet despite its significance, insights into early developmental events in humans still remain largely unknown. While recent advances show that stem cells can mimic embryogenesis1-9 to unravel hidden developmental mechanisms, a stem cell-based model of early human embryogenesis is lacking. Here, we use human extended pluripotent stem cells10to reconstitute early human development in 3-dimensions and recapitulate early embryo-like events. We first perform a systematic characterisation to reveal unique signalling requirements for building the human pre-implantation blastocyst. Further, we show that these in vitro stem cell-derived blastocyst-like structures are able to undertake spatiotemporal self-organisation to mimic peri-implantation remodelling in which a polarised rosette opens up the amniotic cavity within a developing disc. The hallmarks of human early development displayed by this stem cell-based in vitro model mimics features of embryonic day 3 to day 9/10 of natural development. Thus, this platform represents a tractable model system to contribute to the basic understanding of cellular and molecular mechanisms governing early embryonic events in humans and to provide valuable insights into the design of differentiation protocols for human stem cells in clinical applications.

category: developmental biology


title: Wrack enhancement of post-hurricane vegetation and geomorphological recovery in a coastal dune

abstract: Coastal ecosystems such as sand dunes, mangrove forests, and salt marshes provide natural storm protection for vulnerable shorelines. At the same time, storms erode and redistribute biological materials among coastal systems via wrack. Yet how such cross-ecosystem subsidies affect post-storm recovery is not well understood. Here, we report an experimental investigation into the effect of storm wrack on eco-geomorphological recovery of a coastal embryo dune in north-eastern Florida, USA, following hurricane Irma. We contrasted replicated 100-m2 wrack-removal and unmanipulated (control) plots, measuring vegetation and geomorphological responses over 21 months. Relative to controls, grass cover was reduced 4-fold where diverse storm wrack, including seagrass rhizomes, seaweed, and wood, was removed. Wrack removal was also associated with a reduction in mean elevation, which persisted until the end of the experiment when removal plots had a 14% lower mean elevation compared to control plots. These results suggest that subsides of wrack re-distributed from other ecosystem types (e.g. seagrasses, macroalgae, uplands): i) enhances the growth of certain dune-building grasses; and ii) boosts the geomorphological recovery of coastal dunes. Our study also indicates that the practice of post-storm beach cleaning to remove wrack - a practice widespread outside of protected areas - may undermine the resilience of coastal dunes and their services.

category: ecology


title: High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation

abstract: Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to genome 3D structure remains poorly understood. Here we used the highly-predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B-cells. After confirming that the model gives good predictions of Hi-C data for the non-malignant human B-cell derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy chain locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodelling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequence per se. Simulations of the IGH-CCND1 reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassing CCND1 and the IGH super-enhancers. We predicted how the structure and expression of CCND1 changes in these different cell lines, validating this using qPCR and fluorescence in situ hybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation break-points.

category: genomics


title: DNA methylation is not a driver of gene expression reprogramming in young honey bee workers

abstract: Intragenic DNA methylation, also called gene body methylation, is an evolutionarily-conserved epigenetic mechanism in animals and plants. In social insects, gene body methylation is thought to contribute to behavioral plasticity, for example between foragers and nurse workers, by modulating gene expression. However, recent studies have suggested that the majority of DNA methylation is sequence-specific, and therefore cannot act as a flexible mediator between environmental cues and gene expression. To address this paradox, we examined whole-genome methylation patterns in the brains and ovaries of young honey bee workers that had been subjected to divergent social contexts: the presence or absence of the queen. Although these social contexts are known to bring about extreme changes in behavioral and reproductive traits through differential gene expression, we found no significant differences between the methylomes of workers from queenright and queenless colonies. In contrast, thousands of regions were differentially methylated between colonies, and these differences were not associated with differential gene expression in a subset of genes examined. Methylation patterns were highly similar between brain and ovary tissues and only differed in nine regions. These results strongly indicate that DNA methylation is not a driver of differential gene expression between tissues or behavioral morphs. Finally, despite the lack of difference in methylation patterns, queen presence affected the expression of all four DNA methyltransferase genes, suggesting that these enzymes have roles beyond DNA methylation. Therefore, the functional role of DNA methylation in social insect genomes remains an open question.


title: Drug-bound and -free outward-facing structures of a multidrug ABC exporter point to a swing mechanism

abstract: Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved two ATP-Mg2+-bound outward-facing (OF) conformations of the Bacillus subtilis (homodimeric) BmrA, one by X-ray crystallography without drug, and another by single-particle cryo-EM with rhodamine 6G (R6G). Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5-6 of the other. R6G induces a rearrangement of TM1-2, highlighting a flexibility that was confirmed by H/D exchange and molecular dynamics simulations. The latter also shows a fast post-release occlusion of the cavity driven by hydrophobicity. Altogether, these data support a new swing mechanism for drug transport.

category: biochemistry


title: TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins

abstract: TMEM106B is an integral membrane protein of late endosomes and lysosomes involved in neuronal function, its over-expression being associated with familial frontotemporal lobar degeneration, and under-expression linked to hypomyelination. It has also been identified in multiple screens for host proteins required for productive SARS-CoV2 infection. Because standard approaches to understand TMEM106B at the sequence level find no homology to other proteins, it has remained a protein of unknown function. Here, the standard tool PSI-BLAST was used in a non-standard way to show that the lumenal portion of TMEM106B is a member of the LEA-2 domain superfamily. The non-standard tools (HMMER, HHpred and trRosetta) extended this to predict two yeast LEA-2 proteins in the lumenal domains of the degradative vacuole, equivalent to the lysosome: one in Vac7, a regulator of PI(3,5)P2 production, and three in Tag1 which signals to terminate autophagy. Further analysis of previously unreported LEA-2 structures indicated that LEA-2 domains have a long, conserved lipid binding groove. This implies that TMEM106B, Vac7 and Tag1 may all be lipid transfer proteins in the lumen of late endocytic organelles.

category: bioinformatics


title: Ensemble Switching Unveils a Kinetic Rheostat Mechanism of the Eukaryotic Thiamine PyrophosphateRiboswitch

abstract: Thiamine pyrophosphate (TPP) riboswitches regulate thiamine metabolism by inhibiting the translation of enzymes essential to thiamine synthesis pathways upon binding to thiamine pyrophosphate in cells across all domains of life. Recent work on the Arabidopsis thaliana TPP riboswitch suggests a multi-step TPP binding process involving multiple riboswitch conformational ensembles and that Mg2+ dependence underlies the mechanism of TPP recognition and subsequent transition to the translation-inhibiting state of the switching sequence followed by changes in the expression platform. However, details of the relationship between TPP riboswitch conformational changes and interactions with TPP and Mg2+ in the aptamer domain constituting this mechanism are unknown. Therefore, we integrated single-molecule multiparameter fluorescence and force spectroscopy with atomistic molecular dynamics simulations and found that conformational transitions within the aptamer domain associated with TPP and Mg2+ ligand binding occurred between at least five different ensembles on timescales ranging from s to ms. These dynamics are at least an order of magnitude faster than folding and unfolding kinetics associated with translation-state switching in the switching sequence. Moreover, we propose that two pathways exist for ligand recognition. Together, our results suggest a dynamic ensemble switching of the aptamer domain that may lead to the translation-inhibiting state of the riboswitch. Additionally, our results suggest that multiple configurations could enable inhibitory tuning manifested through ligand-dependent changes via ensemble switching and kinetic rheostat-like behavior of the Arabidopsis thaliana TPP riboswitch.

category: biophysics


title: Injury caused by alcoholic cardiomyopathy in spontaneous ethanol drinking rats

abstract: When speaking of pathologies caused or aggravated by the constant ingestion of ethanol, people with liver and central nervous system diseases soon come to mind, however, the acute intake of large amounts of ethanol and chronic abuse induce toxic effects in the majority of tissues. The heart is highlighted, since alcoholic cardiomyopathy (AC) has prevalence among alcoholics of 23 to 40% and occurs more frequently in men than in women. AC is characterized by dilation and poor contraction of one or both ventricles in the presence of increased ventricular wall thickness, along with a long history of ethanol abuse and no other cause identified. Our aim is to quantify the rate of cardiac tissue replacement, collagen fiber deposition and pro inflammatory cytokines in the left ventricle myocardium of volunteer ethanol drinking rats.

category: pathology


title: Deep learning from multiple experts improves identification of amyloid neuropathologies

abstract: Pathologists can label pathologies differently, making it challenging to yield consistent assessments in the absence of one ground truth. To address this problem, we present a DL approach that draws on a cohort of experts, weighs each contribution, and is robust to noisy labels. We collected 100,495 annotations on 20,099 candidate amyloid beta neuropathologies (cerebral amyloid angiopathy (CAA), and cored and diffuse plaques) from three institutions, independently annotated by five experts. DL methods trained on a consensus-of-two strategy yielded 12.6-26% improvements by area under the precision recall curve (AUPRC) when compared to those that learned individualized annotations. This strategy surpassed individual-expert models, even when unfairly assessed on benchmarks favoring them. Moreover, ensembling over individual models was robust to hidden random annotators. In blind prospective tests of 52,555 subsequent expert-annotated images, the models labeled pathologies like their human counterparts (consensus model AUPRC=0.74 cored; 0.69 CAA). This study demonstrates a means to combine multiple ground truths into a common-ground DL model that yields consistent diagnoses informed by multiple and potentially variable expert opinion.


title: GWAS-associated variants, non-genetic factors and transient transcriptome in Multiple Sclerosis etiopathogenesis: a colocalization analysis

abstract: A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. We previously suggested a stochastic etiologic model where small-scale random perturbations could reach a threshold for MS development. The recently described mapping of the transient transcriptome (TT), including intergenic and intronic RNAs, seems appropriate to verify this model through a rigorous colocalization analysis. We show that genomic regions coding for the TT were significantly enriched for MS-associated GWAS variants and DNA binding sites for molecular transducers mediating putative, non-genetic, etiopathogenetic factors for MS (e.g., vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction). These results suggest a model whereby TT-coding regions are hotspots of convergence between genetic ad non-genetic factors of risk/protection for MS, and plausibly for other complex disorders. Our colocalization analysis also provides a freely available data resource (www.mscoloc.com) for future research on MS transcriptional regulation.

category: neuroscience


title: GWAS-associated variants, non-genetic factors, and transient transcriptome in Multiple Sclerosis etiopathogenesis: a colocalization analysis


title: Face processing of social cognition in patients with first episode psychosis: Its deficits and association with the right subcallosal anterior cingulate cortex

abstract: The clinical importance of social cognition is well acknowledged in patients with psychosis, in particular those with first episode psychosis (FEP). Nevertheless, its brain substrates and circuitries remain elusive, lacking precise analysis between multimodal brain characteristics and behavioral sub-dimensions within social cognition. In the present study, we examined face processing of social cognition in 79 FEP patients and 80 healthy controls (HCs). We looked for a possible correlation between face processing and multimodal MRI characteristics such as resting-state functional connectivity (rsFC) and brain volume. We observed worse recognition accuracy, longer recognition response time, and longer memory response time in FEP patients when compared with HCs. Of these, memory response time was selectively correlated with specific rsFCs, which included the right subcallosal sub-region of BA24 in the ACC (scACC), only in FEP patients. The volume of this region was also correlated with memory response time in FEP patients. The scACC is functionally and structurally important in FEP-associated abnormalities of face processing measures in social cognition.


title: Individualized event structure drives individual differences in whole-brain functional connectivity

abstract: Resting-state functional connectivity is typically modeled as the correlation structure of whole-brain regional activity. It is studied widely, both to gain insight into the brains intrinsic organization but also to develop markers sensitive to changes in an individuals cognitive, clinical, and developmental state. Despite this, the origins and drivers of functional connectivity, especially at the level of densely sampled individuals, remain elusive. Here, we leverage novel methodology to decompose functional connectivity into its precise framewise contributions. Using two dense sampling datasets, we investigate the origins of individualized functional connectivity, focusing specifically on the role of brain network "events" - short-lived and peaked patterns of high-amplitude cofluctuations. Here, we develop a statistical test to identify events in empirical recordings. We show that the patterns of cofluctuation expressed during events are repeated across multiple scans of the same individual and represent idiosyncratic variants of template patterns that are expressed at the group level. Lastly, we propose a simple model of functional connectivity based on event cofluctuations, demonstrating that group-averaged cofluctuations are suboptimal for explaining participant-specific connectivity. Our work complements recent studies implicating brief instants of high-amplitude cofluctuations as the primary drivers of static, whole-brain functional connectivity. Our work also extends those studies, demonstrating that cofluctuations during events are individualized, positing a dynamic basis for functional connectivity.


title: Cell-intrinsic functions of the transcription factor Bhlhe40 in activated B cells and T follicular helper cells restrain the germinal center reaction and prevent lymphomagenesis

abstract: The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction - a process that relies on a complex interplay between specialized effector subsets of B and CD4 T lymphocytes - GC B cells and T follicular helper (TFH) cells. Intriguingly, several key positive regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Conditional Bhlhe40 inactivation confirmed cell-autonomous functions of Bhlhe40 in both GC B and TFH cells, while the GC phenotype was further enhanced upon loss of Bhlhe40 in both cell types. This negative regulation of the GC reaction by Bhlhe40 was of crucial importance, as Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.

category: immunology


title: Natural genetic variation drives microbiome selection in the Caenorhabditis elegans gut

abstract: Host genetic landscapes can shape microbiome assembly in the animal gut by contributing to the establishment of distinct physiological environments. However, the genetic determinants contributing to the stability and variation of these microbiome types remain largely undefined. Here, we use the free-living nematode Caenorhabditis elegans to identify natural genetic variation among wild strains of C. elegans strains that drives assembly of distinct microbiomes. To achieve this, we first established a diverse model microbiome that represents the phylogenetic and functional diversity naturally found in the C. elegans microbiome. Using this community, we show that C. elegans utilizes immune, xenobiotic and metabolic signaling pathways to favor the assembly of different microbiome types. Variations in these pathways were associated with the enrichment for specific commensals, including the Alphaproteobacteria Ochrobactrum. Using RNAi and mutant strains, we showed that host selection for Ochrobactrum is mediated specifically by host insulin signaling pathways. Ochrobactrum recruitment is blunted in the absence of daf-2/IGFR and requires the insulin signaling transcription factors daf-16/FOXO and pqm-1/SALL2. Further, the ability of C. elegans to enrich for Ochrobactrum is correlated positively with host outcomes, as animals that develop faster are larger and have higher gut Ochrobactrum colonization as adults. These results highlight a new role for the highly conserved insulin signaling pathways in the regulation of microbiome composition in C. elegans.

category: microbiology


title: Antimalarials in mosquitoes overcome Anopheles and Plasmodium resistance to malaria control strategies

abstract:
The spread of insecticide resistance in Anopheles mosquitoes and drug resistance in Plasmodium parasites is contributing to a global resurgence of malaria, making the generation of control tools that can overcome these issues an urgent public health priority. We recently showed that the transmission of Plasmodium falciparum parasites can be efficiently blocked when exposing Anopheles gambiae females to antimalarials deposited on a treated surface, with no negative consequences on mosquito fitness. Here, we demonstrate this approach can overcome the hurdles of insecticide resistance in mosquitoes and drug resistant in parasites. We show that the transmission-blocking efficacy of mosquito-targeted antimalarials is maintained when field-derived, insecticide resistant Anopheles are exposed to the potent cytochrome b inhibitor atovaquone, demonstrating that this drug escapes insecticide resistance mechanisms that could potentially interfere with its function. Moreover, this approach prevents transmission of field-derived, artemisinin resistant P. falciparum parasites (Kelch13 C580Y mutant), proving that this strategy could be used to prevent the spread of parasite mutations that induce resistance to front-line antimalarials. Atovaquone is also highly effective at limiting parasite development when ingested by mosquitoes in sugar solutions, including in ongoing infections. These data support the use of mosquito-targeted antimalarials as a promising tool to complement and extend the efficacy of current malaria control interventions.

Significance StatementEffective control of malaria is hampered by resistance to vector-targeted insecticides and parasite-targeted drugs. This situation is exacerbated by a critical lack of chemical diversity in both interventions and, as such, new interventions are badly needed. Recent laboratory studies have shown that an alternative approach based on treating Anopheles mosquitoes directly with antimalarial compounds can render the vector incapable of transmitting the Plasmodium parasites that cause malaria. While promising, showing that mosquito-targeted antimalarials remain effective against wild parasites and mosquitoes, including drug- and insecticide-resistant populations, respectively, is crucial to the future viability of this approach. In this study, carried out in the US and Burkina Faso, we show that antimalarial exposure is highly effective, even against extremely resistant mosquitoes, and can block transmission of drug-resistant parasites. By combining lab, and field-based studies in this way we have demonstrated that this novel approach can be effective in areas where conventional control measures are no longer as effective.


title: Systems analysis of gut microbiome influence on metabolic disease in HIV and high-risk populations

abstract:
Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV and has been linked with inflammation, anti-retroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease is associated with gut microbiome composition outside the context of HIV but has not been deeply explored in HIV infection nor in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the contribution of increased bacterial translocation and associated systemic inflammation that has been described in HIV-positive and HR-MSM individuals has not been explored. We used a multi-omic approach to explore relationships between impaired metabolic health, defined using fasting blood markers, gut microbes, immune phenotypes and diet. Our cohort included ART-treated HIV positive MSM with and without LD, untreated HIV positive MSM, and HR-MSM. For HIV positive MSM on ART, we further explored associations with the plasma metabolome. We found that elevated plasma lipopolysaccharide binding protein (LBP) was the most important predictor of impaired metabolic health and network analysis showed that LBP formed a hub joining correlated microbial and immune predictors of metabolic disease. Taken together, our results suggest the role of inflammatory processes linked with bacterial translocation and interaction with the gut microbiome in metabolic disease among HIV positive and negative MSM.

Importance StatementThe gut microbiome in people living with HIV (PLWH) is of interest as chronic infection often results in long term comorbidities. Metabolic disease is prevalent in PLWH even in well-controlled infection and has been linked with the gut microbiome in previous studies, but little attention has been given to PLWH. Furthermore, integrated analyses that consider gut microbiome together with diet, systemic immune activation, metabolites, and demographics have been lacking. In a systems-level analysis of predictors of metabolic disease in PLWH and men who are at high risk of acquiring HIV, we found that increased LBP, an inflammatory marker indicative of compromised intestinal barrier function, was associated with worse metabolic health. We also found impaired metabolic health associated with specific dietary components, gut microbes, and host and microbial metabolites. This work lays the framework for mechanistic studies aimed at targeting the microbiome to prevent or treat metabolic endotoxemia in HIV-infected individuals.


title: Cdk8 directly regulates glycolysis via phosphorylation of Gcr2

abstract: CDK8 encodes an evolutionarily conserved Mediator complex kinase subunit that functions in general and context-specific transcription regulation by phosphorylating core components of the transcription machinery and gene-specific transcription factors. To better understand the role Cdk8 in transcription regulation, we performed high-resolution gene expression time course analysis following nuclear depletion of Cdk8. Focusing on the earliest gene expression alterations revealed dysregulation of genes encoding glycolysis enzymes, suggesting a functional link to Gcr1 and Gcr2, key transcriptional activators of these genes. Consistently, we found that nuclear depletion of Cdk8 altered the mRNA levels of glycolysis genes as well as the promoter occupancy of Gcr2, but not Gcr1. Examination of the Gcr2 protein sequence revealed a putative Cdk8 phosphorylation site at serine 365, which we confirmed using in vitro and in vivo assays. Importantly, phospho-mutant GCR2 recapitulated the growth and gene expression defects of the GCR2 deletion mutant, effects not observed with a phospho mimetic mutant. As such, our work highlights Gcr2 as a new Cdk8 substrate, revealing that its phosphorylation is critical for the activation of genes encoding glycolysis enzymes.

category: molecular biology


title: DNA origami patterning of synthetic T cell receptors reveals spatial control of the sensitivity and kinetics of signal activation

abstract: T cell receptor clustering plays a key role in triggering cell activation, but the relationship between the spatial configuration of clusters and elicitation of downstream intracellular signals remains poorly understood. We developed a DNA-origami-based system that is easily adaptable to other cellular systems and enables rich interrogation of responses to a variety of spatially defined inputs. Using a chimeric antigen receptor (CAR) T cell model system with relevance to cancer therapy, we studied signaling dynamics at single cell resolution. We found that the spatial arrangement of receptors determines the ligand density threshold for triggering and encodes the temporal kinetics of signaling activities. We also showed that signaling sensitivity of a small cluster of high-affinity ligands is enhanced when surrounded by non-stimulating low-affinity ligands. Our results suggest that cells measure spatial arrangements of ligands and translates that information into distinct signaling dynamics, and provide insights into engineering new immunotherapies.


title: An extended DNA-free intranuclear compartment organizes centrosomal microtubules in Plasmodium falciparum

abstract: Rapid proliferation of Plasmodium falciparum parasites in human red blood cells is the cause of malaria and is underpinned by an unconventional cell division mode, called schizogony. Contrary to model organisms, P. falciparum replicates by multiple rounds of closed and asynchronous nuclear divisions that are not interrupted by cytokinesis. Organization and dynamics of the critical nuclear division factors are, however, poorly understood. Centriolar plaques, the centrosomes of P. falciparum, are important regulators of division and serve as microtubule organizing centers. Early microscopy studies reveal an acentriolar, amorphous structure although its detailed organization remains elusive. Intranuclear microtubules mediate chromosome segregation, but the small size of parasite nuclei has precluded detailed analysis of their arrangement by classical fluorescence microscopy. We apply recently developed STED, expansion microscopy, and live cell imaging protocols to describe the reconfiguration of microtubules during schizogony. Analysis of centrin, nuclear pore, and microtubule positioning reveals a bipartite organization of the centriolar plaque. While centrin is extranuclear, we confirm by correlative light and electron tomography that microtubules are nucleated in a previously unknown and extended intranuclear compartment, which is devoid of chromatin. This study enables us to build a working model of the organization of an unconventional centrosome and better understand the diversity of eukaryotic cell division modes.


title: Intriguing effects of selection intensity on the evolution of prosocial behaviors

abstract:
In many models of evolving populations, genetic drift has an outsized role relative to natural selection, or vice versa. While there are many scenarios in which one of these two assumptions is reasonable, intermediate balances between these forces are also biologically relevant. In this study, we consider some natural axioms for modeling intermediate selection intensities, and we explore how to quantify the long-term evolutionary dynamics of such a process. To illustrate the sensitivity of evolutionary dynamics to drift and selection, we show that there can be a "sweet spot" for the balance of these two forces, with sufficient noise for rare mutants to become established and sufficient selection to spread. This balance allows prosocial traits to evolve in evolutionary models that were previously thought to be unconducive to the emergence and spread of altruistic behaviors. Furthermore, the effects of selection intensity on long-run evolutionary outcomes in these settings, such as when there is global competition for reproduction, can be highly non-monotonic. Although intermediate selection intensities (neither weak nor strong) are notoriously difficult to study analytically, they are often biologically relevant; and the results we report suggest that they can elicit novel and rich dynamics in the evolution of prosocial behaviors.

Author summaryTheoretical models of populations have been useful for assessing when and how traits spread, in large part because they are simple. Rather than being used to reproduce empirical data, these idealized models involve relatively few parameters and are utilized to gain a qualitative understanding of what promotes or suppresses a trait. For prosocial traits, which entail a cost to self to help another, one thing that mathematical models often suggest is that competition to reproduce must be localized, meaning an individual must be fitter than just a small subset of the population in order to produce an offspring. We show here that this finding is not robust. Such traits can indeed proliferate when there is global competition for reproduction, which we demonstrate by increasing the degree to which fitness affects birth rates. Since this kind of "stronger selection" has also been observed empirically, we discuss how it is incorporated into theoretical models more broadly.

category: evolutionary biology


title: Directed evolution of the rRNA methylating enzyme Cfr reveals molecular basis of antibiotic resistance

abstract: Alteration of antibiotic binding sites through modification of ribosomal RNA (rRNA) is a common form of resistance to ribosome-targeting antibiotics. The rRNA-modifying enzyme Cfr methylates an adenosine nucleotide within the peptidyl transferase center, resulting in the C-8 methylation of A2503 (m8A2503). Acquisition of cfr results in resistance to eight classes of ribosome-targeting antibiotics. Despite the prevalence of this resistance mechanism, it is poorly understood whether and how bacteria modulate Cfr methylation to adapt to antibiotic pressure. Moreover, direct evidence for how m8A2503 alters antibiotic binding sites within the ribosome is lacking. In this study, we performed directed evolution of Cfr under antibiotic selection to generate Cfr variants that confer increased resistance by enhancing methylation of A2503 in cells. Increased rRNA methylation is achieved by improved expression and stability of Cfr through transcriptional and post-transcriptional mechanisms, which may be exploited by pathogens under antibiotic stress as suggested by natural isolates. Using a variant which achieves near-stoichiometric methylation of rRNA, we determined a 2.2 [A] cryo-EM structure of the Cfr-modified ribosome. Our structure reveals the molecular basis for broad resistance to antibiotics and will inform the design of new antibiotics that overcome resistance mediated by Cfr.


title: A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis.

abstract: The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine, appears to be attractive target for anti-Tuberculosis (TB) drug discovery. Starvation of M. tuberculosis deleted for either argB or argF genes led to rapid sterilization of these strains in mice while Chemical inhibition of ArgJ with Pranlukast was also found to clear chronic M. tuberculosis infection in animal models. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is explored using a fragment-based approach. We reveal several hits for these enzymes validated with biochemical and biophysical assays, and X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential of more enzymes in this pathway to be targeted with dedicated drug discovery programmes.


title: An Off-the-Shelf Bioadhesive Patch for Sutureless Repair of Gastrointestinal Defects

abstract:
Surgical sealing and repair of injured and resected gastrointestinal (GI) organs are critical requirements for successful treatment and tissue healing. Despite being the standard of care, hand-sewn closure of GI defects using sutures faces various limitations and challenges. The process remains technically complicated and time-consuming. The needle-piercing and pointwise closure also inflict tissue damage and stress concentration, raising the risk of local failure and subsequent anastomotic leaks. To address these limitations and challenges, we introduce an off-the-shelf bioadhesive GI patch capable of atraumatic, rapid, robust, and sutureless repair of GI defects. The GI patch synergistically integrates a non-adhesive top layer and a dry bioadhesive bottom layer, resulting in a thin, flexible, transparent, and ready to use dressing with tissue-matching mechanical properties. Rapid, robust, and sutureless sealing capability of the GI patch is systematically characterized based on various standard tests in ex vivo porcine GI organ models. In vitro and in vivo rat models are utilized to validate biocompatibility and biodegradability of the GI patch including comprehensive cytotoxicity, histopathology, immunofluorescence, and blood analyses. To validate the GI patchs efficacy in a clinically relevant setting, we demonstrate successful sutureless in vivo sealing and healing of GI defects; namely in rat stomach and colon, and porcine colon injury models. The proposed GI patch not only provides a promising alternative to suture for repair of GI defects but also offers potential clinical opportunities in the treatment and repair of other organs.

One Sentence SummaryAn off-the-shelf bioadhesive patch is introduced for facile sutureless repair of gastrointestinal defects, addressing various limitations of conventional suture-based treatments.

category: bioengineering


title: VCFcontam: A Machine Learning Approach to Estimate Cross-Sample Contamination from Variant Call Data

abstract:
The quality of genotyping calls resulting from DNA sequencing is reliant on high quality starting genetic material. One factor that can reduce sample quality and lead to misleading genotyping results is genetic contamination of a sample by another source, such as cells or DNA from another sample of the same or different species. Cross-sample contamination by individuals of the same species is particularly difficult to detect in DNA sequencing data, because the contaminating sequence reads look very similar to those of the intended base sample. We introduce a new method that uses a support vector regression model trained on in silico contaminated datasets to predict empirical contamination using a collection of variables drawn from VCF files, including the fraction of sites that are heterozygous, the fraction of heterozygous sites with imbalanced allele counts, and parameters describing distributions fit to heterozygous allele fractions in a sample. We use the method described here to train a model that can accurately predict the extent of cross-sample contamination within 1% of the actual fraction, for simulated contaminated samples in the 0-5% contamination range, directly from the VCF file.

DefinitionsO_ST_ABSLesser alleleC_ST_ABSThe allele in a heterozygous position that received less sequencing read support (which may be either the REF or ALT allele).

Lesser allele fraction (LAF)The number of sequencing reads supporting the less frequently observed allele divided by the sum of reads supporting both alleles in the genotype at a given genomic position.


title: Thermal stimulation neurophysiology of pressure phosphenes

abstract: To investigate effect on the intensity of pressure phosphenes (PP) of various methods of heating hands, as well as manual influence on cervical spine. This study included subjective assessments of the PP intensity in 10 healthy men, and chronometry of bioelectrical activity of brain and heart using electroencephalography (EEG) and electrocardiography (ECG). EEG and ECG frequency spectra respond synchronously to pressure, heat and light. The time of excitation of potential oscillations in the visual area of the cortex of both hemispheres is consistent with the delay in the onset of PP flaring. The effect of PP stimulation is enhanced when the hands and body are heated in a humid environment and at temperatures above 42 {degrees}C. Stimulation of PP by heating indicates the convergence of impulses from neurons of the lateral geniculate body (LGB) and nuclei of the thalamus, which are responsible for thermoreceptors in the skin of the palms and fingers. The thermal stimulation effect of PP is enhanced at temperatures above 42 {degrees}C due to the fact that thermoreceptors work as pain receptors. The mechanism of PP generation is dominated by the processes of redistribution and recombination of charges in the layers of the retina and LGB.


title: Thermal stimulation of pressure phosphenes


title: Large-scale design and refinement of stable proteins using sequence-only models

abstract: Engineered proteins generally must possess a stable structure in order to achieve their designed function. Stable designs, however, are astronomically rare within the space of all possible amino acid sequences. As a consequence, many designs must be tested computationally and experimentally in order to find stable ones, which is expensive in terms of time and resources. Here we report a neural network model that predicts protein stability based only on sequences of amino acids, and demonstrate its performance by evaluating the stability of almost 200,000 novel proteins. These include a wide range of sequence perturbations, providing a baseline for future work in the field. We also report a second neural network model that is able to generate novel stable proteins. Finally, we show that the predictive model can be used to substantially increase the stability of both expert-designed and model-generated proteins.


title: Molecular Response to PARP1 Inhibition in Ovarian Cancer Cells as Determined by Mass Spectrometry Based Proteomics

abstract: Poly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment. We found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, consistent with transcript changes in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and {beta}-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-{varkappa}B signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for therapeutic inhibition in combination with PARP1i. When tested experimentally, the combination of PARPi with an inhibitor of fatty acid synthase (TVB-2640) has a 3-fold synergistic effect and is therefore of particular pre-clinical interest. Our study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.

category: cancer biology


title: Neural Networks for parameter estimation in microstructural MRI: a study with a high-dimensional diffusion-relaxation model of white matter microstructure

abstract: Specific features of white-matter microstructure can be investigated by using biophysical models to interpret relaxation-diffusion MRI brain data. Although more intricate models have the potential to reveal more details of the tissue, they also incur time-consuming parameter estimation that may con-verge to inaccurate solutions due to a prevalence of local minima in a degenerate fitting landscape. Machine-learning fitting algorithms have been proposed to accelerate the parameter estimation and increase the robustness of the attained estimates. So far, learning-based fitting approaches have been restricted to lower-dimensional microstructural models where dense sets of training data are easy to generate. Moreover, the degree to which machine learning can alleviate the degeneracy problem is poorly understood. For conventional least-squares solvers, it has been shown that degeneracy can be avoided by acquisition with optimized relaxation-diffusion-correlation protocols that include tensor-valued diffusion encoding; whether machine-learning techniques can offset these acquisition require-ments remains to be tested. In this work, we employ deep neural networks to vastly accelerate the fitting of a recently introduced high-dimensional relaxation-diffusion model of tissue microstructure. We also develop strategies for assessing the accuracy and sensitivity of function fitting networks and use those strategies to explore the impact of acquisition protocol design on the performance of the network. The developed learning-based fitting pipelines were tested on relaxation-diffusion data acquired with optimized and sub-sampled acquisition protocols. We found no evidence that machine-learning algorithms can by themselves replace a careful design of the acquisition protocol or correct for a degenerate fitting landscape.


title: Electro-Metabolic Sensing Through Capillary ATP-Sensitive K+ Channels and Adenosine to Control Cerebral Blood Flow

abstract:
The dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuro/glial-derived compounds that regulate regional and global cerebral perfusion. The membrane potential (VM) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K+ channel (KATP) is a key regulator of vascular VM in other beds, but whether brain capillaries possess functional KATP channels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express KATP channels that robustly control VM. We further show that the endogenous mediator adenosine acts through A2A receptors and the Gs/cAMP/PKA pathway to activate capillary KATP channels. Moreover, KATP channel stimulation in vivo causes vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of KATP channels in cECs and pericytes and suggest their significant influence on CBF.

HIGHLIGHTSO_LICapillary network cellular components--endothelial cells and pericytes--possess functional KATP channels.
C_LIO_LIActivation of KATP channels causes profound hyperpolarization of capillary cell membranes.
C_LIO_LICapillary KATP channels are activated by exogenous adenosine via A2A receptors and cAMP-dependent protein kinase.
C_LIO_LIKATP channel activation by adenosine or synthetic openers increases cerebral blood flow.
C_LI


title: Hippocampal and thalamic afferents form distinct synaptic microcircuits in the mouse frontal cortex

abstract: Neural circuits within the frontal cortex support the flexible selection of goal-directed behaviors by integrating input from brain regions associated with sensory, emotional, episodic, and semantic memory functions. From a connectomics perspective, determining how these disparate afferent inputs target their synapses to specific cell types in the frontal cortex may prove crucial in understanding circuit-level information processing. Here, we used monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting four distinct classes of local inhibitory interneurons and four distinct classes of excitatory projection neurons in mouse infralimbic cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide received a large proportion of inputs from hippocampal regions, while interneurons expressing neuron-derived neurotrophic factor received a large proportion of inputs from thalamic regions. A more moderate hippocampal-thalamic dichotomy was found among the inputs targeting excitatory neurons that project to the basolateral amygdala, lateral entorhinal cortex, nucleus reuniens of the thalamus, and the periaqueductal gray. Together, these results show a prominent bias among hippocampal and thalamic afferent systems in their targeting to genetically or anatomically defined sets of frontal cortical neurons. Moreover, they suggest the presence of two distinct local microcircuits that control how different inputs govern frontal cortical information processing.


title: Synaptotagmin rings as high sensitivity regulators of synaptic vesicle docking and fusion

abstract:
Synchronous release at neuronal synapses is accomplished by a machinery that senses calcium influx and fuses the synaptic vesicle and plasma membranes to release neurotransmitters. Previous studies suggested the calcium sensor Synaptotagmin (Syt) is a facilitator of vesicle docking and both a facilitator and inhibitor of fusion. On phospholipid monolayers, the Syt C2AB domain spontaneously oligomerized into rings that are disassembled by Ca2+, suggesting Syt rings may clamp fusion as membrane-separating "washers" until Ca2+-mediated disassembly triggers fusion and release (Wang et al., 2014). Here we combined mathematical modeling with experiment to measure mechanical properties of Syt rings and to test this mechanism. Consistent with experiment, the model quantitatively recapitulates observed Syt ring-induced dome and volcano shapes on phospholipid monolayers, and predicts rings are stabilized by anionic phospholipid bilayers or bulk solution with ATP. The selected ring conformation is highly sensitive to membrane composition and bulk ATP levels, a property that may regulate vesicle docking and fusion in ATP-rich synaptic terminals. We find the Syt molecules hosted by a synaptic vesicle oligomerize into a halo, unbound from the vesicle, but in proximity to sufficiently PIP2-rich plasma membrane (PM) domains the PM-bound trans Syt ring conformation is preferred. Thus, the Syt halo serves as landing gear for spatially directed docking at PIP2-rich sites that define the active zones of exocytotic release, positioning the Syt ring to clamp fusion and await calcium. Our results suggest the Syt ring is both a Ca2+-sensitive fusion clamp and a high-fidelity sensor for directed docking.

SignificanceSynchronous neurotransmitter release relies on directed docking of synaptic vesicles at active zones in axon terminals, where calcium influx activates membrane fusion and release. In vitro, the calcium sensor Synaptotagmin oligomerizes into rings disassembled by calcium. Here, experiment and modeling suggest the Synaptotagmin molecules hosted by an undocked vesicle oligomerize into a tethered, unbound halo in ATP-rich synaptic terminals. The halo directs vesicle docking to PIP2-rich plasma membrane domains in active zones, where the trans-bound ring conformation is favored, interposed between the membranes to clamp fusion until calcium triggers ring disassembly and neurotransmitter release. The mechanism exploits the extreme sensitivity of Synaptotagmin ring binding preferences to solution and membrane composition, with ~15 -fold-enhanced sensitivity for rings of ~15 molecules.


title: Context-dependent miR-21 regulation of TLR7-mediated autoimmune and foreign antigen driven antibody-forming cell and germinal center responses

abstract:
MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), though the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. Herein, using the TLR7 agonist imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody forming cells (AFC), without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21 deficient Sle1b (Sle1b.miR-21KO) mice that were associated with reduced interferon, proinflammatory cytokines, and effector CD4+ T cell responses. RNAseq analysis on B cells from Sle1b.miR-21KO mice revealed reduced activation and response to interferon and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I interferon stimulation. Our findings in the B6.Sle1b.Yaa spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and Tfh responses. Finally, immunization with T-dependent antigen revealed a role for miR-21 in foreign antigen driven GC and Ab, but not AFC responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign antigen driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development.

Key PointsO_LImiR-21 has context dependent effects on AFC and GC responses
C_LIO_LImiR-21 promotes TLR7-driven autoimmunity with activation of multiple B cell pathways
C_LIO_LImiR-21 is required for optimal B cell responses to T-dependent foreign antigen
C_LI


title: Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair

abstract: Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger a rapid calcium-activated scrambling and cytosolic exposure of sphingomyelin. Subsequent metabolic conversion of sphingomyelin by neutral sphingomyelinases on the cytosolic surface of injured lysosomes promotes their repair, also when ESCRT function is compromised. Conversely, blocking turnover of cytosolic sphingomyelin renders cells more sensitive to lysosome-damaging drugs. Our data indicate that calcium-activated scramblases, sphingomyelin, and neutral sphingomyelinases are core components of a previously unrecognized membrane restoration pathway by which cells preserve the functional integrity of lysosomes.


title: Endomitosis controls tissue-specific gene expression during development

abstract: Polyploid cells contain more than two copies of the genome and are found in many plant and animal tissues. Different types of polyploidy exist, in which the genome is confined to either one nucleus (mononucleation) or two or more nuclei (multinucleation). Despite the widespread occurrence of polyploidy, the functional significance of different types of polyploidy are largely unknown. Here, we assess the function of multinucleation in C. elegans intestinal cells through specific inhibition of binucleation without altering genome ploidy. Through single worm RNA sequencing, we find that binucleation is important for tissuespecific gene expression, most prominently for genes that show a rapid upregulation at the transition from larval development to adulthood. Regulated genes include vitellogenins, which encode yolk proteins that facilitate nutrient transport to the germline. We find that reduced expression of vitellogenins in mononucleated intestinal cells leads to progeny with developmental delays and reduced fitness. Together, our results show that binucleation facilitates rapid upregulation of intestine-specific gene expression during development, independently of genome ploidy, underscoring the importance of spatial genome organization for polyploid cell function.


title: A wild-derived antimutator drives germline mutation spectrum differences in a genetically diverse murine family

abstract: Summary ParagraphAlthough germline mutation rates and spectra can vary within and between species, genetic modifiers of these traits have long eluded detection. In this study, we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory mouse strains C57BL/6J (B) and DBA/2J (D). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes. We show that mice inheriting D haplotypes at a quantitative trait locus (QTL) on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily due to the activity of a C>A-dominated mutational signature known as SBS18. The B and D QTL haplotypes encode different alleles of the DNA repair gene Mutyh, which underlies the heritable colorectal cancer syndrome in which SBS18 was first identified. The B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.

category: genetics


title: A natural mutator allele shapes mutation spectrum variation in mice


title: Progressive and predictive markers of disease evolution: platelet transcriptome in chronic myeloproliferative neoplasms

abstract:
Predicting disease progression remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs) as a model, we identify the blood platelet transcriptome as a proxy for highly sensitive progression biomarkers that also enables prediction of advanced disease via machine learning algorithms. Using RNA sequencing (RNA-seq), we derive disease-relevant gene expression in purified platelets from 120 peripheral blood samples constituting two time-separated cohorts of patients diagnosed with one of three MPN subtypes at sample acquisition - essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), and healthy donors (n=21). The MPN platelet transcriptome reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy and discriminates each clinical phenotype. Leveraging this dataset that shows a characteristic progressive expression gradient across MPN, we develop a machine learning model (Lasso-penalized regression) and predict advanced subtype MF at high accuracy and under two conditions of external validation: i) temporal: our two Stanford cohorts, AUC-ROC of 0.96; and ii) geographical: independently published data of an additional n=25 MF and n=46 healthy donors, AUC-ROC of 0.97). Lasso-derived signatures offer a robust core set of < 5 MPN transcriptome markers that are progressive in expression. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis-associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs demonstrates a proof of principle for disease risk stratification and progression beyond genetic data alone, with potential utility in other progressive disorders.

HighlightsLeveraging two independent and mutually validating MPN patient cohorts, we identify progressive transcriptomic markers that also enable externally validated prediction in MPNs.

Our platelet RNA-Seq data identifies impaired protein homeostasis as prominent in MPN progression and offers putative targets of therapy.

VISUAL ABSTRACT

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title: Platelet transcriptome yields progressive markers in chronic myeloproliferative neoplasms and identifies putative targets of therapy


title: Massively parallel reporter perturbation assay uncovers temporal regulatory architecture during neural differentiation

abstract: Gene regulatory elements play a key role in orchestrating gene expression during cellular differentiation, but what determines their function over time remains largely unknown. Here, we performed perturbation-based massively parallel reporter assays at seven early time points of neural differentiation to systematically characterize how regulatory elements and motifs within them guide cellular differentiation. By perturbing over 2,000 putative DNA binding motifs in active regulatory regions, we delineated four categories of functional elements, and observed that activity direction is mostly determined by the sequence itself, while the magnitude of effect depends on the cellular environment. We also find that fine-tuning transcription rates is often achieved by a combined activity of adjacent activating and repressing elements. Our work provides a blueprint for the sequence components needed to induce different transcriptional patterns in general and specifically during neural differentiation.


title: α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity.

abstract: -Synuclein aggregation is a key driver of neurodegeneration in Parkinsons disease and related syndromes. Accordingly, obtaining a molecule that targets -synuclein pathogenic assemblies with high affinity and selectivity is a long-pursued objective. Here, we have exploited the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of -helical peptides that bind selectively to these -synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into an unprecedented anti-aggregation potency and the ability to abrogate the oligomers toxicity. With a structure-function relationship in hand, we identified a human peptide expressed in the brain and in the gastrointestinal tract with exceptional binding, antiaggregation, and detoxifying properties, which suggests it might play a protective role against synucleinopathies. The chemical entities we describe here represent a new therapeutic paradigm and are promising tools to assist diagnosis by selectively detecting -synuclein pathogenic species in biofluids.


title: Neuronal mechanisms of novelty seeking

abstract: Humans and other primates interact with the world by observing and exploring visual objects. In particular, they often seek out the opportunities to view novel objects that they have never seen before, even when they have no extrinsic primary reward value. However, despite the importance of novel visual objects in our daily life, we currently lack an understanding of how primate brain circuits control the motivation to seek out novelty. We found that novelty-seeking is regulated by a small understudied subcortical region, the zona incerta (ZI). In a task in which monkeys made eye movements to familiar objects to obtain the opportunity to view novel objects, many ZI neurons were preferentially activated by predictions of future novel objects and displayed burst excitations before gaze shifts to gain access to novel objects. Low intensity electrical stimulation of ZI facilitated gaze shifts, while inactivations of ZI reduced novelty-seeking. Surprisingly, additional experiments showed that this ZI-dependent novelty seeking behavior is not regulated by canonical neural circuitry for reward seeking. The habenula-dopamine pathway, known to reflect reward predictions that control reward seeking, was relatively inactive during novelty-seeking behavior in which novelty had no extrinsic reward value. Instead, high channel-count electrophysiological experiments and anatomical tracing identified a prominent source of control signals for novelty seeking in the anterior ventral medial temporal cortex (AVMTC), a brain region known to be crucially involved in visual processing and object memory. In addition to their well-known function in signaling the novelty or familiarity of objects in the current environment, AVMTC neurons reflected the predictions of future novel objects, akin to the way neurons in reward-circuitry predict future rewards in order to control reward-seeking. Our data uncover a network of primate brain areas that regulate novelty-seeking. The behavioral and neural distinctions between novelty-seeking and reward-processing highlight how the brain can accomplish behavioral flexibility, providing a mechanism to explore novel objects.


title: Environmental, structural and taxonomic diversity factors drive aboveground carbon stocks in a semi-deciduous tropical rainforest strata in Cameroon

abstract:
Tropical forests play an important role in biodiversity conservation and ecosystem functioning. Few studies have teased apart the independent effects of biotic and abiotic factors on aboveground carbon across tree size groups and the whole tree community level in a tropical semi-deciduous rainforest. This study aims to analyze the relative and independent effects of abiotic (topography, soil fertility/texture and disturbance) and biotic factors on carbon stocks across tree size groups, as well as at the whole tree community in semi-deciduous plots, including logged plots.

We used data from 30 1-ha plots and 22,064 trees distributed in a semi-deciduous tropical rainforest of Cameroon. For each plot, we quantified disturbance, topography and eleven soil conditions. Besides, we quantified three taxonomic richness and diversity Gini index. We used structural equation models to test the hypothesis that all drivers have independent, positive effects on aboveground carbon stocks across tree-sized groups and the whole tree community.

The logging disturbance decreased aboveground carbon stocks for the whole tree community and trees size groups across our site except for large trees. Topographical factors (i.e., slope and elevation) increased aboveground carbon (AGC) of the whole tree community and the large trees. In contrast, soil nitrogen (Nsoil) and clay proportion increased AGC of the small stems and understorey trees groups. This study found that biotics factors have some indirect and direct effects on AGC. Taxonomic diversity through niche complementarity had a positive relationship with aboveground carbon stocks across the trees size groups and the whole tree community, while diversity Gini index had strongest relationships with aboveground carbon stocks.

The significant effects of structural diversity on aboveground carbon stocks of the whole tree community, large trees, and understory trees highlight the importance of maintaining a layered structure and tall trees in the forest.


title: New SARS-CoV-2 lineages could evade CD8+ T-cells response

abstract:
BackgroundMany SARS-CoV-2 variants of concern have emerged since the Covid-19 outburst, notably the lineages detected in the UK, South Africa, and Brazil. Their increased transmissibility and higher viral load put them in the spotlight. Much has been investigated on the ability of those new variants to evade antibody recognition. However, not enough attention has been given to pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of infection by new lineages.

MethodsIn this work, we investigated the SARS-CoV-2-specific CD8+ T cell epitopes from the main variants of concern and the potential of associated mutations to trigger or hinder CD8+ T-cells response. We also estimated the populations coverage of these different lineages, considering peptide binding predictions to class I HLA alleles from 29 countries to investigate differences in the fraction of individuals expected to respond to a given epitope set from new and previous lineages.

ResultsWe observed a lower populational coverage for 20B/S.484K (P.2 lineage) in contrast to an increased coverage found for 20H/501Y.V2 (B.1.351 Lineage) and 20J/501Y.V3 (P.1 lineage) compared to a reference lineage. Moreover, mutations such as Spike N501Y and Nucleocapsid T205I were predicted to have an overall higher affinity through HLA-I than the reference sequence.

ConclusionsIn summary, the data in this work provided evidence for the existence of potentially immunogenic and conserved epitopes across new SARS-CoV-2 variants, but also highlights the reduced populationals coverage for the Brazilian lineage P.2, suggesting its potential to evade from CD8+ T-cell responses. Our results also may guide efforts to characterize and validate relevant peptides to trigger CD8+ T-cell responses, and design new universal T-cell-inducing vaccine candidates that minimize detrimental effects of viral diversification and at the same time induce responses to a broad human population.


title: What makes our lungs look red?

abstract:
What makes our lungs look red? This seems to be a naIve and trivial question. Indeed, all the textbooks tell us that what makes our body red is the presence of blood, or more precisely the red blood cells (RBC). Here we provide some experimental evidence as well arguments to prove that this belief is wrong, or only partially true. In fact, we identified an important population of red cells located outside of the blood vessels as highly compacted clusters, in the connection tissues of the lungs of several species of animals including rat and human being. These red cells possessed each a nucleus, expressing several biomarkers of different cell types such as PF4, vWF, SCF-1R, CD200R, TGF-b, etc... Interestingly, being morphologically heterogeneous, they react collectively to certain stimuli. For example, they aggregated on collagen fibers forming clusters of cells resembling that observed in vivo. The red cells may have some features of Hematopoietic Stem Cells, since they were capable of differentiating into other cell types such as alveolar macrophages. In nasal polyps, these cells formed vessel-like structures, confined within a CD31-positive tubes. Upon exposure to toxic chemicals, they formed dense networks, suggesting a possible role in coagulation. Furthermore, the number of these red cells was greatly increased in the lungs of diseased donors, especially in the lungs of CF patients. Instead of being secreted as what happens in normal red cells, vWF proteins were tethered on the cytoplasmic membrane of the red cells isolated from the lungs of CF donors, which may explain at least partially the fibrotic nature of the CF lungs.

Taken together, we conclude that what makes the lungs look red is not the red blood cells, rather a distinct population of red cells, we call them Red Soma Cells (RSC). We believe that the discovery and characterization of this important population of cells will have profound theoretic as well as therapeutic implications.


title: Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by CDS composition and mRNA localisation

abstract:
BackgroundRegulation of protein output at the level of translation allows for a rapid adaptation to dynamic changes to the cells requirements. This precise control of gene expression is achieved by complex and interlinked biochemical processes that modulate both the protein synthesis rate and stability of each individual mRNA. A major factor coordinating this regulation is the Ccr4-Not complex. Despite playing a role in most stages of the mRNA life cycle, no attempt has been made to take a global integrated view of how the Ccr4-Not complex affects gene expression.

ResultsThis study has taken a comprehensive approach to investigate post-transcriptional regulation mediated by the Ccr4-Not complex assessing steady-state mRNA levels, ribosome position, mRNA stability and protein production transcriptome-wide. Depletion of the scaffold protein CNOT1 results in a global upregulation of mRNA stability and the preferential stabilisation of mRNAs enriched for G/C-ending codons. We also uncover that mRNAs targeted to the ER for their translation have reduced translational efficiency when CNOT1 is depleted, specifically downstream of the signal sequence cleavage site. In contrast, translationally upregulated mRNAs are normally localised in p-bodies, contain disorder-promoting amino acids and encode nuclear localised proteins. Finally, we identify ribosome pause sites that are resolved or induced by the depletion of CNOT1.

ConclusionWe define the key mRNA features that determine how the human Ccr4-Not complex differentially regulates mRNA fate and protein synthesis through a mechanism linked to codon composition, amino acid usage, and mRNA localisation.


title: Good host - bad host: molecular and evolutionary basis for survival, its failure, and virulence factors of the zoonotic nematode Anisakis pegreffii

abstract: Parasitism is a highly successful life strategy and a driving force in genetic diversity that has evolved many times over. Consequently, parasitic organisms have adopted a rich display of traits associated with survival that guarantees an effective "communication" with the host immunity and a balance with surrounding microbiome. However, gain/loss of hosts along the evolutionary axis represents a complex scenario that as contemporary onlookers, we can observe only after a long time displacement. The zoonotic and monophyletic Anisakidae diverged from its terrestrial sister group Ascarididae 150-250 Ma, although a split from their common ancestral host, a terrestrial amniote, seemingly happened already in Early Carboniferous (360.47 Ma). Faced with the sea-level rise during the Permian-Triassic extinction (215 Ma), anisakids acquired a semiaquatic tetrapod host, and as a result of lateral host-switches in Cenozoic, colonised marine mammals, co-evolving with their "new hosts". Although contemporary anisakids have lost the ability to propagate in terrestrial hosts, they can survive for a limited time in humans. To scrutinize anisakid versatility to infect evolutionary-distant host, we performed transcriptomic profiling of larvae infecting the accidental host (rat) and compared it to that of larvae infecting an evolutionary-familiar, paratenic host (fish). Identified differences and the modeling of handful of shared transcripts, provides the first insights into evolution of larval nematode virulence, warranting further investigation of shared transcript as potential drug therapy targets. Our findings have also revealed some key intrinsic cues that direct larval fate during infection.


title: A robust voice-selective response in the human brain as revealed by electrophysiological recordings and fast periodic auditory stimulation

abstract:
Voices are arguably among the most relevant sounds in humans everyday life, and several studies have suggested the existence of voice-selective regions in the human brain. Despite two decades of research, defining the human brain regions supporting voice recognition remains challenging. Moreover, whether neural selectivity to voices is merely driven by acoustic properties specific to human voices (e.g. spectrogram, harmonicity), or whether it also reflects a higher-level categorization response is still under debate. Here, we objectively measured rapid automatic categorization responses to human voices with Fast Periodic Auditory Stimulation (FPAS) combined with electroencephalography (EEG). Participants were tested with stimulation sequences containing heterogeneous non-vocal sounds from different categories presented at 4 Hz (i.e., 4 stimuli/second), with vocal sounds appearing every 3 stimuli (1.333 Hz). A few minutes of stimulation are sufficient to elicit robust 1.333 Hz voice-selective focal brain responses over superior temporal regions of individual participants. This response is virtually absent for sequences using frequency-scrambled sounds, but is clearly observed when voices are presented among sounds from musical instruments matched for pitch and harmonicity-to-noise ratio. Overall, our FPAS paradigm demonstrates that the human brain seamlessly categorizes human voices when compared to other sounds including matched musical instruments and that voice-selective responses are at least partially independent from low-level acoustic features, making it a powerful and versatile tool to understand human auditory categorization in general.

Significance statementVoices are arguably among the most relevant sounds we hear in our everyday life, and several studies have corroborated the existence of regions in the human brain that respond preferentially to voices. However, whether this preference is driven by specific acoustic properties of voices or if it rather reflects a higher-level categorization response to voices is still under debate. We propose a new approach to objectively identify rapid automatic voice-selective responses with frequency tagging and electroencephalographic recordings. In four minutes of recording only, we recorded robust voice-selective responses independent from low-level acoustic cues, making this approach highly promising for studying auditory perception in children and clinical populations.


title: Yersinia pestis lipopolysaccharide remodeling confers resistance to a Xenopsylla cheopis cecropin

abstract: Fleas are major vectors of Yersinia pestis, the causative agent of plague. It has been proposed that Y. pestis has developed the ability to overcome the innate immune responses of fleas. Despite the fact that they transmit a number of bacterial infections, very little is known about the immune responses in fleas. In this study, we describe the antimicrobial activities of cecropin from Xenopsylla cheopis (cheopin), a major vector for Y. pestis in the wild. This is the first cecropin-class antimicrobial peptide described from Siphonaptera insects. Cheopin showed potent activity against Gram-negative bacteria, but little activity against wild-type Y. pestis KIM6+. Deletion of the aminoarabinose operon, which is responsible for the 4-amino-4-deoxy-L-arabinose (Ara4N) modification of LPS, rendered Y. pestis highly susceptible to cheopin. Confocal microscopy and whole cell binding assays indicated that Ara4N modification reduces the affinity of cheopin for Y. pestis. Further, cheopin only permeabilized bacterial membranes in the absence of Ara4N-modified LPS, which was correlated with bacterial killing. This study provides insights into innate immunity of the flea and evidence for the crucial role of Ara4N modification of Y. pestis LPS in conferring resistance against flea antimicrobial peptides.


title: Rare transmission of commensal and pathogenic bacteria in the gut microbiome of hospitalized adults

abstract:
Bacterial bloodstream infections are a major cause of morbidity and mortality among patients undergoing hematopoietic cell transplantation (HCT). Although previous research has demonstrated that pathogenic organisms may translocate from the gut microbiome into the bloodstream to cause infections, the mechanisms by which HCT patients acquire pathogens in their microbiome have not yet been described. We hypothesized that patient-patient transmission may be responsible for pathogens colonizing the microbiome of HCT patients, and that patients who share time and space in the hospital are more likely to share bacterial strains.

Here, we used linked-read and short-read metagenomic sequencing to analyze 401 stool samples collected from 149 adults undergoing HCT and hospitalized in the same unit over five years. We used metagenomic assembly and strain-specific comparison methods to investigate transmission of gut microbiota between individuals. While patients who shared time and space in the hospital did not converge in overall microbiome composition, we did observe four pairs of patients who harbor identical or nearly identical E. faecium strains in their microbiome. These strains may be the result of transmission between patients who shared a room and bathroom, acquisition from a common source in the hospital or transmission from an unsampled source.

We also observed identical Akkermansia muciniphila and Hungatella hathewayi strains in two pairs of patients. In both cases, the patients were roommates for at least one day, the strain was absent in the putative recipients microbiome prior to the period of roommate overlap and the putative recipient had a microbiome perturbed by antibiotic treatment for a bloodstream infection. Finally, we identified multiple patients who harbored identical strains of several species commonly found in commercial probiotics and dairy products, including Lactobacillus rhamnosus, Lactobacillus gasseri and Streptococcus thermophilus. Overall, our findings indicate that pathogenic organisms from a single source are not frequently colonizing the gut microbiome of multiple patients. However, the potential transmission of commensal microbes with immunomodulatory properties raises questions about the recovery of microbiome diversity after HCT, and indicates that patients in this setting may acquire new microbes by sharing space with others.


title: Radiation Threats to Humans in Space and an alternative approach with Probiotics

abstract: Space type radiation is an important factor to consider for scientists on International Space Stations, especially high linear transfer energy (LET) since it has imminent effects on microorganisms. The abundances of bacteria are a good indicator of how radiation influences the gut microbiome. The current study is an attempt towards this; thus, we have employed a public dataset (Bioproject code PRJNA368790) of 80 mice samples treated with a range of doses from 0Gy to 1Gy and feces samples were collected at different time points of post radiation treatment. Metagenomic analysis was performed on this data to understand the effect of radiation doses on the abundance of microbial species or microbial diversity implementing the DADA2 and Phyloseq pipelines. Our analyses have shown that 0.1Gy high LET radiation had the significant effect on the species of bacteria. There is a significant decrease in four types of bacteria, i.e., Bifidobacterium longum, Bifidobacterium castoris, Lactobacillus gasseri and Lactobacillus johnsonii, with p-value of 7.05x10-5, 0.020, 0.057and 0.020, respectively. Additionally, pathway analysis indicates the protein coding products of these bacteria are involved in the GABAergic synaptic pathway. Further, our study has shown the significant difference between post radiation time points, i.e., 10 days vs.30 days and suggested the acclimatization period could be around 10 days for these bacteria.


title: Persistence of SARS-CoV-2 virus and viral RNA on hydrophobic and hydrophilic surfaces and investigating contamination concentration

abstract:
The transmission of SARS-CoV-2 is likely to occur through a number of routes, including contact with contaminated surfaces. Many studies have used RT-PCR analysis to detect SARS-CoV-2 RNA on surfaces but seldom has viable virus been detected. This paper investigates the viability over time of SARS-CoV-2 dried onto a range of materials and compares viability of the virus to RNA copies recovered, and whether virus viability is concentration dependant.

Viable virus persisted for the longest time on surgical mask material and stainless steel with a 99.9% reduction in viability by 124 and 113 hours respectively. Viability of SARS-CoV-2 reduced the fastest on a polyester shirt, with a 99.9% reduction within 2.5 hours. Viability on cotton was reduced second fastest, with 99.9% reduction in 72 hours. RNA on all the surfaces exhibited a one log reduction in genome copy recovery over 21 days.

The findings show that SARS-CoV-2 is most stable on non-porous hydrophobic surfaces. RNA is highly stable when dried on surfaces with only one log reduction in recovery over three weeks. In comparison, SARS-CoV-2 viability reduced more rapidly, but this loss in viability was found to be independent of starting concentration. Expected levels of SARS-CoV-2 viable environmental surface contamination would lead to undetectable levels within two days. Therefore, when RNA is detected on surfaces it does not directly indicate presence of viable virus even at high CT values.

ImportanceThis study shows the impact of material type on the viability of SARS-CoV-2 on surfaces. It demonstrates that the decay rate of viable SARS-CoV-2 is independent of starting concentration. However, RNA shows high stability on surfaces over extended periods. This has implications for interpretation of surface sampling results using RT-PCR to determine the possibility of viable virus from a surface. Unless sampled immediately after contamination it is difficult to align RNA copy numbers to quantity of viable virus on a surface.


title: Optimized structure of monoubiquitinated FANCD2 (human) at Lys 561: a theoretical approach

abstract: Fanconi anaemia pathway repairs inter-strand cross linking damage (ICL) of the DNA. Monoubiquitination of FANCD2 and FANCI is very crucial for ICL repairing. In this work we have tried to understand the monoubiquitinated FANCD2 structure, which facilitates the FANCD2 for binding the damage part of the chromatin. Crystal structure of the monoubiquitinated FANCD2 alone is not available, therefore we have developed the optimized structure of the human monoubiquitinated (Lys 561) FANCD2. As there is no suitable software or web server we have developed a method for building up monoubiquitinated product and validated on simplest monoubiquitinated protein, diubiquitin. We have predicted the structure of human monoubiquitinated FANCD2 by using our method and studied the interaction with DNA by docking studies. Molecular Dynamics (MD) simulation was used to understand the stability of the structure. Large structural differences have been observed between FANCD2 and monoubiquitinated FANCD2. DNA docking studies suggest that the binding site varies for the FANCD2 and monoubiquitinated FANCD2.


title: Temporally distinct oscillatory codes of retention and manipulation of verbal working memory

abstract: Most psychophysiological studies of working memory (WM) target only the short-term memory construct, while short-term memory is only a part of the WM responsible for the storage of sensory information. Here, we aimed to further investigate oscillatory brain mechanisms supporting the executive components of WM - the part responsible for the manipulation of information. We conducted an exploratory reanalysis of a previously published EEG dataset where 156 participants (82 females) performed tasks requiring either simple retention or retention and manipulation of verbal information in WM. A relatively long delay period (>6s) was employed to investigate the temporal trajectory of the oscillatory brain activity. Compared to baseline, theta activity was significantly enhanced during encoding and the delay period. Alpha-band power decreased during encoding and switched to an increase in the first part of the delay before returning to the baseline in the second part; beta-band power remained below baseline during encoding and the delay. The difference between the manipulation and retention tasks in spectral power had diverse temporal trajectories in different frequency bands. The difference maintained over encoding and the first part of the delay in theta, during the first part of the delay in beta, and during the whole delay period in alpha. Our results suggest that task-related modulations in theta power co-vary with the demands on the executive control network; beta suppression during mental manipulation can be related to the activation of motor networks; alpha is likely to reflect the activation of language areas simultaneously with sensory input blockade.


title: 16S rRNA Gene Amplicon Profiling of the New Zealand parasitic blowfly Calliphora vicina.

abstract: Here, we present a 16S rRNA gene amplicon sequence data set and profiles demonstrating the bacterial diversity of larval and adult Calliphora vicina, collected from Ashhurst, New Zealand (May 2020). The three dominant genera among adult male and female C. vicina were Serratia and Morganella (phylum Proteobacteria) and Carnobacterium (phylum Firmicutes), while the larvae were also dominated by the genera Lactobacillus (phylum Firmicutes).


title: Using recent baselines as benchmarks for megafauna restoration places an unfair burden on the Global South

abstract: The potential for megafauna restoration is unevenly distributed across the world, along with the socio-political capacity of countries to support these restoration initiatives. We show that choosing a recent baseline to identify species indigenous range puts a higher burden for megafauna restoration on countries in the Global South, which also have less capacity to support these restoration initiatives. We introduce the Megafauna Index, which considers large mammals potential species richness and range area at country-level, to explore how the responsibility for megafauna restoration distributes across the world according to four scenarios using various temporal benchmarks to define species indigenous range - current, historical (1500AD), mid-Holocene and Pleistocene. We test how the distribution of restoration burden across the world correlates to indicators of conservation funding, human development, and governance. Using a recent or historical baseline as a benchmark for restoration puts a higher pressure on African and southeast Asian countries while lifting the responsibility from the Global North, where extinctions happened a long time ago. When using a mid-Holocene or Pleistocene baseline, new opportunities arise for megafauna restoration in Europe and North America respectively, where countries have a higher financial and societal capacity to support megafauna restoration. These results contribute to the debate around benchmarks in rewilding initiatives and the ethical implications of using recent baselines to guide restoration efforts. We suggest that countries from the Global North should reflect on their responsibility in supporting global restoration efforts, by increasing their support for capacity building in the South and taking responsibility for restoring lost biodiversity at home.


title: Host phenology drives the evolution of intermediate parasite virulence

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe traditional mechanistic trade-offs resulting in a negative correlation between transmission and virulence are the foundation of nearly all current theory on the evolution of parasite virulence. Several ecological factors have been shown to modulate the optimal virulence strategies predicted from mechanistic trade-off models, but these ecological factors have not yet been shown to be sufficient to explain the intermediate virulence strategies observed in any natural system. The timing of seasonal activity, or phenology, is a common factor that influences the types and impact of many ecological interactions but is difficult to incorporate into virulence evolution studies. We develop a mathematical model of a disease system with seasonal host activity to study the evolutionary consequences of host phenology on the virulence of obligate-killer parasite. Results from this model demonstrated that seasonal host activity is sufficient to drive the evolution of intermediate parasite virulence in some types of natural disease systems, even when a traditional mechanistic trade-off between transmission and virulence is not assumed in the modeling framework. The optimal virulence strategy in these systems can be determined by both the duration of the host activity period as well as the variation in the host emergence timing. Parasites with low virulence strategies are favored in environments with long host activity periods and in environments in which hosts emerge synchronously. The results demonstrate that host phenology can be sufficient to select for intermediate optimal virulence strategies, providing an alternative mechanism to account for virulence evolution in some natural systems.


title: Host phenology can drive the evolution of intermediate virulence strategies in some parasites


title: Host phenology can drive the evolution of intermediate virulence strategies in some obligate-killer parasites


title: DeepLncLoc: a deep learning framework for long non-coding RNA subcellular localization prediction based on subsequence embedding

abstract:
MotivationLong non-coding RNAs (IncRNAs) are a class of RNA molecules with more than 200 nucleotides. A growing amount of evidence reveals that subcellular localization of lncRNAs can provide valuable insights into their biological functions. Existing computational methods for predicting lncRNA subcellular localization use k-mer features to encode lncRNA sequences. However, the sequence order information is lost by using only k-mer features.

ResultsWe proposed a deep learning framework, DeepLncLoc, to predict lncRNA subcellular localization. In DeepLncLoc, we introduced a new subsequence embedding method that keeps the order information of lncRNA sequences. The subsequence embedding method first divides a sequence into some consecutive subsequences, and then extracts the patterns of each subsequence, last combines these patterns to obtain a complete representation of the lncRNA sequence. After that, a text convolutional neural network is employed to learn high-level features and perform the prediction task. Compared to traditional machine learning models with k-mer features and existing predictors, DeepLncLoc achieved better performance, which shows that DeepLncLoc could effectively predict lncRNA subcellular localization. Our study not only presented a novel computational model for predicting lncRNA subcellular localization but also provided a new subsequence embedding method which is expected to be applied in other sequence-based prediction tasks.

AvailabilityThe DeepLncLoc web server, source code and datasets are freely available at http://bioinformatics.csu.edu.cn/DeepLncLoc/, and https://github.com/CSUBioGroup/DeepLncLoc.

Contactlimin@mail.csu.edu.cn


title: Programmed mechano-chemical coupling in reaction-diffusion active matter

abstract: Embryo morphogenesis involves a complex combination of pattern-forming mechanisms. However, classical in vitro patterning experiments explore only one mechanism at a time, thus missing coupling effects. Here, we conjugate two major pattern-forming mechanisms --reaction-diffusion and active matter-- by integrating dissipative DNA/enzyme reaction networks within an active gel composed of cytoskeletal motors and filaments. We show that the strength of the flow generated by the active gel controls the mechano-chemical coupling between the two subsystems. This property was used to engineer a synthetic material where contractions trigger chemical reaction networks both in time and space, thus mimicking key aspects of the polarization mechanism observed in C. elegans oocytes. We anticipate that reaction-diffusion active matter will promote the investigation of mechano-chemical transduction and the design of new materials with life-like properties.