title: Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

abstract: Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the {beta}2 adrenergic receptor ({beta}2-AR; i.e. agonistic autoantibodies; {beta}2-agAAb) and is linked to the elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimers Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the {beta}2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against {beta}2-AR. In addition, different species of amyloid beta (A{beta}) monomers were tested (A{beta}1-14, A{beta}10-25, A{beta}10-37 A{beta}1-40, A{beta}1-42, A{beta}28-40, and [Pyr]-A{beta}3-42). Our results demonstrate that none of the short-chain A{beta} (A{beta}1-14, A{beta}10-25, or A{beta}28-40) showed any agonistic or inhibitory effect on {beta}2-AR. Contrary, long-chain [Pyr]-A{beta}3-42, representing a major neurogenic plaque component, exerted an activation that was blocked by the {beta}2-AR antagonist ICI118.551 indicating that the effect was realized via the {beta}2-AR. Moreover, the long chain A{beta}1-40, A{beta}1-42, and A{beta}10-37 yet not the short-chain A{beta} peptides prevented the clenbuterol induced desensitization of the {beta}2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the {beta}2-AR like the {beta}2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimers Disease, we postulate that overstimulation of the {beta}2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.


title: Brain-optimized neural networks learn non-hierarchical models of representation in human visual cortex

abstract: Deep neural networks (DNNs) trained to perform visual tasks learn representations that align with the hierarchy of visual areas in the primate brain. This finding has been taken to imply that the primate visual system forms representations by passing them through a hierarchical sequence of brain areas, just as DNNs form representations by passing them through a hierarchical sequence of layers. To test the validity of this assumption, we optimized DNNs not to perform visual tasks but to directly predict brain activity in human visual areas V1-V4. Using a massive sampling of human brain activity, we constructed brain-optimized networks that predict brain activity even more accurately than task-optimized networks. We show that brain-optimized networks can learn representations that diverge from those formed in a strict hierarchy. Brain-optimized networks do not need to align representations in V1-V4 with layer depth; moreover, they are able to accurately model anterior brain areas (e.g., V4) without computing intermediary representations associated with posterior brain areas (e.g., V1). Our results challenge the view that human visual areas V1-V4 act--like the early layers of a DNN--as a serial pre-processing sequence for higher areas, and suggest they may subserve their own independent functions.

category: neuroscience


title: White matter connections of high-level visual areas predict cytoarchitecture better than category-selectivity

abstract: Ventral temporal cortex (VTC) consists of high-level visual regions that are arranged in consistent anatomical locations across individuals. This consistency has led to several hypotheses about the factors that constrain the functional organization of VTC. A prevailing theory is that white matter connections influence the organization of VTC, however, the nature of this constraint is unclear. Here, we test two hypotheses: (1) white matter tracts are specific for each category or (2) white matter tracts are specific to cytoarchitectonic areas of VTC. To test these hypotheses, we used diffusion magnetic resonance imaging (dMRI) to identify white matter tracts and functional magnetic resonance imaging (fMRI) to identify category-selective regions in VTC in children and adults. We find that in childhood, white matter connections are linked to cytoarchitecture rather than category-selectivity. In adulthood, however, white matter connections are linked to both cytoarchitecture and category-selectivity. These results suggest a rethinking of the view that category-selective regions in VTC have category-specific white matter connections early in development. Instead, these findings suggest that the neural hardware underlying the processing of categorical stimuli may be more domain-general than previously thought, particularly in childhood.


title: White matter connections of high-level visual areas predict cytoarchitecture better than category-selectivity in childhood, but not adulthood


title: PERSISTENT RELIEF OF MOTOR SYMPTOMS IN A PARKINSONIAN MOUSE MODEL AFTER INDUCTION OF LTD AT CORTICAL INPUTS TO INDIRECT PATHWAY STRIATAL NEURONS

abstract: In Parkinsons disease (PD) patients, dopamine replacement therapy requires days to reach maximal effects, and the return of symptoms without treatment is similarly delayed. We previously postulated that these phenomena are mediated by plasticity of coritcostriatal synapses. As dopamine depletion is expected to promote aberrant potentiation of the cortical inputs onto indirect pathway neurons, we reasoned that induction of LTD here could reduce motor deficits in a PD model. Optogenetic cortical stimulation combined with a D2 receptor agonist, quinpirole, induces robust optical LTD (oLTD) in brain slices from 6-OHDA lesioned mice. When lesioned mice were subjected to corticostriatal oLTD treatment over 5 days, motor performance was improved for >3 weeks. Consistent with LTD induction, oLTD-treated mice had reduced VGLUT1 expression in striatum and greater excitability of D2 neurons. These findings suggest that reversing aberrant corticostriatal synaptic plasticity in the indirect pathway may lead to persistent relief of PD motor symptoms.


title: Brain temperature affects quantitative features of hippocampal sharp wave ripples

abstract: Biochemical mechanisms are temperature-dependent. Brain temperature shows wide variations across brain states, and such changes may explain quantitative changes in network oscillations. Here we report on the coupling of various hippocampal sharp wave ripple features to brain temperature. Ripple frequency, occurrence rate and duration correlated with temperature dynamics. By focal manipulation of the brain temperature in the hippocampal CA1 region, we show that ripple frequency can be increased and decreased by local heating and cooling, respectively. Changes of other parameters, such as the rate of SPW-R and ripple duration were not consistently affected. Our findings suggest that brain temperature in the CA1 region plays a leading role in affecting the ripple frequency, whereas other parameters of SPW-Rs may be determined by mechanisms upstream from the CA1 region. These findings illustrate that physiological variations of brain temperature exert important effects on hippocampal circuit operations.


title: Characterizing Potential Tetrodotoxin Resistance in Domain IV of the Voltage-Gated Sodium Channel Nav1.4 of Pacific Chorus Frogs, Pseudacris regilla

abstract: Animals that frequently encounter toxins often evolve mechanisms of toxin resistance. Both predators that consume toxic prey and organisms in physical contact with a toxin or pollutant in their environment may experience natural selection for resistance. Based on observations that Pacific Chorus Frogs (Pseudacris regilla) sometimes eat and mistakenly amplect tetrodotoxin (TTX)-defended Taricha newts, we hypothesized that P. regilla may possess resistance to TTX. We tested this prediction by comparing the amino acid sequences of the domain IV pore loop of the muscle voltage-gated sodium channel gene SCN4A (Nav1.4 protein) in populations of P. regilla that are sympatric and allopatric with Taricha. We identified a single substitution in the domain IV pore loop of Nav1.4 in P. regilla that has been hypothesized to provide TTX resistance based on computational modeling, though its role in resistance has been challenged. Nonetheless, both allopatric and sympatric P. regilla had this substitution, suggesting that it may be unrelated to TTX exposure from Taricha. Thus, there is no conclusive evidence that P. regilla has evolved TTX resistance encoded by amino acid substitutions in this domain. In addition, California occurrence data from the last 50 years indicate that Taricha activity peaks in January while the activity of P. regilla peaks in April. These relatively distinct activity patterns suggest that P. regilla may not be exposed to levels of TTX from Taricha that are high enough to require mutations in SCN4A. Nevertheless, other unidentified mechanisms of TTX resistance could be present in P. regilla and other species that are sympatric with toxic newts.

category: evolutionary biology


title: Single-Cell Transcriptomics reveals relaxed evolutionary constraint of spermatogenesis in two passerine birds as compared to mammals

abstract: Spermatogenesis is a complex process where spermatogonia develop into haploid, mobile sperm cells. The genes guiding this process are subject to an evolutionary trade-off between preserving basic functions of sperm while acquiring new traits ensuring advantages in competition over fertilization of female gametes. In species with XY sex chromosomes, the outcome of this trade-off is found to vary across the stages of spermatogenesis but remains unexplored for species with ZW sex chromosomes. Here we characterize avian spermatogenesis at single cell resolution from testis of collared and pied flycatchers. We find evidence for relaxed evolutionary constraint of genes expressed in spermatocyte cells going through meiosis. An overrepresentation of Z-linked differentially expressed genes between the two species at this stage suggests that this relaxed constraint is associated with the lack of sex-chromosome silencing during meiosis. We conclude that the high throughput of bird spermatogenesis, at least partly, is explained by relaxed developmental constraint.


title: Modified dN/dS for accounting transition and transversion frequency difference and non-sense substitution in genomes

abstract: The dN/dS value is estimated in homologous protein coding gene sequences between two closely related organisms for studying selection on the genes. In the usual method of calculation of synonymous (S) and non-synonymous (NS) sites in codons, the transition and transversion rates are considered same as well as no difference of pretermination codons from the other codons regarding NS substitutions is considered. In this study we are proposing a modification in the method by estimating the S and the NS sites in codons by considering difference between the transition and transversion rates and the NS substitutions leading to non-sense codons in pretermination codons. So, the dN/dS value calculated by our approach was higher than that calculated by the earlier method. The modified method was applied in estimating dN/dS in 29 homologous gene sequences of Escherichia coli and Salmonella enterica. Impact of codon degeneracy and pretermination codons on the dN/dS values estimated by our method were observed clearly. Our method of estimation that considers the above features is a realistic representation of dN/dS values in coding sequences.


title: Plant longevity, drought and island isolation favoured rampant evolutionary transitions towards insular woodiness

abstract: Insular woodiness (IW)--the evolutionary transition from herbaceousness towards woodiness on islands--is one of the most iconic features of island floras. Since pioneering work by Darwin and Wallace, five IW drivers have been proposed: (i) favourable aseasonal climate and (ii) lack of large native herbivores promote plant longevity that (iii) results in prolonged flowering favouring outcrossing. Alternatively, (iv) competition for sunlight requires taller and stronger stems, and (v) drought favours woodiness to safeguard root-to-shoot water transport. However, information on the occurrence of IW is fragmented, hampering tests of these potential drivers. Here, we identify 1,097 insular woody species (IWS) on 375 islands, and infer at least 175 evolutionary transitions on 31 archipelagos, concentrated in six angiosperm families. Structural equation models reveal that the IWS richness on oceanic islands correlates with aseasonal favourable climate, followed by increased drought and island isolation (approximating competition). When continental islands are included, reduced herbivory pressure by large native mammals, increased drought and island isolation are most relevant. The repeated evolution of IW opens promising avenues to disentangle the variation in gene regulatory networks triggering wood formation, and emphasize individual archipelagos as laboratories of evolution, where similar environmental conditions replicate convergent evolution of similar traits.


title: The spatial scale of adaptation in a native annual plant and its implications for responses to climate change

abstract: Spatial patterns of adaptation provide important insights into agents of selection and expected responses of populations to climate change. Robust inference into the geographic scale of adaptation can be gained through reciprocal transplant experiments that combine multiple source populations and common gardens. To quantify the scale of local adaptation and examine the consequences of a warming climate on the species range, we performed reciprocal transplant experiments at four common gardens with 22 populations sampled across a ~1200 km latitudinal gradient within the native range of common ragweed, Ambrosia artemisiifolia. We found evidence of local adaptation at the northernmost common garden, but maladaptation at the two southern gardens, where more southern populations outperformed local populations. Overall, the spatial scale of climate adaptation was large -- at the three gardens where distance between source populations and gardens explained variation in fitness, it took an average of 820 km for fitness to decline to 50% of its predicted maximum. However, fitness declined more sharply with distance in southern transplant sites. Taken together, these results suggest that climate change has already caused maladaptation, especially across the southern portion of the range, and may result in northward range contraction over time.


title: Transcriptional mapping of the macaque retina and RPE-choroid reveals conserved inter-tissue transcription drivers and signaling pathways

abstract:
PurposeThe macula and fovea comprise a highly sensitive visual detection tissue that is susceptible to common disease processes like age-related macular degeneration (AMD). Our understanding of the molecular determinants of high acuity vision remains unclear, as few model organisms possess a human-like fovea. We explore transcription factor networks and receptor-ligand interactions to elucidate tissue interactions in the macula and peripheral retina and concomitant changes in the underlying retinal pigment epithelium (RPE)/choroid.

MethodsPoly-A selected, 100 bp paired-end RNA-sequencing (RNA-seq) was performed across the macular/foveal, perimacular, and temporal peripheral regions of the neural retina and RPE/choroid tissues of four adult Rhesus macaque eyes to characterize region- and tissue-specific gene expression. RNA-seq reads were mapped to both the macaque and human genomes for maximum alignment and analyzed for differential expression and Gene Ontology (GO) enrichment.

ResultsComparison of the neural retina and RPE/choroid tissues indicated distinct, contiguously changing gene expression profiles from fovea through perimacula to periphery. Top GO enrichment of differentially expressed genes in the RPE/choroid included cell junction organization and epithelial cell development. Expression of transcriptional regulators and various disease-associated genes show distinct location-specific preference and retina-RPE/choroid tissue-tissue interactions.

ConclusionsRegional gene expression changes in the macaque retina and RPE/choroid is greater than that found in previously published transcriptome analysis of the human retina and RPE/choroid. Further, conservation of human macula-specific transcription factor profiles and gene expression in macaque tissues suggest a conservation of programs required for retina and RPE/choroid function and disease susceptibility.

category: genomics


title: Immune-responsive biodegradable scaffolds for enhancing neutrophil regeneration

abstract: Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

category: bioengineering


title: FAME: Fragment-based Conditional Molecular Generation for Phenotypic Drug Discovery

abstract: De novo molecular design is a key challenge in drug discovery due to the complexity of chemical space. With the availability of molecular datasets and advances in machine learning, many deep generative models are proposed for generating novel molecules with desired properties. However, most of the existing models focus only on molecular distribution learning and target-based molecular design, thereby hindering their potentials in real-world applications. In drug discovery, phenotypic molecular design has advantages over target-based molecular design, especially in first-in-class drug discovery. In this work, we propose the first deep graph generative model (FAME) targeting phenotypic molecular design, in particular gene expression-based molecular design. FAME leverages a conditional variational autoencoder framework to learn the conditional distribution generating molecules from gene expression profiles. However, this distribution is difficult to learn due to the complexity of the molecular space and the noisy phenomenon in gene expression data. To tackle these issues, a gene expression denoising (GED) model that employs contrastive objective function is first proposed to reduce noise from gene expression data. FAME is then designed to treat molecules as the sequences of fragments and learn to generate these fragments in autoregressive manner. By leveraging this fragment-based generation strategy and the denoised gene expression profiles, FAME can generate novel molecules with a high validity rate and desired biological activity. The experimental results show that FAME outperforms existing methods including both SMILES-based and graph-based deep generative models for phenotypic molecular design. Furthermore, the effective mechanism for reducing noise in gene expression data proposed in our study can be applied to omics data modeling in general for facilitating phenotypic drug discovery.

category: bioinformatics


title: Towards a structurally resolved cancer interactome

abstract: Protein-protein interactions (PPIs) are involved in almost all essential cellular processes. Perturbation of PPI networks plays critical roles in tumorigenesis, cancer progression and metastasis. While numerous high-throughput experiments have produced a vast amount of data for PPIs, these datasets suffer from high false positive rates and exhibit a high degree of discrepancy. Coevolution of amino acid positions between protein pairs has proven to be useful in identifying interacting proteins and providing structural details of the interaction interfaces with the help of deep learning methods like AlphaFold (AF). In this study, we applied AF to investigate the cancer protein-protein interactome. We predicted 1,798 PPIs for cancer driver proteins involved in diverse cellular processes such as transcription regulation, signal transduction, DNA repair and cell cycle. We modeled the spatial structure for the predicted binary protein complexes, 1,087 of which lacked previous 3D structure information. Our predictions offer novel structural insight into many cancer-related processes such as the MAP kinase cascade and Fanconi anemia pathway. We further investigated the cancer mutation landscape by mapping somatic missense mutations (SMMs) in cancer to the predicted PPI interfaces and performing enrichment and depletion analyses. Interfaces enriched or depleted with SMMs exhibit different preferences for functional categories. Interfaces enriched in mutations tend to function in pathways that are deregulated in cancers and they may help explain the molecular mechanisms of cancers in patients; interfaces lacking mutations appear to be essential for the survival of cancer cells and thus may be future targets for PPI modulating drugs.


title: The effector protein CgNLP1 of Colletotrichum gloeosporioides from Hevea brasiliensis disrupts nuclear localization of necrosis-induced transcription factor HbMYB8-like to suppress plant defense signaling

abstract:
O_LIColletotrichum gloeosporioides is the dominant causal agent of rubber tree anthracnose and leads to serious loss of natural rubber production. Fungi secrete numerous effectors to modulate host defense systems. Understanding the molecular mechanisms by which fungal effectors regulate plant defense is of great importance for the development of novel strategies for disease control.
C_LIO_LIHere, we identified an NLP effector gene, CgNLP1, which contributed to virulence of C. gloeosporioides to rubber tree. Transient expression of CgNLP1 in the leaves of Nicotiana benthamiana induced ethylene production in plants. Ectopic expression of CgNLP1 in Arabidopsis significantly enhanced the resistance to Botrytis cinerea and A. brassicicola.
C_LIO_LICgNLP1 was shown to target a R2R3 type transcription factor HbMYB8-like in rubber tree, which localized on nucleus and induced necrosis in N. benthamiana. CgNLP1 disrupted nuclear accumulation of HbMYB8-like and suppressed necrosis induced by HbMYB8-like mediated SA signal pathway.
C_LIO_LIThis work suggested a strategy whereby C. gloeosporioides exploited CgNLP1 effector to suppress host defense to facilitate infection by disrupting the subcellular compartment of a host defense regulator HbMYB8-like.
C_LI

category: pathology


title: Targeted photothrombotic stroke leads to disruptions in neurovascular coupling

abstract:
Functional neuroimaging, which measures hemodynamic responses to brain activity, has great potential for monitoring stroke patients. However, the neurophysiological interpretations of these hemodynamic signals remain a challenge as the stroke is likely to alter both neural activity and neurovascular coupling. To address this challenge, we simultaneously captured neural activity, through fluorescence calcium imaging, and hemodynamics, through intrinsic optical signal imaging, during longitudinal stroke recovery. We found that photothrombotic stroke to somatosensory forelimb region altered neurovascular coupling in the acute phase (2 days and 1 week post-stroke) within the affected forelimb and peri-infarct regions. Neurovascular coupling was reestablished in the chronic phase (4 weeks post-stroke), and acute recovery of neurovascular coupling predicted sensorimotor function. Stroke also resulted in increases in the power of global brain oscillations, which showed distinct patterns between calcium and hemodynamics. Increased calcium excitability in the contralesional hemisphere was associated with increased intrahemispheric connectivity. Additionally, acute increases in hemodynamic oscillations were associated with improved sensorimotor outcomes.

TeaserAcute ischemic stroke leads to neurovascular uncoupling and the extent of early recoupling predicts sensorimotor recovery.

category: physiology


title: Impact of a native hemiparasite and mowing on performance of a major invasive weed, European blackberry

abstract:
O_LIPlant invasions are a major global threat to biodiversity. Traditional methods of weed control are falling short, and novel and environmentally friendly control tools are needed. Native parasitic plants are showing promise as effective biocontrols for some of the worst weeds, however, their application is in its infancy.
C_LIO_LIFirst, we established the native parasitic plant, Cassytha pubescens on unmown invasive European blackberry (Rubus anglocandicans), at three field sites (Belair, Horsnell and Blackwood) in South Australia to measure the impact of infection host performance. Concurrently, we established the parasite on hosts that were mown at two of these sites (Horsnell and Blackwood), to determine the impact of mowing, a commonly used control method, in conjunction with infection by C. pubescens.
C_LIO_LIFruit production, midday quantum yield and electron transport rates of infected R. anglocandidans were significantly lower than uninfected plants at only one site, Blackwood. Predawn quantum yield, and foliar nitrogen and phosphorus concentrations of infected plants were significantly lower than uninfected ones across all three sites. Stomatal conductance was negatively affected by infection at one site (Belair). Mowing enhanced parasite impact on host nitrogen concentration at one site (Horsnell), and infection negatively affected host stomatal conductance at the same site, irrespective of whether plants were mown or not.
C_LIO_LIWe have demonstrated that this native biocontrol can be artificially established on invasive European blackberry in the field, with negative consequences for its performance. Our results demonstrate the feasibility of implementing native parasitic plants as weed biocontrols to protect biodiversity, and are aligned with the Biotic Resistance hypothesis that invasive species are susceptible and sensitive to enemies native to their newly invaded habitat.
C_LI

category: plant biology


title: Reference-based comparison of adaptive immune receptor repertoires

abstract: B- and T-cell receptor (immune) repertoires can represent an individuals immune history. While current repertoire analysis methods aim to discriminate between health and disease states, they are typically based on only a limited number of parameters (e.g., clonal diversity, germline usage). Here, we introduce immuneREF: a quantitative multi-dimensional measure of adaptive immune repertoire (and transcriptome) similarity that allows interpretation of immune repertoire variation by relying on both repertoire features and cross-referencing of simulated and experimental datasets. immuneREF is implemented in an R package and was validated based on detection sensitivity of immune repertoires with known similarities and dissimilarities. To quantify immune repertoire similarity landscapes across health and disease, we applied immuneREF to >2400 datasets from individuals with varying immune states (healthy, [autoimmune] disease and infection [Covid-19], immune cell population). Importantly we discovered, in contrast to the current paradigm, that blood-derived immune repertoires of healthy and diseased individuals are highly similar for certain immune states, suggesting that repertoire changes to immune perturbations are less pronounced than previously thought. In conclusion, immuneREF implements population-wide analysis of immune repertoire similarity and thus enables the study of the adaptive immune response across health and disease states.

category: systems biology


title: Focusing perceptual attention in one modality constrains subsequent learning in another modality

abstract: Attention is central to learning stimulus-outcome relationships. In addition to its role in learning, attention has been conceptualized as a sensory filter that improves perception. It remains unexplored whether these two aspects of attention interact at the behavioral and neural level. Thus, we investigated how learning novel stimulus-outcome associations in a multi-modal environment is influenced by the degree to which perceptual attention has been focused onto a single modality. We trained head-fixed rats to discriminate compound auditory-visual stimuli using one modality and then reduced stimulus discriminability in that modality. We observed perceptual learning and increased EEG Granger causality between frontal cortex and the behaviorally relevant sensory cortex, suggesting that perceptual attention was engaged. We then presented novel and easily discriminable stimuli in both modalities and measured outcome-driven learning to discriminate stimuli in the other modality. We observed slowed learning after engaging perceptual attention onto the previously relevant modality by requiring practice with difficult discriminations. This result could not be explained by changes in nonattentional factors, such as arousal (measured with pupillometry), number of rewards received, or shifted response criterion (measured using response velocity). Our work demonstrates that perceptual attention constrains outcome-based learning by changing the strength of modality-specific cortico-cortical interactions.


title: The positive dimension of schizotypy is associated with a reduced attenuation and precision of self-generated touch

abstract: The brain predicts the sensory consequences of our movements and uses these predictions to attenuate the perception of self-generated sensations. Accordingly, self-generated touch feels weaker than externally generated touch of identical intensity. In schizophrenia, this somatosensory attenuation is substantially reduced, suggesting that patients with positive symptoms fail to accurately predict and process self-generated touch. Here we hypothesized that a similar impairment might exist in healthy nonclinical individuals with high positive schizotypal traits. One hundred healthy participants (53 female) scored for schizotypal traits and underwent a well-established psychophysics force discrimination task to quantify how they perceived self-generated and externally generated touch. The perceived intensity of tactile stimuli delivered to their left index finger (magnitude) and the ability to discriminate the stimuli (precision) were measured. We observed that higher positive schizotypal traits were associated with reduced somatosensory attenuation and poorer somatosensory precision of self-generated touch. These effects were specific to positive schizotypy and were not observed for the negative or disorganized dimensions of schizotypy. The results suggest that positive schizotypal traits are associated with a reduced ability to predict and process self-generated tactile stimuli. Given that the positive dimension of schizotypy represents the analogue of positive psychotic symptoms of schizophrenia, deficits in processing self-generated tactile information could indicate increased liability to schizophrenia.


title: An in vitro neuronal model replicating the in vivo maturation and heterogeneity of perineuronal nets

abstract: The perineuronal net (PNN) is a condensed form of extracellular matrix (ECM) that enwraps specific populations of neurons and regulates plasticity. To create a PNN, only three classes of components are needed: membrane bound hyaluronan by its synthetic enzyme hyaluronan synthases (HASs), a link protein and a CSPG. However, there is redundancy within the classes as multiple HAS isoforms, link proteins and CSPGs have been found in the PNN in vivo. The effect of this heterogeneity has on PNN function is unresolved. Currently, the most common way to address this question is through the creation and study of PNN component in knockout animals. Here, we reported the development of a primary neuronal culture model which reproduces the in vivo maturation and heterogeneity of PNNs. This model accurately replicated mature cortical PNNs, both in terms of the heterogeneity in PNN composition and its maturation. PNNs transitioned from an immature punctate morphology to the reticular morphology as observed in the mature CNS. We also observed a small population of PNNs that were mature at an earlier time point and a distinct composition, highlighting further heterogeneity. This model will provide a valuable tool for the study of PNN biology, their roles in diseases and the development of PNN focused plasticity treatment.


title: Targeting Noradrenergic Neurons of the Locus Coeruleus: A Comparison of Model Systems and Strategies

abstract: The locus coeruleus (LC) noradrenergic system is involved in a plethora of physiological and pathophysiological processes. Refining our understanding of LC function largely relies on selective transgene expression in molecularly defined cells, enabling targeted manipulation and read-out of noradrenergic neurons. Here, we performed a side-by-side comparison of the most commonly used strategies and model systems enabling genetic access to the locus coeruleus. We report substantial differences among them both in terms of transgene expression efficacy, and in their molecular specificity. These findings are of critical importance for interpreting the results obtained from past experiments using the respective targeting strategies, as well as for the design of future studies.


title: Amacrine cells shape retinal functions while dynamically preserving circuits for colour vision

abstract:
In vertebrate vision, the feature extracting circuits of the inner retina are driven by heavily pre-processed photoreceptor signals. For example, in larval zebrafish, outer retinal circuits serve to split "colour" from "greyscale" information across their four ancestral cone-photoreceptor types. How then can the inner retina simultaneously preserve such incoming spectral information despite the need to combine cone-signals to shape new greyscale functions?

To address this question, we imaged light-driven signals from the axon terminals of retinal bipolar cells in the presence and pharmacological absence of inhibition from amacrine cells. Surprisingly, this manipulation had no net effect on the inner retinal representation of colour-opponency, despite profound impacts on all tested greyscale functions such as the gain and kinetics of bipolar cell light responses. This  dynamic balance was achieved by amacrine cells driving opponency in some bipolar cells, while at the same time suppressing pre-existing opponency in others, such that the net change across the network was essentially zero. To do so, amacrine cells near-exclusively leveraged the On-channel, and correspondingly, a direct in vivo survey of amacrine cell functions revealed that all their colour-opponent responses were located in the On-layer. In contrast, Off-stratifying amacrine cells were largely achromatic. We conclude that complex interactions within the inner retina that underlie greyscale visual processing tasks are intricately balanced via the On-channel to not notably alter the pre-existing population representation of colour information.


title: Improved production and expanded application of CVS-N2c-ΔG virus for retrograde tracing

abstract: Neurotropic virus tracers, particularly those with low toxicity and high efficient tracing, are powerful tools for structural and functional dissections of neural circuits. The retrograde trans-mono-synaptic technology based on rabies virus CVS-N2c strain has reduced cytotoxicity and enhanced efficiency, attains long-term gene manipulation for functional studies, but suffers from difficult preparation and low yield. To overcome these shortcomings, an improved production system was established for rapid rescue and preparation of CVS-N2c-{Delta}G virus, CVS-N2c-{Delta}G with the same titer as SAD-B19-{Delta}G can be prepared within a short time. Meanwhile, we found that N2cG coated CVS-N2c-{Delta}G allows efficient retrograde access to projection neurons, and further expand its application in VTA/SNc to DLS pathway that unaddressed by rAAV9-Retro, and the efficiency is 6 folds higher than that of rAAV9-Retro. Then the trans-synaptic efficiency of CVS-N2c-{Delta}G virus was evaluated. Results showed that the trans-mono-synaptic efficiency of oG-mediated CVS-N2c-{Delta}G was 2-3 folds higher than that of oG-mediated SAD-B19-{Delta}G, but there was no difference between oG-mediated and N2cG-mediated CVS-N2c-{Delta}G system. In addition, codon modified N2cG (optiG) did not increase the efficiency of CVS-N2c-{Delta}G tracing. Finally, we found that the CVS-N2c-{Delta}G produced by the improved method can be used for monitoring neural activity of projection neurons, and the time window can be maintained for 3 weeks, and it can also express sufficient recombinases for efficient transgene recombination. That is, the virus produced by the improved production system does not affect its own function, paving the way for its further optimization, popularization and application in structural and functional studies of neural circuits.


title: Look-up and look-down neurons in the mouse visual thalamus during freely moving exploration

abstract:
The traditional view that visuomotor integration is a property of higher brain centres has recently been challenged by the discovery in head-fixed rodents that locomotion increases neuronal activity throughout the early visual system (including the retina). Any appreciation of the importance of this behavioural modulation of visual inputs must encompass a comprehensive understanding of the range of behaviours engaged by this mechanism. This information is unavailable from head-fixed preparations in which head and body postures are fundamentally constrained and dissociated from their natural coupling with visual experience.

We addressed this deficit by recording spiking activity from the primary visual thalamus during freely moving exploration, while simultaneously applying frame-by-frame quantification of postures and movements to robust 3D reconstructions of head and body. We found that postures associated with the animal looking up/down affected activity in >50% neurons. The extent of this effect was comparable to that induced by locomotion. Moreover, the two effects were largely independent and jointly modulated neuronal activity. Thus, while most units were excited by locomotion, some expressed highest firing when the animal was looking up ("look up" neurons) while others when the animal was looking down ("look-down" neurons). These results were observed in the dark, thus representing a genuine behavioural modulation, and were amplified in a lit arena.

These findings define the influence of natural exploratory behaviour on activity in the early visual system and reveal the importance of up/down postures in gating neuronal activity in the primary visual thalamus.


title: Crosstalk of Histone Modifications in the Healthy Human Immune System

abstract: Chromatin remodeling through post-translational modifications of histone tails (HPTM) is fundamental for regulation and maintenance of DNA-centered processes. Systems level understanding of coordination and interactions between HPTMs and their impact on the functional state of the immune cells remain unexplored due to the technical reasons. We leveraged large biologically heterogeneous data (>27 million cells), comprising of primary human immune cells profiled for 33 HPTMs and 4 histone variants at the single-cell level using high-dimensional mass cytometry (EpiTOF), to discover and map relations between HPTMs at the systems level. Briefly, we elucidated a comprehensive epigenetic network of HPTM interactions, discovered a novel subset of hematopoietic progenitors with distinct epigenetic profile, and revealed hitherto undescribed associations between a decrease in global methylations, modulation of one-carbon metabolism, and immune cell life span. Ultimately our work lays a foundation for future studies aimed at understanding complexity of HPTM interactions in immune response in infectious or autoimmune diseases, cancers, and vaccination.

category: immunology


title: Amphibian mucus triggers a developmental transition in the frog-killing chytrid fungus

abstract: The frog-killing fungus Batrachochytrium dendrobatidis (Bd) grows within the mucus-coated skin of amphibians. Each lifecycle, Bd transitions from its motile, dispersal form to its sessile growth form in a complex process called encystation. Although encystation is critical to Bd growth, whether and how this developmental transition is triggered by external signals was previously unknown. We discovered that exposure to amphibian mucus triggers rapid and reproducible encystation within minutes. This response can be recapitulated with purified mucin, the bulk component of mucus, but not by similarly-viscous methylcellulose or simple sugars. Mucin-induced encystation does not require gene expression, but does require surface adhesion, calcium signaling, and modulation of the actin cytoskeleton. Mucus-induced encystation may represent a key mechanism for synchronizing Bd development with arrival at the host.

category: cell biology


title: Alteration of myocardial structure and function in RAF1associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs

abstract: Noonan syndrome (NS), the most common among the RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c.770C>T missense change. We characterize the molecular, structural and functional consequences of aberrant RAF1 -associated signaling on the cardiac models. Ultrastructural assessment of the sarcomere revealed a shortening of the I-bands along the Z disc area in both iPSC-derived RAF1S257L cardiomyocytes, and myocardial tissue biopsies. The disease phenotype was partly reverted by using both MEK inhibition, and a gene-corrected isogenic RAF1L257S cell line. Collectively, our findings uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction that remarkably recapitulates the human disease. These insights represent a basis to develop future targeted therapeutic approaches.


title: Non-Invasive classification of macrophage polarisation by 2P-FLIM and machine learning

abstract: 1.In this study, fluorescence lifetime imaging of NAD(P)H-based cellular autofluorescence is applied as a non-invasive modality to classify two contrasting states of human macrophages by proxy of their governing metabolic state. Macrophages were obtained from human blood-circulating monocytes, polarised using established treatments, and metabolically challenged using small molecules to validate their responding metabolic actions in extracellular acidification and oxygen consumption. Fluorescence lifetime imaging microscopy (FLIM) quantified variations in NAD(P)H-derived fluorescent lifetimes in large field-of-view images of individual polarised macrophages also challenged, in real-time with small molecule perturbations of metabolism during imaging. We uncover FLIM parameters that are pronounced under the action of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) which strongly stratifies the phenotype of polarised human macrophages. This stratification and parameters emanating from a FLIM approach, served as the basis for machine learning models. Applying a random forest model, identified three strongly governing FLIM parameters, achieving a ROC AUC value of 0.944 when classifying human macrophages.


title: A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys

abstract: Non-human primates (NHP) are attractive laboratory animal models that accurately reflect both developmental and pathological features of humans. Here we present a compendium of cell types from the cynomolgus monkey Macaca fascicularis (denoted as  Monkey Atlas) using both single-cell chromatin accessibility (scATAC-seq) and RNA sequencing (scRNA-seq) data at the organism-wide level. The integrated cell map enables in-depth dissection and comparison of molecular dynamics, cell-type composition and cellular heterogeneity across multiple tissues and organs. Using single-cell transcriptomic data, we inferred pseudotime cell trajectories and cell-cell communications to uncover key molecular signatures underlying their cellular processes. Furthermore, we identified various cell-specific cis-regulatory elements and constructed organ-specific gene regulatory networks at the single-cell level. Finally, we performed a comparative analysis of single-cell landscapes among mouse, cynomolgus monkey and human, and we showed that cynomolgus monkey has significantly higher degree of cell-type similarity to human than mouse. Taken together, our study provides a valuable resource for NHP cell biology.


title: Multi-curve fitting and tubulin-lattice signal removal for structure determination of large microtubule-based motors

abstract: Revealing high-resolution structures of microtubule-associated proteins (MAPs) is critical for understanding their fundamental roles in various cellular activities, such as cell motility and intracellular cargo transport. Nevertheless, large molecular motors that dynamically bind and release microtubule networks are challenging for cryo-electron microscopy (cryo-EM). Traditional structure determination of MAPs bound to microtubules needs alignment information from the reconstruction of microtubules, which cannot be readily applied to large MAPs without a fixed binding pattern. Here, we developed a comprehensive approach to estimate the microtubule networks (multicurve fitting), model the tubulin-lattice signals, and remove them (tubulin-lattice subtraction) from the raw cryo-EM micrographs. The approach does not require an ordered binding pattern of MAPs on microtubules, nor does it need a reconstruction of the microtubules. We demonstrated the capability of our approach using the reconstituted outer-arm dynein bound to microtubule doublets. In addition, we applied our multi-curve fitting approach to other biological filaments and achieved accurate estimations. Our work provides a new tool to determine high-resolution structures of large MAPs bound to curved microtubule networks.

category: biophysics


title: The relaxin receptor RXFP1 signals through a mechanism of autoinhibition

abstract: The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology and an established therapeutic target. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of an LDLa module and leucine-rich repeats. The molecular mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood, hindering the development of therapeutics targeting the receptor. Here we present the cryo-electron microscopy structure of active-state human RXFP1, bound to the endogenous agonist relaxin-2 and heterotrimeric Gs proteins. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition, wherein the receptors extracellular loop 2 occupies the orthosteric site in the active state but is inhibited by the ectodomain in the absence of relaxin-2. Together, these data provide a model for relaxin receptor signaling, explaining how an unusual but important GPCR sub-family functions and providing a path to rational drug development targeting the relaxin receptors.

category: pharmacology and toxicology


title: Tracing 3D apoplasmic complexity in vascular tissue of live conifer needles by X-ray computed tomography

abstract: Architecture and conducting area of vascular elements along conifer needles are fundamentally different from broad leaves. We hypothesised that the needles unique transfusion tissue offers different mechanisms for water allocation and used multimodal imaging to dissect the critical water exchange interfaces in this xerophytic leaf type. Our study examined intact conifer needles with X-ray computed tomography (XCT) and water-soluble tracers, allowing to render the functional 3D structure of the water-filled apoplast and the complementary symplasmic domain inside the bundle sheath. Segmentation of these data, together with fluorescence and electron microscopy of axial phloem and xylem elements along the needle, enabled quantification of the dimensions of the conducting tissue complex. The transfusion tracheid system between the endodermis-type bundle sheath and the axial venation formed a sponge-like apoplast domain. Transfusion parenchyma cell chains bridged this domain not directly but as tortuous symplasmic pathways between bundle sheath and axial phloem, which is nearly exclusively accessible at flanks. The transfusion tissue extends the plasma membrane surface for phloem loading and provides a large volume space. We discuss that this unique tissue plays an important role in the subtle interplay between water uptake/storage and sugar transport that has evolved to cope with desiccation stress.


title: Common synaptic inputs are not distributed homogeneously among the motor neurons that innervate synergistic muscles

abstract: The force generated by the muscles involved in an action is produced by common synaptic inputs received by the engaged motor neurons. The purpose of our study was to identify the low-dimensional latent components, defined hereafter as neural modules, underlying the discharge rates of the motor units from two knee extensors (vastus medialis and lateralis) and two hand muscles (index and thumb muscles) during isometric contractions. The neural modules were extracted by factor analysis from the pooled motor units and no assumptions were made regarding the orthogonality of the modules or the association between the modules and each muscle. Factor analysis identified two independent neural modules that captured most of the covariance in the discharge rates of the motor units in the synergistic muscles. Although the neural modules were strongly correlated with the discharge rates of motor units in each of the synergistic pair of muscles, not all motor units in a muscle were correlated with the neural module for that muscle. The distribution of motor units across the pair of neural modules differed for each muscle: 80% of the motor units in first dorsal interosseous were more strongly correlated with the neural module for that muscle, whereas the proportion was 70%, 60%, and 45% for the thenar, vastus medialis, and vastus lateralis muscles. All other motor units either belonged to both modules or to the module for the other muscle (15% for vastus lateralis). Based on a simulation of 480 integrate-and-fire neurons receiving independent and common inputs, we demonstrate that factor analysis identifies the three neural modules with high levels of accuracy. Our results indicate that the correlated discharge rates of motor units arise from at least two sources of common synaptic input that are not distributed homogeneously among the motor neurons innervating synergistic muscles.


title: Universal guide for skull extraction and custom-fitting of implants to continuous and discontinuous skulls

abstract:
Intracranial neurophysiological recordings require chronic implants to provide transcranial access to the brain. Especially in larger animals, which participate in experiments over extended periods of time, implants should match the skull curvature to promote osseointegration and avoid tissue and bacterial ingress over time. Proposed CAD methods for designing implants to date have focused on naive animals with continuous and even skull surfaces and calculate Boolean differences between implant and skull surface to fit the implant to the skull curvature. However, custom-fitting by calculating the difference fails, if a discontinuous skull surface needs to be matched. Also, the difference method does not allow designs with constant material thickness along the skull curvature, e.g. to allow fixed screw lengths. We present a universal step-by-step guide for custom-fitting implants which overcomes these limitations. It is suited for unusual skull conditions, like surface discontinuities or irregularities and includes virtual bending as a process to match skull surfaces while maintaining implant thickness. We demonstrate its applicability for a wide spectrum of scenarios, ranging from complex-shaped single-pieced implants to detailed multi-component implant systems built on even or discontinuous skull. The guide uses only a few software tools and the final virtual product can be manufactured using CNC milling or 3D printing. A detailed description of this process is available on GitHub including step-by-step video instructions suitable for users without any prior knowledge in CAD programming. We report the experience with these implants over several years in 11 rhesus monkeys.

Significance StatementChronic implants are essential for intracranial neurophysiological recordings. In this study we show how to custom-design and -fit such implants for rhesus monkeys (Macacca mulatta). Different to existing approaches, our procedure is not limited to even skull surfaces but can be applied to discontinuous or irregular surfaces. It furthermore presents a description of virtual implant bending to match the skull curvature while maintaining implant thickness. The final virtual product can be manufactured using CNC milling or 3D printing. In contrast to previous studies, this guide is suited for users without any prior expertise in CAD programming using our step-by-step video instructions.


title: Time-resolved parameterization of aperiodic and periodic brain activity

abstract:
Macroscopic neural dynamics comprise both aperiodic and periodic components. Recent advances in parameterizing neural power spectra offer practical tools for evaluating these features separately. Although neural signals vary dynamically and express non-stationarity in relation to ongoing behaviour and perception, current methods yield static spectral decompositions. Here, we introduce Spectral Parameterization Resolved in Time (SPRiNT) as a novel method for decomposing complex neural dynamics into periodic and aperiodic spectral elements in a time-resolved manner. First, we demonstrate, with naturalistic synthetic data, SPRiNTs capacity to reliably recover time-varying spectral features and emphasize SPRiNTs specific strengths over other time-frequency parameterization approaches based on wavelets. Second, we use SPRiNT to further illustrate how aperiodic spectral features fluctuate across time in resting-state electroencephalography (n = 178) and relate changes in aperiodic parameters to participants demographics and behaviour. Lastly, we use SPRiNT to demonstrate aperiodic dynamics related to movement behaviour in intracranial recordings in rodents. We foresee SPRiNT responding to growing neuroscientific interests in the parameterization of time-varying neural power spectra and advancing the quantitation of complex neural dynamics at the natural time scales of behaviour.

Significance StatementThe new method and reported findings address a growing interest in neuroscience for research tools that can reliably decompose brain activity at the mesoscopic scale into interpretable components. We show that the new approach proposed herein is capable of tracking transient, dynamic spectral (aperiodic and periodic) components across time, both in synthetic simulated and experimental data. We anticipate that this novel technique, SPRiNT, will enable new neuroscience inquiries that reconcile multifaceted neural dynamics with complex behaviour.


title: The interplay of active and passive mechanisms in slow axonal transport

abstract:
A combination of intermittent active movement of transient aggregates and a paused state that intervenes between periods of active transport has been proposed to underly the slow, directed transport of soluble proteins in axons. A component of passive diffusion in the axoplasm may also contribute to slow axonal transport, although quantitative estimates of the relative contributions of diffusive and active movement in the slow transport of a soluble protein, and in particular how they might vary across developmental stages, are lacking. Here, we propose and study a model for slow axonal transport, addressing data from bleach-recovery measurements on a small, soluble, protein, Choline Acetyltransferase (ChAT), in thin axons of the lateral chordotonal (lch5) sensory neurons of Drosophila. ChAT is mainly present in soluble form in the axon and catalyses the acetylation of choline at the synapse. It does not form particulate structures in axons and moves at rates characteristic of slow component b ({approx} 1-10 mm/day or 0.01-0.1 m/s). Using our model, which incorporates active transport, paused and diffusive states, we predict bleach recovery and cargo trajectories obtained through kymographs, comparing these to experimental observations at different developmental stages. We show that changes in the diffusive fraction of cargo during these developmental stages dominate bleach recovery and that a combination of active motion with a paused state alone cannot reproduce the data. We compared predictions of the model with results from photoactivation experiments. The importance of the diffusive state in reproducing the bleach recovery signal in the slow axonal transport of small soluble proteins is our central result.

STATEMENT OF SIGNIFICANCEWhile the fast axonal transport of cargo in axons is by now well-understood, the nature of slow transport remains controversial. A number of different models having been proposed for slow axonal transport, including models which allow for transitions between an intermittently moving molecular-motor driven state and a stalled state. How mechanisms for slow axonal transport are modulated during development is unexplored. We study a number of different models for slow axonal transport, comparing their predictions to data on transport of the enzyme Choline Acetyltransferase (ChAT) in thin lateral chordotonal (lch5) sensory neurons of Drosophila larva, across developmental stages where flux increases significantly. We show that accounting for changes in the diffusive fraction of cargo during these developmental stages is essential and diffusion cannot be neglected in the modelling of the slow axonal transport of small soluble proteins.


title: Evaluating the Phytotoxicity of Methanolic Extracts of Parthenium hysterophorus L. on Selected Crops and Weeds

abstract: Herbicides made from natural molecules may be a good environmentally friendly alternative to synthetic chemical herbicides for weed control. As a result, this investigation was carried out to ascertain the phytotoxicity of Parthenium hysterophorus L. as well as to identify its phenolic components. Germination of seeds and development of seedlings of Vigna subterranea (L.) Verdc, Raphanus sativus (L.) Domin, Cucurbita maxima Duchesne., Cucumis sativus L., Solanum lycopersicum L., Capsicum frutescens L., Zea mays L., Abelmoschus esculentus (L.) Moench, Daucus carota L., Digitaria sanguinalis (L.) Scop and Eleusine indica (L.) Gaertn were investigated using P. hysterophorus leaf, stem, and flower methanol extracts. Six concentrations (25, 50, 75, 100, and 150 g L-1) were comparison to the control (distilled water). The concentration of extracts increased, the rate of the seed sprouting and seedling growth decreased. EC50 values showed that the extraction of leaf of P. hysterophorus (811) was phytotoxic in comparison to the stem (1554) and flower (1109) extract. According to PCA analysis, Raphanus sativus, Solanum lycopersicum, Capsicum frutescens, Abelmoschus esculentus, Daucus carota, Digitaria sanguinalis, and Eleusine indica were all very susceptible to allelochemicals. A LC-MS analysis revealed that the P. hysterophorus leaf extract contained 7 phenolic compounds that were responsible for inhibition. These studies also revealed that the leaf of P. hysterophorus is a major source of phytotoxicity, which could be valuable in the future for developing a natural herbicide.


title: Context-aware information selection and model recommendation with ACCORDION

abstract:
Querying new information from knowledge sources, in general, and published literature, in particular, aims to provide precise and quick answers to questions raised about a system under study. In this paper, we present ACCORDION (ACCelerating and Optimizing model RecommenDatIONs), a novel methodology and a tool to enable efficient addressing of biological questions, by automatically recommending models that recapitulate desired dynamic behavior. Our approach integrates information extraction from literature, clustering, simulation and formal analysis to allow for automated, consistent, and robust assembling, testing and selection of context-specific models. We used ACCORDION in nine benchmark case studies and compared its performance with other previously published tools. ACCORDION is comprehensive as it can capture all relevant knowledge from literature, obtained by automated literature search and machine reading. At the same time, as our results show, ACCORDION is selective, recommending only the most relevant and useful subset (15-20%) of candidate model extensions found in literature, while guided by baseline model context and goal properties. ACCORDION is very effective, also demonstrated by our results, as it can reduce the error of the initial baseline model by more than 80%, recommending models that closely recapitulate desired behavior, and outperforming previously published tools. In this process, ACCORDION can also suggest more than one highly scored model, thus providing alternative solutions to user questions and novel insights for treatment directions.

Contact{yaa38@pitt.edu, nmzivanov@pitt.edu}

Supplementary informationSupplementary data are available.

Availabilityhttp://www.biodesignlab.pitt.edu/accordion


title: Lipid-polymer hybrid nanoparticles utilize B cells and dendritic cells to elicit distinct antigen-specific CD4+ and CD8+ T cell responses

abstract: Antigen presenting cells (APCs) have been extensively studied for treating cancers and autoimmune diseases. Dendritic cells (DCs) are potent APCs that uptake and present antigens (Ags) to activate immunity or tolerance. Despite their active use in cellular immunotherapies, DCs face several challenges that hinder clinical translation, such as inability to control Ag dosing for tuning immune responses and low abundance in peripheral blood. B cells are a potential alternative to DCs, but their poor non-specific Ag uptake capabilities compromise controllable priming of T cells. We developed phospholipid-conjugated Ags (L-Ags) and lipid-polymer hybrid nanoparticles (L/P-Ag NPs) as Ag delivery platforms to expand the range of accessible APCs for use in priming CD4+ and CD8+ T cells. These delivery platforms were evaluated using DCs, CD40-activated B cells, and resting B cells as a diverse set of APCs to understand the impact of various Ag delivery mechanisms for generation of Ag-specific T cell responses. L-Ag delivery (termed depoting) of MHC class I and II-restricted Ags successfully loaded all APC types in a tunable manner and primed both Ag-specific CD8+ and CD4+ T cells, respectively. Incorporating L-Ags and polymer-conjugated Ags (P-Ag) into NPs can direct Ags to different uptake pathways to engineer the dynamics of presentation and shape T cell responses. DCs were capable of processing and presenting Ag delivered from both L- and P-Ag NPs yet B cells could only utilize Ag delivered from L-Ag NPs. Multivariate analysis of cytokines secreted from APC:T cell co-cultures indicated that L-Ag NPs primed different T cell responses than P-Ag NPs. Altogether, we show that L-Ags and P-Ags can be rationally paired within a single NP to leverage distinct delivery mechanisms to access multiple Ag processing pathways in two APC types, offering a modular delivery platform for engineering immunotherapies.


title: Alphavirus nsP2 protease structure and cleavage prediction: Possible relevance to the pathogenesis of viral arthritis

abstract: Alphaviruses are a diverse genus of arboviruses capable of infecting many vertebrates including humans. Human infection is common in equatorial and subtropical regions and is often accompanied by arthralgia or encephalitis depending on viral lineage. No antivirals or vaccines have been approved, and many alphavirus lineages have only recently been discovered and classified. Alphavirus nsP2 protease is an important virulence factor yet is commonly thought to be a simple papain-like protease which only cleaves viral polyproteins. Here, I reveal novel molecular mechanisms of these proteases via sequence and predicted structure alignment and propose novel cellular mechanisms for the pathogenesis of viral arthritis by predicting which human proteins are likely cleaved by these proteases. In addition to the known primary cysteine mechanism in all alphaviruses and a secondary serine mechanism documented in chikungunya virus (CHIKV), I discovered secondary cysteine and threonine mechanisms exist in many other alphaviruses and that these secondary mechanisms coevolve with their viral polyprotein cleavages. As for cleavage prediction, neural networks trained on 93 different putative viral polyprotein cleavages achieved a Matthews correlation coefficient of 0.965, and, when applied to the human proteome, predicted that hundreds of proteins may be vulnerable. Notable pathways likely affected by cleavages include the cytoskeleton and extracellular matrix, antiproteases, protein translation/folding/glycosylation/ubiquitination, cellular differentiation, inflammation, and vesicle trafficking, hinting that this viral protease is a more important virulence factor than previously believed.


title: Human glioblastoma cell motility depends on the activity of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase

abstract: Cancer cells in similar functional states are found in all glioblastoma, despite the genomic heterogeneity observed between and within these brain tumors. Metabolism being downstream of all signaling pathways regulating cell behaviors, we looked for metabolic weaknesses in link with motility, a key functional state for glioblastoma aggressiveness. A signature-driven data reduction approach highlighted motile cells present in thirty tumors from four independent single-cell transcriptomic datasets. Analyses integrating trajectory modeling disclosed, as characteristic of motile cells, enhanced oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). The soundness of this prediction was verified using migration and invasion assays with patient-derived cells and tissue organoids. Pharmacological and genetic manipulations showed that enhanced ROS production and MPST activity are required for the cells motility. Biochemical assays indicated that MPST acts by protecting protein cysteine residues from dismal hyperoxidation. In vivo, MPST knockdown translated in reduced tumor burden, and a robust increase in mice survival. These results show that enhanced oxidative stress coupled with MPST mobilization plays a key role in glioblastoma cell motility.

category: cancer biology


title: Identification of Piperlongumine (PL) as an new E3 ligase ligand to induce targeted protein degradation

abstract: PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. Through competitive activity-based protein profiling, we found that piperlongumine (PL), a natural product, binds multiple E3 ligases. To evaluate whether PL can be used as an E3 ligase ligand, we generated a series of PL and SNS-032 (a selective CDK9 inhibitor) conjugates and found that the lead conjugate 955 can potently degrade CDK9 in a ubiquitin-proteasome dependent manner. In addition, 955 is more potent than SNS-032 against various tumor cells in vitro. Through TurboID-based proteomics and mechanistic studies, we identified KEAP1 as the E3 ligase recruited by PL to degrade CDK9. These findings demonstrate that PL is a novel E3 ligase ligand that can be used to generate potent anticancer PROTACs.


title: Identification of Piperlongumine (PL) as a new E3 ligase ligand to induce targeted protein degradation


title: Evaluation of Various Drugs' Influence on Alzheimer's Disease Progress Using a New Analytical Model Based on Cellular Automata

abstract: This article aims to introduce and propose a novel mathematical model for the study of Alzheimers disease (AD) progress. The presented model is based on Cellular Automata for better representation of AD progression. The differential equations of the Puri-Li model are utilized to calculate the number of Amyloid-{beta} molecules. Also, a new definition for AD rate is presented in this study. Moreover, other useful factors such as Critical Rate (CR) and Warning Rate (WR) are defined to determine the status of AD progression. To get exact insight into the neuron-to-neuron communications, the model is obtained for a 3x3 neuron system to investigate the influence of drug injection on the reduction of AR, CR, and WR factors. It is shown that using drugs can decrease AR and CR factors and also enhance the WR. The presented study can be utilized for the investigation of various factors in the control and treatment of AD progression.


title: 4R-Tobacco-Cembranoid is a Positive Allosteric Modulator of the Alpha7 Nicotinic Acetylcholine Receptor that modulates inflammation-induced thermal hypersensitivity in mice

abstract: Alpha7 nicotinic acetylcholine receptors (7nAChRs) are activated in response to inflammation and modulate pain in humans and rodent models. The use of 7nAChRs agonists as a therapeutic option for inflammation and pain is challenged by unwanted effects resulting from constant activation and/or desensitization of 7nAChRs. Positive allosteric modulators (PAMs) represent a compelling alternative as they increase endogenous nicotinic transmission but do not result in progressive desensitization or loss of receptor function. In the present study, we evaluated the function of the 4R tobacco cembranoid (4R) as a PAM of 7nAChR that reduces inflammation and pain-related behaviors in mouse models of inflammatory pain. Our electrophysiological experiments show that 4R potentiates choline-evoked currents in SH-SY5Y cells overexpressing 7nAChRs in a dose-dependent manner. At the behavioral level, we show that subcutaneous administration of 4R decreases inflammation-induced thermal but not tactile hypersensitivity or formalin-induced spontaneous nociceptive responses in both male and female mice. We further show reduced inflammation-induced paw edema in 4R-treated males, with no measurable effect observed in female mice. Altogether, the results from the experiments in this study identify 4R as a PAM of 7nAChRs that reduces thermal hypersensitivity in male and female mice and inflammation in a sex-specific manner. These findings highlight the use of 4R as a potential novel treatment strategy for pain and inflammation.


title: A scalp geometry parameter-space for optimization and implementation of conventional TMS coil placement

abstract: Transcranial magnetic stimulation efficacy is largely dependent upon coil position and orientation. A good method for describing coil placement is required for both computational optimization (planning) and actual placement (implementation). In coordinate dependent parameter-spaces (CDPs), three-dimensional coordinates are used to represent coil position and three orthogonal unit vectors are used to represent coil orientation. A CDP can precisely describe arbitrary coil placement; therefore it offers great advantage in computational optimization which checks through all possible placements. However, a neuronavigation system is usually required to accurately implement the optimized CDP parameters on a participants head. Routine clinical practice, on the other hand, often uses the International 10-20 system to describe coil placement. Although the 10-20 system can only perform modeling and placement at limited scalp landmarks, it allows the synthesis of different individuals targeting effects to find group-optimal parameters; it also allows manual placement, which is important for commonly-seen use cases without individual MRI scans and navigation devices. This study proposes a new scalp geometry based parameter-space (SGP), integrating the advantages of CDP and 10-20 methods. Our SGP 1) can quantitatively specify all possible conventional coil positions and orientations on an individuals scalp, which is important for electrical modeling and optimization, 2) maintains inter-individual correspondence, which is important for synthesizing TMS effects from different individuals and studies. 3) enables fast and simple manual implementation. Demonstration experiments were conducted to illustrate the application of an SGP-based framework for both individual and group-based optimization. A measurement experiment was performed to evaluate speed, precision and reliability of SGP-based manual implementation; results show it surpasses previous manual placement methods.


title: Extraversion is associated with lower brain amyloid deposition in cognitively normal older adults.

abstract: Emerging evidence suggests that some personality traits may link to the vulnerability to or protection for Alzheimers disease (AD). A causal mechanism underlying this relationship, however, remains largely unknown. Using 18F-Florbetaben positron emission tomography (PET) binding to beta-amyloid (A{beta}) plaques, a pathological feature of AD, and functional magnetic resonance imaging (fMRI), we investigated pathological and functional correlates of extraversion and neuroticism in a group of healthy young and older subjects. We quantified a level of brain A{beta} deposition in older individuals. Brain activity was measured in young adults using a task-switching fMRI paradigm. When we correlated personality scores of extraversion and neuroticism with these pathological and functional measures, higher extraversion, but not neuroticism, was significantly associated with lower global A{beta} measures among older adults, accounting for age and sex. This association was present across widespread brain regions. Among young subjects, higher extraversion was associated with lower activity during task switching in anterior cingulate cortex, left anterior insular cortex, left putamen, and middle frontal gyrus bilaterally, while higher neuroticism was associated with increased activity throughout the brain. The present results suggest that possibly via efficient neuronal activity, extraversion, one of lifelong personality traits, may confer the protective mechanism against the development of A{beta} pathology during aging.


title: Keystone species determine the productivity of synthetic microbial biofilm communities

abstract: Microbes typically reside in multi-species communities, whose interactions have considerable impacts on the robustness and functionality of such communities. To manage microbial communities, it is essential to understand the factors driving their assemblage and maintenance. Even though the community composition could be easily assessed, interspecies interactions during community establishment remain poorly understood. Here, we combined co-occurrence network analysis with quantitative PCR to examine the importance of each species within synthetic communities (SynComs) of pellicle biofilms. Genome-scale metabolic models and in vivo experiments indicated that the biomass of SynComs was primarily affected by keystone species that are acting either as metabolic facilitators or as competitors. Our study suggests that a combination of co-occurrence network analysis and metabolic modeling could explain the importance of keystone species in SynComs.

category: microbiology


title: A highly attenuated Vesiculovax vaccine rapidly protects nonhuman primates against lethal Marburg virus challenge

abstract:
BackgroundMarburg virus (MARV), an Ebola-like virus, remains an eminent threat to public health as demonstrated by its high associated mortality rate (23-90%) and recent emergence in West Africa for the first time. Although a recombinant vesicular stomatitis virus (rVSV)-based vaccine (Ervebo) is licensed for Ebola virus disease (EVD), no approved countermeasures exist against MARV. Results from clinical trials indicate Ervebo prevents EVD in 97.5-100% of vaccinees 10 days onwards post-immunization.

Methodology/FindingsGiven the rapid immunogenicity of the Ervebo platform against EVD, we tested whether a similar, but highly attenuated, rVSV-based Vesiculovax vector expressing the glycoprotein (GP) of MARV (rVSV-N4CT1-MARV-GP) could provide swift protection against Marburg virus disease (MVD). Here, groups of cynomolgus monkeys were vaccinated 7, 5, or 3 days before exposure to a lethal dose of MARV (Angola variant). All subjects (100%) immunized one week prior to challenge survived; 80% and 20% of subjects survived when vaccinated 5- and 3-days pre-exposure, respectively. Lethality was associated with higher viral load and aberrant innate immunity signaling, whereas survival correlated with development of MARV GP-specific antibodies and early expression of NK cell-, B-cell-, and cytotoxic T-cell-related transcriptional signatures.

Conclusions/SignificanceThese results emphasize the utility of Vesiculovax vaccines for MVD outbreak management. The highly attenuated nature of rVSV-N4CT1 vaccines, which are clinically safe in humans, may be preferable to vaccines based on the same platform as Ervebo (rVSV "delta G" platform), which in some trial participants induced vaccine-related adverse events in association with viral replication including arthralgia/arthritis, dermatitis, and cutaneous vasculitis.

Author SummaryMarburg virus (MARV) is one of the deadliest viruses known to man. One of the most effective vaccines against this pathogen uses a recombinant vesicular stomatitis virus (rVSV) platform to express MARV glycoprotein (GP) immunogen. As rVSV-based vaccines may be used as medical interventions to mitigate or prevent outbreaks of MARV, defining the time window needed to elicit protection is vital. Here, a rVSV vector expressing MARV glycoprotein (rVSV-N4CT1-MARV-GP) fully protected nonhuman primates from lethality and disease when given as soon as 1 week prior to exposure. At 5- and 3-days pre-exposure, partial protection (80% and 20% survival, respectively) was achieved. Vaccination with rVSV-N4CT1-MARV-GP appears to "jump-start" the immune system to allow sufficient time for MARV-specific adaptive responses to form. This fast- acting vaccine is based on a similar platform as Ervebo, the only FDA- and EU-approved vaccine for preventing Ebola virus infection. The rVSV-N4CT1-MARV-GP vaccine features additional attenuations in the rVSV backbone that may contribute to a more acceptable safety profile in vaccinees, as Ervebo in some recipients induced vaccine- related adverse events including rashes and joint pain.


title: Mechanical strain stimulates COPII-dependent trafficking via Rac1

abstract: Secretory trafficking from the endoplasmic reticulum (ER) is subject to regulation by extrinsic and intrinsic factors. While much of the focus has been on biochemical triggers, little is known whether and how the ER is subject to regulation by mechanical signals. Here, we show that COPII-dependent ER-export is regulated by mechanical strain. Mechanotransduction to the ER was mediated via a previously unappreciated ER-localized pool of the small GTPase Rac1. Mechanistically, we show that Rac1 interacts with the small GTPase Sar1 to drive budding of COPII carriers and stimulate ER-to-Golgi transport. Altogether, we establish an unprecedented link between mechanical strain and export from the ER.


title: Real-time precision opto-control of chemical processes in live cells

abstract: Precision control of molecular activities and chemical reactions in live cells is a long-sought capability by life scientists. No existing technology can probe molecular targets in cells and simultaneously control the activities of only these targets at high spatial precision and on the fly. We develop a real-time precision opto-control (RPOC) technology that detects a chemical-specific optical response from molecular targets during laser scanning and uses the optical signal to trigger an acousto-optic modulator, which allows a separate laser beam to only interact with the molecules of interest without affecting other parts of the sample. RPOC can automatically probe and control biomolecular activities and chemical processes in dynamic living samples with submicron spatial accuracy, nanoseconds response time, and high chemical specificity.


title: D2BGAN: Dual Discriminator Bayesian Generative Adversarial Network for Deformable MR-Ultrasound Registration Applied to Brain Shift compensation

abstract:
PurposeIn neurosurgery, image guidance is provided based on the patient to pre-operative data registration with a neuronavigation system. However, the brain shift phenomena invalidate the accuracy of the navigation system during neurosurgery. One of the most common approaches for brain shift compensation is using intra-operative ultrasound (iUS) imaging followed by registration of iUS with pre-operative magnetic resonance (MR) images. While, due to the unpredictable nature of brain deformation and the low quality of ultrasound images, finding a satisfactory multimodal image registration approach remains a challenging task.

MethodsWe proposed a new automatic unsupervised end-to-end MR-iUS registration approach based on the Dual Discriminator Bayesian Generative Adversarial Network (D2BGAN). The proposed network consists of two discriminators and is optimized by introducing a Bayesian loss function to improve the generator functionality and adding a mutual information loss function to the discriminator for similarity measurement. An evaluation was performed using the RESECT training dataset based on the organizers manual landmarks.

ResultsThe mean Target Registration Error (mTRE) after MR-iUS registration using D2BGAN reached 0.75{+/-}0.3 mm. The D2BGAN illustrated a clear advantage by 85% improvement in the mTRE of MR-iUS registration over the initial error. Also, the results confirmed that the proposed Bayesian loss function rather than the typical loss function outperforms the accuracy of MR-iUS registration by 23%.

ConclusionThe D2BGAN improved the registration accuracy while allowing us to maintain the intensity and anatomical information of the input images in the registration process. It promotes the advancement of deep learning-based multi-modality registration techniques.


title: Integrated analysis reveals FOXA1 and Ku70/Ku80 as direct targets of ivermectin in prostate cancer

abstract: Ivermectin is a widely used antiparasitic drug and shows promising anticancer activity in various cancer types. Although multiple signaling pathways modulated by ivermectin have been identified, few studies have focused on the exact target of ivermectin. Herein, we report the pharmacological effects and direct targets of ivermectin in prostate cancer (PCa). Ivermectin caused G0/G1 arrest, induced cell apoptosis, DNA damage, and decreased androgen receptor (AR) signaling in PCa cells. Using integrated omics profiling, including RNA-seq and thermal proteome profiling, we found that the forkhead box protein A1 (FOXA1) and non-homologous end joining (NHEJ) repair executer Ku70/Ku80 were the direct targets of ivermectin. The binding of ivermectin and FOXA1 reduced the chromatin accessibility of AR and the G0/G1 cell cycle regulator E2F1, leading to cell proliferation inhibition. The binding of ivermectin and Ku70/Ku80 impaired the NHEJ repair ability. Cooperating with the downregulation of homologous recombination repair after AR inhibition, ivermectin triggered synthetic lethality. Our findings demonstrate the anticancer effect of ivermectin in prostate cancer, indicating that its use may be a new therapeutic approach for PCa.


title: Stochastic resonance and bifurcations in a heterogeneous neuronal population explain intrinsic oscillatory patterns in entorhinal cortical stellate cells

abstract: Stellate cells in the medial entorhinal cortex manifest peri-threshold oscillatory patterns in their membrane voltage. Although different theoretical frameworks have been proposed to explain these activity patterns, these frameworks do not jointly account for heterogeneities in intrinsic properties of stellate cells and stochasticity in ion-channel and synaptic physiology. In this study, we first performed in vitro patch-clamp electrophysiological recordings from rat MEC stellate cells and found pronounced cell-to-cell variability in their characteristic physiological properties. We demonstrate that stochasticity introduced into either a simple nonlinear dynamical system (Hopf bifurcation) or into heterogeneous biophysical models yielded activity patterns that were qualitatively similar to peri-threshold oscillations in stellate cells. We developed five quantitative metrics for identification of valid oscillatory traces and confirmed that these metrics reliably captured the variable amplitude and non-rhythmic oscillatory patterns observed in our electrophysiological recordings. We analyzed traces from a stochastic Hopf bifurcation system for further confirmation on the reliability of these quantitative metrics in detecting oscillatory patterns. Apart from providing confirmation, these analyses provided a key insight about the manifestation of stochastic resonance in the stochastic bifurcation system, but not with theta-filtered noise. We then validated peri-threshold activity patterns obtained from a heterogeneous population of stellate cell models, with each model assessed with multiple trials of different levels and forms of noise (ion-channel, synaptic, and additive) at different membrane depolarizations. Strikingly, the validation process confirmed the manifestation of heterogeneous stochastic bifurcations across all models and revealed the detection of the highest number of valid oscillatory traces at an optimal level of each form of noise. The manifestation of stochastic resonance in this heterogeneous model population explained why intrinsic theta oscillations might not be observed under in vivo conditions where noise levels are typically high. Together, we provide several lines of evidence that demonstrate heterogeneous stochastic bifurcations as a unifying framework that fully explains peri-threshold oscillatory patterns in stellate cells and argue for state-dependence in the manifestation of these oscillations.


title: SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level

abstract: Cardiac manifestations are commonly observed in COVID-19 patients and prominently contributed to overall mortality. Human myocardium could be infected by SARS-CoV-2, and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are susceptible to SARS-CoV-2 infection. However, molecular mechanisms of SARS-CoV-2 gene-induced injury and dysfunction of human CMs remain elusive. Here, we find overexpression of three SARS-CoV-2 coding genes, Nsp6, Nsp8 and M, could globally compromise transcriptome of hPSC-CMs. Integrated transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with hPSC-CMs of Nsp6, Nsp8 or M overexpression identified concordantly activated genes enriched into apoptosis and immune/inflammation responses, whereas reduced genes related to heart contraction and functions. Further, Nsp6, Nsp8 or M overexpression induce prominent apoptosis and electrical dysfunctions of hPSC-CMs. Global interactome analysis find Nsp6, Nsp8 and M all interact with ATPase subunits, leading to significantly reduced cellular ATP level of hPSC-CMs. Finally, we find two FDA-approved drugs, ivermectin and meclizine, could enhance the ATP level, and ameliorate cell death and dysfunctions of hPSC-CMs overexpressing Nsp6, Nsp8 or M. Overall, we uncover the global detrimental impacts of SARS-CoV-2 genes Nsp6, Nsp8 and M on the whole transcriptome and interactome of hPSC-CMs, define the crucial role of ATP level reduced by SARS-CoV-2 genes in CM death and functional abnormalities, and explore the potentially pharmaceutical approaches to ameliorate SARS-CoV-2 genes-induced CM injury and abnormalities.

category: molecular biology


title: How does the host community structure affect the epidemiological dynamics of emerging infectious diseases?

abstract: Many pathogens, especially those responsible for emerging infectious diseases, are transmitted in a host community. How the host community structure affects an epidemic is still debated, particularly whether increasing the host community complexity would tend to amplify or dilute the incidence of an epidemic in a target population, e.g. humans or cattle. In this paper, we build a stochastic SIR model and compare epidemiological dynamics in a target population between three simple host community structures with an increasing complexity. Globally, our results show two possible main outcomes. First, an intermediate host can have a diluting effect by preventing the direct transmission from hosts to the target population, thus reducing the prevalence of infection. Second, when two sources of infection are considered, the effects of the epidemic are generally amplified. By highlighting that the structure of the ecological hosts network can dramatically affect epidemics, our results may have implications for the control of emerging infectious diseases.

category: ecology


title: Interpreting the Evolutionary Echoes of a Protein Complex Essential for Inner-Ear Mechanosensation

abstract: The sensory epithelium of the inner ear, found in all extant lineages of vertebrates, has been subjected to over 500 million years of evolution, resulting in the complex inner ear of modern vertebrates. Inner-ear adaptations are as diverse as the species in which they are found, and such unique anatomical variations have been well studied. However, the evolutionary details of the molecular machinery that are required for hearing are less well known. Two molecules that are essential for hearing in vertebrates are cadherin-23 and protocadherin-15, proteins whose interaction with one another acts as the focal point of force transmission when converting sound waves into electrical signals that the brain can interpret. This interaction exists in every lineage of vertebrates, but little is known about the structure or mechanical properties of these proteins in most non-mammalian lineages. Here, we use various techniques to characterize the evolution of this protein interaction. Results show how evolutionary sequence changes in this complex affect its biophysical properties both in simulations and experiments, with variations in interaction strength and dynamics among extant vertebrate lineages. Evolutionary simulations also characterize how the biophysical properties of the complex in turn constrain its evolution and provide a possible explanation for the increase in deafness-causing mutants observed in cadherin-23 relative to protocadherin-15. Together, these results suggest a general picture of tip-link evolution in which selection acted to modify the tip-link interface, while subsequent neutral evolution combined with varying degrees of purifying selection drove additional diversification in modern tetrapods.


title: The demographic costs of sexually antagonistic selection in partially selfing populations

abstract: Classic population genetics theory has been fundamental to understanding the evolution of sex-differences and the maintenance of sexually antagonistic (SA) genetic variation, but these models have rarely considered the demographic consequences of intralocus sexual antagonism. In this paper we develop a stage-structured mendelian matrix model and jointly analyze the evolutionary and demographic consequences of SA selection in obligately outcrossing (i.e., dioecious/gonochorous) and partially selfing hermaphrodite populations. We focus on identifying parameter conditions under which SA polymorphism is maintained and the population growth rate remains positive. Additionally, we analyze the effects of inbreeding depression manifesting at different life-history stages and give an illustrative example of the potential for SA polymorphism in real populations using empirically estimated demographic rates for the hermaphroditic flowering plant Mimulus guttatus. Our results show that when population intrinsic growth rates approach one, extinction occurs across large swathes of parameter space favoring SA polymorphism or the fixation of male-beneficial alleles, and that inbreeding depression is a significant problem for maintaining SA polymorphism in partially selfing populations. Despite these demographic challenges, our example with M. guttatus appears to show that demographic rates observed in some real populations are capable of sustaining large regions of viable SA polymorphic space.


title: Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in brain phenotypes and unveils a new role for the major vault protein

abstract: Using mouse genetic studies, we set out to identify which of the 30 genes causes brain size and other NeuroAnatomical Phenotypes (NAPs) at the autism-associated 16p11.2 locus. We show that multiple genes mapping to this region interact to regulate brain size in contrast to previous studies, with female significantly less affected. Major Vault Protein (MVP), the main component of the vault organelle, is a highly conserved protein found in higher and lower eukaryotic cells, yet its function is not understood. Here we find MVP expression highly specific to the limbic system and Mvp as the top driver gene of NAPs, regulating the morphology of neurons, postnatally and specifically in male. Finally, we demonstrate that the double hemideletion Mvp::Mapk3 rescues NAPs, increases phosphorylation of ERK and alters behavioral performances, suggesting that MVP and ERK share the same signalling pathway, in vivo. Our results highlight that sex-specific cellular and neuroanatomical mechanisms must be considered in neurological disorders such as autism. Most importantly, it provides the first evidence for the involvement of the vault organelle in the regulation of the mammalian brain size and limbic structures.

category: genetics


title: Gut Microbiome of Helminth Infected Indigenous Malaysians Is Context Dependent

abstract: While microbiomes in industrialized societies are well characterized, indigenous populations with traditional lifestyles have microbiomes that are more akin to those of ancient humans. However, metagenomic data in these populations remains scarce and the association with soil-transmitted helminth infection status is unclear. Here, we sequenced 650 metagenomes of indigenous Malaysians from 5 villages with different prevalence of helminth infections. Individuals from villages with higher prevalence of helminth infections have more unmapped reads and greater microbial diversity. Microbial community diversity and composition were most strongly associated with different villages and the effects of helminth infection status on the microbiome varies by village. Longitudinal changes in the microbiome in response to albendazole anthelmintic treatment was observed in both helminth infected and uninfected individuals. Inference of bacterial population replication rates from origin of replication analysis identified specific replicating taxa associated with helminth infection. Our results indicated that helminth effects on the microbiota was highly dependent on context and effects of albendazole on the microbiota can be confounding for the interpretation of deworming studies. Furthermore, a substantial quantity of the microbiome remains undescribed and this large dataset from indigenous populations associated with helminth infections should facilitate characterization of the disappearing microbiome from developed industrialized societies.