title: GeneCodis 4: Expanding the modular enrichment analysis to regulatory elements

abstract: GeneCodis is a web-based tool for functional enrichment analysis that allows researchers to integrate different sources of annotations. It extracts sets of significant concurrent annotations and assigns a statistical score to evaluate those that are significantly enriched in the input list. Since its first release in 2007, it has been widely employed to analyze lists of genes in order to interpret the underlying biological mechanisms. Here we present GeneCodis 4, a new release that expands the functional analysis provided by the application, to accept regulatory elements, including lists of, transcription factors, CpG sites and miRNAs. It also incorporates new annotation databases and improved interactive visualizations functionalities to explore results. GeneCodis 4 is freely available at https://genecodis.genyo.es.


title: North America Insect Invades the World: the Case of the Flood Mosquito, Aedes vexans (Diptera: Culicidae), from Mitochondrial DNA

abstract: The flood mosquito, Aedes vexans (Diptera: Culicidae), native of Canada, and currently present in all continents, has a vector competence for 30 arboviruses, being responsible for transmitting diseases, like West Nile fever, Rift Valley fever, Saint Louis Encephalitis and Eastern Equine Encephalitis. Hence, knowing the structure and gene flow of A. vexans is important to develop adequate vector control strategies for this species. For this, from partial sequences of the mitochondrial COI gene available in Bold and GenBank, it was possible to determine the Haplotypic (Hd) and nucleotide ({pi}) gene diversity, genetic structuring and gene flow at global, continental, and country levels. In total, 1184 sequences were recovered, distributed between America (88.60%), Europe (7.35%), Asia (3.89%), and Africa (0.17%). From these, 395 haplotypes (H) were detected without presence of pseudogenes (NUMTs), with H1 being the most frequent (24.58%) and between H12 - H395 the least frequent varying between 0.93% (H12) and 0.08% (H395). Phylogenetically, the haplotypes were grouped into six clades. Clade I grouped haplotypes from countries in America and Europe, while clades II and III presented haplotypes exclusively from Asia and Europe; clade IV grouped only one haplotype from Africa and the last ultimo clade V grouped haplotypes from America and Africa. The global Hd and {pi} was 0.92 and 0.01, respectively. In addition, evidence was obtained of genetic structuring among continents (7.07%), countries (1.62%), and within countries (91.30%; FST = 0.08, p < 0.05) and no isolation by distance was detected (r = 0.003, p > 0.05). These results suggest that the mosquito populations that invaded other continents originate directly from the American continent, where possibly transcontinental commercial routes favored their long-distance dispersion.

category: bioinformatics


title: Compositional perturbation autoencoder for single-cell response modeling

abstract: Recent advances in multiplexed single-cell transcriptomics experiments are facilitating the high-throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible, so computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep-learning approaches for single-cell response modeling. CPA encodes and learns transcriptional drug responses across different cell type, dose, and drug combinations. The model produces easy-to-interpret embeddings for drugs and cell types, which enables drug similarity analysis and predictions for unseen dosage and drug combinations. We show that CPA accurately models single-cell perturbations across compounds, doses, species, and time. We further demonstrate that CPA predicts combinatorial genetic interactions of several types, implying that it captures features that distinguish different interaction programs. Finally, we demonstrate that CPA can generate in-silico 5,329 missing genetic combination perturbations (97.6% of all possibilities) with diverse genetic interactions. We envision our model will facilitate efficient experimental design and hypothesis generation by enabling in-silico response prediction at the single-cell level, and thus accelerate therapeutic applications using single-cell technologies.


title: Learning interpretable cellular responses tocomplex perturbations in high-throughput screens


title: Design and application of a knowledge network for automatic prioritization of drug mechanisms

abstract:
MotivationDrug repositioning is an attractive alternative to de novo drug discovery due to reduced time and costs to bring drugs to market. Computational repositioning methods, particularly non-black-box methods that can account for and predict a drugs mechanism, may provide great benefit for directing future development. By tuning both data and algorithm to utilize relationships important to drug mechanisms, a computational repositioning algorithm can be trained to both predict and explain mechanistically novel indications.

ResultsIn this work, we examined the 123 curated drug mechanism paths found in the drug mechanism database (DrugMechDB) and after identifying the most important relationships, we integrated 18 data sources to produce a heterogeneous knowledge graph, MechRepoNet, capable of capturing the information in these paths. We applied the Rephetio repurposing algorithm to MechRepoNet using only a subset of relationships known to be mechanistic in nature and found adequate predictive ability on an evaluation set with AUROC value of 0.83. The resulting repurposing model allowed us to prioritize paths in our knowledge graph to produce a predicted treatment mechanism. We found that DrugMechDB paths, when present in the network were rated highly among predicted mechanisms. We then demonstrated MechRepoNets ability to use mechanistic insight to identify a drugs mechanistic target, with a mean reciprocal rank of .525 on a test set of known drug-target interactions. Finally, we walked through a repurposing example of the anti-cancer drug imantinib for use in the treatment of asthma, to demonstrate this methods utility in providing mechanistic insight into repurposing predictions it provides.

Availability and implementationThe Python code to reproduce the entirety of this analysis is available at: https://github.com/SuLab/MechRepoNet

Contactasu@scripps.edu

Supplementary informationSupplemental information is available at Bioinformatics online.


title: Identifying essential genes across eukaryotes by machine learning

abstract: Identifying essential genes on a genome scale is resource intensive and has been performed for only a few eukaryotes. For less studied organisms essentiality might be predicted by gene homology. However, this approach cannot be applied to non-conserved genes. Additionally, divergent essentiality information is obtained from studying single cells or whole, multi-cellular organisms, and particularly when derived from human cell line screens and human population studies. We employed machine learning across six model eukaryotes and 60,381 genes, using 41,635 features derived from sequence, gene functions and network topology. Within a leave-one-organism-out cross-validation, the classifiers showed a high generalizability with an average accuracy close to 80% in the left-out species. As a case study, we applied the method to Tribolium castaneum and validated predictions experimentally yielding similar performance. Finally, using the classifier based on the studied model organisms enabled linking the essentiality information of human cell line screens and population studies.


title: Folding of VemP into translation-arresting secondary structure is driven by the ribosome exit tunnel

abstract: The ribosome is a fundamental biomolecular complex responsible for protein production in cells. Nascent proteins emerge from the ribosome through a tunnel, where they may interact with the tunnel walls or small molecules such as antibiotics. These interactions can cause translational arrest with notable physiologic consequences. Here, we studied the arrest caused by the regulatory peptide VemP, which is known to form an -helix in the ribosome tunnel near the peptidyl transferase center under specific conditions. We used all-atom molecular dynamics simulations of the entire ribosome and circular dichroism spectroscopy to study the driving forces of helix formation and how VemP causes the translational arrest. To that aim, we compared VemP dynamics in the ribosome tunnel with its dynamics in solution. We show that the VemP sequence has a low helical propensity in water and that the propensity is higher in more hydrophobic solvents. We propose that helix formation within the ribosome is driven by the tunnel environment and that a portion of VemP acts as an anchor. This anchor might slow down VemP progression through the tunnel enabling the -helix formation, which causes the elongation arrest.

category: biophysics


title: Collateral Responses to Classical Cytotoxic Chemotherapies are Heterogeneous and Sensitivities are Sparse

abstract: Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity - the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug - has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we survey collateral responses to acquisition of resistance to four classical chemotherapy agents. Although collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we did not observe collateral sensitivities to any of the cytotoxic agents we studied. Interestingly, we did observe heterogeneity in the phenotypic response to acquisition of resistance to each drug, suggesting the existence of multiple different states of resistance for each drug. Surprisingly, this phenotypic heterogeneity was unrelated to transcriptomic heterogeneity in the resistant cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.

category: cancer biology


title: Aging alters the metabolic flux signature of the ER unfolded protein response in vivo in mice

abstract: Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared to young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, only a significant reduction was seen in the triglyceride fraction. These data indicate that aged mice have an exaggerated response to ER stress, which may indicate that the aging renders the UPRER less effective in resolving proteotoxic stress.

category: physiology


title: Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

abstract: Excessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNull and wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNull and wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), was a trend for increased myocardial enlargement in Ren-bNull mice when compared with control mice. Multiple studies have also demonstrated the association of chronic and acute environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNull mice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies highlight a complex mechanism that masks/unmasks roles for renin-b in cardiovascular physiology.


title: Gas flow permeability and gas pressures in stilt roots of Red Mangrove (Rhizophora mangle L.)

abstract: The Red Mangrove (Rhizophora mangle) is typically rooted in anoxic mud conditions that require special adaptations for root oxygenation. Each plant has multiple "stilt roots" that descend from upper branches and end in roots buried the mud. In cross section each stilt root consists of a core of porous aerenchyma surrounded by an impermeable layer of xylem, and outside the xylem there is a second layer aerenchyma. Oxygen must be provided to the mud roots through the aerenchyma either by diffusion or by gas flow, where the separate layers could provide up- and down-flow pathways. To test whether the stilt roots properties were consistent with gas flow, conductivities were measured. A technique was developed that measured flow conductivities in S.I. scientific units without using a flow meter and a calibrated pressure gauge. The core aerenchyma was more permeable to gas flow than any other plant tissue, except for those stems that are hollow tubes. Because there was little lateral leakage from the core aerenchyma, it had pipe-like properties. In the outer aerenchyma gas conductivity was high, and gas flowed easily through large lenticels on the surface of the stilt root. To complete the calculations, gas pressures in the stilt roots were measured. The calculated gas flow rates through mud roots was not sufficient to supply O2 for root respiration, suggesting that diffusion may be the more important mechanism for these plants.

category: plant biology


title: Quantification and uncertainty of root growth stimulation by elevated CO2 in mature temperate deciduous forest

abstract: Increasing CO2 levels are a major global challenge, and the extent to which increasing anthropogenic CO2 emissions can be mitigated by natural carbon sinks remains poorly understood. The uptake of elevated CO2 (eCO2) by the terrestrial biosphere, and subsequent sequestration as biomass in ecosystems, may act as a negative feedback in the carbon budget, but remains hard to quantify in natural ecosystems. Here, we combine large-scale field observations of fine root stocks and flows, derived from belowground imaging and soil cores, with image analysis, stochastic modelling, and statistical inference, to elucidate belowground root dynamics in a mature temperate deciduous forest under free-air CO2 enrichment to 150ppm above ambient levels. Using over 67k frames of belowground observation, we observe that eCO2 leads to relatively faster root production (a peak volume fold change of 4.52 {+/-} 0.44 eCO2 versus 2.58 {+/-} 0.21 control). We identify an increase in existing root elongation relative to root mass decay as the likely causal mechanism for this acceleration. Direct physical analysis of biomass and width measurements from 552 root systems recovered from soil cores support this picture, with lengths and widths of fine roots significantly increasing under eCO2. We use dynamic measurements to estimate fine root contributions to net primary productivity, finding an increase under eCO2, with an estimated mean annual 204 {+/-} 93 g dw m-2yr-1 eCO2 versus 140 {+/-} 60 g dw m-2 yr-1 control. We also quantify and discuss the uncertainties in such productivity measurements. This multi-faceted approach thus sheds quantitative light on the challenging characterisation of the eCO2 response of root biomass in mature temperate forests.


title: Genome-scale modeling of Pseudomonas aeruginosa PA14 unveils its broad metabolic capabilities and role of metabolism in drug potentiation

abstract: P. aeruginosa is an opportunistic human pathogen that is one of the leading causes of hospital-acquired infections. We have developed an updated genome-scale model (GEM) of Pseudomonas aeruginosa PA14 for systems-study of the pathogen. We used both automated and semi-manual approaches to reconstruct and curate the model. After an extensive literature research, we added organism-specific reactions (e.g., phenazine transport and redox metabolism, cofactor metabolism, carnitine metabolism, oxalate production, etc.) to the model. This effort led to a highly curated, three-compartment, and mass-and-charge balanced BiGG model of PA14 that contains 1509 genes, 1779 metabolic reactions and 1151 unique metabolites. The model (iSD1509) has the largest genome coverage of P. aeruginosa PA14 to date with 424 more genes than the previous model (iPau1129). It is also the most accurate with prediction accuracies as high as 92.4% (for gene essentiality) and 93.5% (for substrate utilization). The model simulates growth in both aerobic and anaerobic conditions. It predicts the biosynthesis of the virulence factor phenazine as a process for the pathogen to grow in low-oxygen environment. Further, a mechanism for the overproduction of a drug susceptibility biomarker (gluconate) can be elucidated by the principles of optimal growth. Finally, the model also simulates drug activity potentiation and protection by fumarate and glyoxylate, respectively, and provides mechanistic explanations for these processes. Overall, iSD1509 can be utilized to decipher the metabolic mechanisms associated with virulence and antibiotic susceptibility of P. aeruginosa PA14 to aid in the development of effective intervention strategies.

category: systems biology


title: Early low-level developmental arsenic exposure impacts mouse hippocampal synapticfunction

abstract:
BackgroundArsenic is a well-established carcinogen known to increase all-cause mortality, but its effects on the central nervous system are less well understood. Recent epidemiological studies suggest that early life exposure to arsenic is associated with learning deficits and behavioral changes, and increased arsenic exposure continues to affect an estimated 200 million individuals worldwide. Previous studies on arsenic exposure and synaptic function have demonstrated a decrease in synaptic transmission and long-term potentiation in adult rodents, but have relied on in vitro or extended exposure in adulthood. Therefore, little is known about the effect of arsenic exposure in development.

ObjectiveHere, we studied the effects of gestational and early developmental arsenic exposure in juvenile mice. Specifically, our objective was to investigate the impact of arsenic exposure on synaptic transmission and plasticity in the hippocampus.

MethodsC57BL/6 females were exposed to arsenic (0, 50ppb, 36ppm) in their drinking water two weeks prior to mating and continued to be exposed to arsenic throughout gestation and after parturition. We then performed field recordings in acute hippocampal slices from the juvenile offspring prior to weaning (P17-P23). In this paradigm, the juvenile mice are only exposed to arsenic in utero and via the mothers milk.

ResultsHigh (36ppm) and relatively low (50ppb) arsenic exposure both lead to decreased basal synaptic transmission in the hippocampus of juvenile mice. There was a mild decrease in paired-pulse facilitation in juvenile mice exposed to high, but not low, arsenic, suggesting the alterations in synaptic transmission are primarily post-synaptic. Finally, high developmental arsenic exposure led to a significant increase in long-term potentiation.

DiscussionThese results suggest that indirect, ecologically-relevant arsenic exposure in early development impacts hippocampal synaptic transmission and plasticity that could underlie learning deficits reported in epidemiological studies.

category: neuroscience


title: The dopamine circuit as a reward-taxis navigation system

abstract: Research on certain circuits in simple organisms, such as bacterial chemotaxis, has enabled the formulation of mathematical design principles, leading to ever more precise experimental tests, catalyzing quantitative understanding. It would be important to map these principles to the far more complex case of a vertebrate behavioral circuit. Here, we provide such a mapping for the midbrain dopamine system. Dopamine transmission plays a key role in learning, motivation, and movement, but its systems-level function is not fully understood. We develop a minimal mechanistic model of the dopamine circuit based on physiological and behavioral data, and show that it can be mapped mathematically to the bacterial chemotaxis circuit. Just as chemotaxis robustly climbs attractant gradients, the dopamine circuit performs  reward-taxis where the attractant is the expected value of reward. The reward-taxis mechanism is based on a circuit feature called fold-change detection, where the circuit outputs the temporal logarithmic derivative of expected reward. The model can explain the general matching law, in which the ratio of responses to concurrent rewards goes as the reward ratio to the power {beta}. It provides an accurate mechanistic value for {beta} as the average gain/baseline ratio of the dopaminergic neurons. Reward-taxis provides testable etiologies for specific dopamine-related disorders.


title: Opposing roles of the dorsolateral and dorsomedial striatum in the acquisition of skilled action sequencing

abstract: The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift co-operatively or competitively remains unclear. Cortical inputs have also been implicated in the shift towards automaticity, but it is unknown if they mirror their downstream striatal targets across this transition. We addressed these questions using a five-step heterogeneous action sequencing task in rats that is optimally performed by automated chains of actions. By optimising automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly the medial prefrontal cortex was not involved, however the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial striatum acts in a gating role to inhibit dorsolateral-striatum driven behavior.


title: Opposing roles of the dorsolateral and dorsomedial striatum in the acquisition of skilled action sequencing in rats


title: Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN

abstract:
Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating CIPN.

HIGHLIGHTSO_LIPaclitaxel induces intra-axonal calcium flux
C_LIO_LISarm1-dependent cADPR production promotes axonal calcium elevation and degeneration
C_LIO_LIAntagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathy in vitro and in vivo
C_LI


title: Spontaneous modulations of high frequency cortical activity

abstract:
ObjectiveWe clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state.

MethodsWe studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70-110 Hz preceding saccade onset would predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation.

ResultsThe whole-brain level dynamic atlas demonstrated transient high-gamma suppression in the striatal region before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%.

ConclusionsWe successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortex per se may prepare actively in advance for massive image motion expected during upcoming prolonged saccades.

SignificanceMeasuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic.

Highlights- The whole-brain level dynamic atlas animated spontaneous high gamma modulations associated with saccadic eye movements.
- Preceding high gamma activity in the striatal cortex predicted the direction and duration of the upcoming saccades.
- Saccade-related high-gamma modulations localized the stimulation-defined visual cortex with an accuracy of 95%.


title: A computational model of typical and impaired reading: the role of visual processing

abstract: Computational modelling has served as a powerful tool to advance our understanding of language processes by making theoretical ideas rigorously specified and testable (a form of " open science" for theory building). In reading research, one of the most influential computational modelling frameworks is the triangle model of reading that characterises the mappings between orthography, phonology and semantics. Currently, most instantiations of the triangle modelling framework start the processes from orthographic levels which abstract away visual processing. Moreover, without visual processing, most models do not provide an opportunity to investigate visual-related dyslexia. To bridge this crucial gap, the present study extended the existing triangle models by implementing an additional visual input. We trained the model to learn to read from visual input without pre-defined orthographic representations. The model was assessed by reading tasks in both intact and after damage (to mimic acquire alexias). The simulation results demonstrated that the model was able to name word and nonwords as well as make lexical decisions. Damage to the visual, phonological or semantic components of the model resulted in the expected reading impairments associated with pure alexia, phonological dyslexia, and surface dyslexia, respectively. The simulation results demonstrated for the first time that both typical and neurologically-impaired reading including both central and peripheral dyslexia could be addressed in this extended triangle model of reading. The findings are consistent with the primary systems account.


title: Dynamics of absolute and relative disparity processing in human visual cortex

abstract:
Cortical processing of binocular disparity is believed to begin in V1 where cells are sensitive to absolute disparity, followed by the extraction of relative disparity in higher visual areas. While much is known about the cortical distribution and spatial tuning of disparity-selective neurons, the relationship between their spatial and temporal properties is less well understood. Here, we use steady-state Visual Evoked Potentials and dynamic random dot stereograms to characterize the temporal dynamics of spatial mechanisms in human visual cortex that are primarily sensitive to either absolute or relative disparity. Stereograms alternated between disparate and non-disparate states at 2 Hz. By varying the spatial frequency content of the disparate fields from a planar surface to corrugated ones, we biased responses towards absolute vs. relative disparities. Reliable Components Analysis was used to derive two dominant sources from the 128 channel EEG records. The first component (RC1) was maximal over the occipital pole while the second component (RC2) was maximal over right lateral occipital electrodes. In RC1, first harmonic responses were sustained, tuned for corrugation frequency, and sensitive to the presence of disparity references, consistent with prior psychophysical sensitivity measurements. By contrast, the second harmonic, associated with transient processing, was not spatially tuned and was indifferent to references, consistent with it being generated by an absolute disparity mechanism. In RC2, the sustained response component showed similar tuning and sensitivity to references. However, sensitivity for absolute disparity dropped off, and transient signals were mainly driven by the lowest corrugation frequencies.

SIGNIFICANCE STATEMENTSustained and transient mechanisms have been demonstrated across sensory systems and may reflect a common coding strategy. This strategy may be useful for the analysis of the form and duration of complex events in the case of sustained signals, and the onset and location of events in the case of transient signals. Here, we provide direct neural correlates of sustained and transient disparity mechanisms in human visual cortex. Early visual cortex is sensitive to both relative and absolute disparity, with the former being processed in a sustained fashion and the latter in a more transient fashion. Outside of early visual cortex, sustained relative disparity responses are readily measurable, but transient responses and responses to absolute disparity are not.


title: Neural bases of risky decisions involving nicotine vapor versus monetary reward

abstract: Substantial effort has gone into neuroimaging studies of neural mechanisms underlying addiction. Human studies of smoking typically either give monetary reward during an fMRI task or else allow subjects to smoke outside the scanner, after the session. This raises a fundamental issue of construct validity, as it is unclear whether the same neural mechanisms process decisions about nicotine that process decisions about money. To address this, we developed a novel MR-compatible nicotine vaping device, such that access to nicotine vapor could be controlled and monitored. We recruited heavy smokers to perform a gambling task with nicotine and monetary reward on separate days. This allowed a direct comparison between the neural mechanisms of choosing and receiving immediate drug vs. monetary reward. We found substantial differences in the neural mechanisms that underlie risky choices about money vs. drug reward, including a reversal of the well-known error effects in the medial prefrontal cortex.


title: Distinct nociresponsive region in mouse primary somatosensory cortex

abstract: Nociception, somatic discriminative aspects of pain, is represented in the primary somatosensory cortex (S1), as is touch, but the separation and the interaction of the two modalities within S1 remain unclear. Here, we show the spatially-distinct tactile and nociceptive processing in the granular barrel field (BF) and the adjacent dysgranular region (Dys) in mouse S1. Simultaneous recording of the multiunit activity across subregions reveals that Dys responses are selective to noxious input whereas those of BF are to tactile input. At the single neuron level, nociceptive information is represented separately from the tactile information in Dys layer 2/3. In contrast, both modalities are converged in a layer 5 neuron in each region. Interestingly, the two modalities interfere with each other in both regions. We further demonstrate that Dys, but not BF, activity is critically involved in neuropathic pain and pain behavior, and thus provide evidence that Dys is a center specialized for nociception in S1.


title: Mechanism underlying the DNA-binding preferences of the Vibrio cholerae and vibriophage VP882 VqmA quorum-sensing receptors

abstract:
Quorum sensing is a chemical communication process that bacteria use to coordinate group behaviors. In the global pathogen Vibrio cholerae, one quorum-sensing receptor and transcription factor, called VqmA (VqmAVc), activates expression of the vqmR gene encoding the small regulatory RNA VqmR, which represses genes involved in virulence and biofilm formation. Vibriophage VP882 encodes a VqmA homolog called VqmAPhage that activates transcription of the phage gene qtip, and Qtip launches the phage lytic program. Curiously, VqmAPhage can activate vqmR expression but VqmAVc cannot activate expression of qtip. Here, we investigate the mechanism underlying this asymmetry. We find that promoter selectivity is driven exclusively by each VqmA DNA-binding domain and key DNA sequences in the vqmR and qtip promoters are required to maintain specificity. A protein sequence-guided mutagenesis approach revealed that the residue E194 of VqmAPhage and A192, the equivalent residue in VqmAVc, in the helix-turn-helix motifs contribute to promoter-binding specificity. A genetic screen to identify VqmAPhage mutants that are incapable of binding the qtip promoter but maintain binding to the vqmR promoter delivered additional VqmAPhage residues located immediately C-terminal to the helix-turn-helix motif as required for binding the qtip promoter. Surprisingly, these residues are conserved between VqmAPhage and VqmAVc. A second, targeted genetic screen revealed a region located in the VqmAVc DNA-binding domain as necessary to prevent VqmAVc from binding the qtip promoter, thus restricting DNA-binding to the vqmR promoter. We propose that the VqmAVc helix-turn-helix motif and the C-terminal flanking residues function together to prohibit VqmAVc from binding the qtip promoter.

AUTHOR SUMMARYBacteria use a chemical communication process called quorum sensing (QS) to orchestrate collective behaviors. Recent studies demonstrate that bacteria-infecting viruses, called phages, also employ chemical communication to regulate collective activities. Phages can encode virus-specific QS-like systems, or they can harbor genes encoding QS components resembling those of bacteria. The latter arrangement suggests the potential for chemical communication across domains, i.e., between bacteria and phages. Ramifications stemming from such cross-domain communication are not understood. Phage VP882 infects the global pathogen Vibrio cholerae, and "eavesdrops" on V. cholerae QS to optimize the timing of its transition from living as a parasite to killing the host, and moreover, to manipulate V. cholerae biology. To accomplish these feats, phage VP882 relies on VqmAPhage, the phage-encoded homolog of the V. cholerae VqmAVc QS receptor and transcription factor. VqmAVc, by contrast, is constrained to the control of only V. cholerae genes and is incapable of regulating phage biology. Here, we discover the molecular mechanism underpinning the asymmetric transcriptional preferences of the phage-encoded and bacteria-encoded VqmA proteins. We demonstrate how VqmA transcriptional regulation is crucial to the survival and persistence of both the pathogen V. cholerae, and the phage that preys on it.

category: microbiology


title: TAZ/TEAD complex regulates TGF-β1-mediated fibrosis in iPSC-derived renal organoids

abstract: Chronic kidney disease (CKD) progresses by replacement of functional tissue compartments with fibrosis, representing a maladaptive repair process. Shifting kidney repair towards a physiologically-intact architecture, rather than fibrosis, is key to blocking CKD progression. In this study, we developed a fibrosis model that uses human induced pluripotent stem cell (iPSC)-based three-dimensional renal organoids, in which exogenous TGF-{beta}1 induces production of extracellular matrix. In these organoids, TGF- {beta}1 increased transcription factor tafazzin (TAZ) expression. Further, in human kidney biopsies, nuclear TAZ expression was markedly increased in mild and moderate fibrosis. In cultured renal tubular cells expressing a fibrogenic program, TAZ formed a trimeric complex with phosphorylated mothers against decapentaplegic homolog 3 (p-SMAD3) and TEA domain protein (TEAD)-4. Overexpression of TEAD4 protein suppressed collagen-11 (COL1A1) promoter activity, and expression of TAZ attenuated this inhibition. INT-767, a dual bile acid receptor agonist binding farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5), decreased the TGF-{beta}1-induced increase in p-SMAD3 and TAZ, and preserved renal organoid architecture. These data demonstrate, in an iPSC-derived renal organoid fibrosis model, that INT767 prevents fibrosis programs early in the course of tubular injury through modulation of the TEAD4/TAZ pathway.

category: cell biology


title: XBP1s-Mediated Endoplasmic Reticulum Proteostasis Network Enhancement Can Selectively Improve Folding and Secretion of an Osteogenesis Imperfecta-Causing Collagen-I Variant

abstract: Osteogenesis imperfecta (OI) is typically caused by autosomal dominant mutations in genes encoding collagen type-I, most commonly resulting in Gly[->]Ser triple-helical domain substitutions that disrupt collagen folding and/or stability. Here, we test the hypothesis that upregulating the endoplasmic reticulum (ER) proteostasis network via the unfolded protein response (UPR) can improve the folding and secretion of the clinically severe, prototypical OI-causing COL1A1 p.G425S collagen-1(I) variant. We first show that small molecule stressors that globally activate the UPR severely ablate collagen-I secretion from both G425S Col1(I)- and wild-type (WT) Col1(I)-expressing primary fibroblasts. In contrast, stress-independent, specific induction of just the UPRs XBP1s transcriptional response enhances collagen-I secretion from G425S Col1(I) patient primary fibroblasts up to ~300% of basal levels. Notably, the effect is selective - collagen-I secretion from WT Col1(I)-expressing healthy donor primary fibroblasts is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S Col1(I), as only modest impacts on collagen-I transcription or synthesis are observed. Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S 1(I) patient fibroblasts includes a higher proportion of the mutant 1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions. These results highlight the potential for ER proteostasis network modulation to improve mutant collagen proteostasis in the collagenopathies, motivating further investigation of the effects generality, underlying mechanism, and potential therapeutic benefits.


title: Extensive transgressive gene expression in a homoploid hybrid species

abstract: Hybridization can result in novel allelic combinations which can impact the hybrid phenotype through changes in gene expression. While mis-expression in F1 hybrids is well documented, how gene expression evolves in stabilized hybrid taxa remains an open question. As gene expression evolves in a stabilizing manner, break-up of co-evolved cis- and trans-regulatory elements could lead to transgressive patterns of gene expression in hybrids. Here, we address to what extent gonad gene expression has evolved in an established and stable homoploid hybrid, the Italian sparrow (Passer italiae). Through comparison of gene expression in gonads from individuals of the two parental species (i.e., house and Spanish sparrow) to that of Italian sparrows, we find evidence for strongly transgressive expression in male Italian sparrows - 22% of testis genes exhibit expression patterns outside the range of both parent species. In contrast, Italian sparrow ovary expression was similar to that of one of the parent species, the house sparrow (Passer domesticus). Moreover, the Italian sparrow testis transcriptome is 26 times as diverged from those of the parent species as the parental transcriptomes are from each other, despite being genetically intermediate. This highlights the potential for regulation of gene expression to produce novel variation following hybridization. Genes involved in mitochondrial respiratory chain complexes and protein synthesis are enriched in the subset that is over-dominantly expressed in Italian sparrow testis, suggesting that selection on key functions have molded the hybrid Italian sparrow transcriptome.

category: evolutionary biology


title: Extensive transgressive gene expression in testis but not ovary in the homoploid hybrid Italian sparrow


title: Template switching in DNA replication can create and maintain RNA hairpins

abstract: The evolutionary origin of ribonucleic acid (RNA) stem structures and the preservation of their base-pairing under a spontaneous and random mutation process have puzzled theoretical evolutionary biologists. DNA replication-related template switching is a mutation mechanism that creates reverse-complement copies of sequence regions within a genome by replicating briefly either along the complementary or nascent DNA strand. Depending on the relative positions and context of the four switch points, this process may produce a reverse-complement repeat capable of forming the stem of a perfect DNA hairpin, or fix the base-pairing of an existing stem. Template switching is typically thought to trigger large structural changes and its possible role in the origin and evolution of RNA genes has not been studied. Here we show that the reconstructed ancestral histories of RNA genes contain mutation patterns consistent with the DNA replication-related template switching. In addition to multi-base compensatory mutations, the mechanism can explain complex sequence changes, though mutations breaking the structure rarely get fixed in evolution. Our results suggest a solution for the longstanding dilemma of RNA gene evolution and demonstrate how template switching can both create perfect stems with a single mutation event and help maintaining the stem structure over time. Interestingly, template switching also provides an elegant explanation for the asymmetric base-pair frequencies within RNA stems.


title: FAN1 nuclease processes and pauses on disease-associated slipped-DNA repeats: Mechanism against repeat expansions

abstract: FAN1 nuclease is a modifier of repeat expansion diseases, including Huntingtons disease (HD), fragile X syndrome, and autism. The age of HD onset correlates with ongoing  inchworm-like repeat expansions (1-3 CAG units/event) in HD brains, and is regulated by three modifiers: The first two, repeat tract length and purity exert their effects by enhancing and slowing CAG expansions, respectively, by affecting the formation of slipped-DNAs -- mutagenic intermediates of instability; which are processed to expansions by the third modifiers, DNA repair proteins. FAN1 protects against hyper-expansions of repeats, by unknown mechanisms. We show FAN1, through iterative cycles bound, dimerized and cleaved slipped-DNAs, yielding striking patterns of distinct exo-nuclease pauses along slip-outs; 5'-C{downarrow}A{downarrow}GC{downarrow}A{downarrow}G-3' and 5'-C{downarrow}T{downarrow}G{downarrow}C{downarrow}T{downarrow}G-3'. The transcriptionally-displaced CAG strand was excised slower than its complementary CTG strand, required A*A and T*T mismatches, as fully-paired hairpins arrested excision progression, while disease-delaying CAA interruptions further slowed FAN1 excision. In contrast, endo-nucleolytic cleavage was insensitive to slip-outs. Rare FAN1 variants were found in autism individuals with CGG/CCG repeat expansions. Excision of CGG/CCG slip-outs were similarly excised, with CGG being slower than CCG. The slip-out specific ligand, Naphthyridine-Azaquinolone, shown to induce contractions of expanded repeats in cells, required FAN1 for its effect, and protected slip-outs from FAN1s exo- but not endo-nucleolytic digestion. FAN1s  inchworm pausing of slip-out excision is suited to minimize incremental expansions and modulating disease onset.

category: genetics


title: A complex CTCF binding code defines TAD boundary structure and function

abstract: Topologically Associating Domains (TADs) compartmentalize vertebrate genomes into sub-Megabase functional neighbourhoods for gene regulation, DNA replication, recombination and repair1-10. TADs are formed by Cohesin-mediated loop extrusion, which compacts the DNA within the domain, followed by blocking of loop extrusion by the CTCF insulator protein at their boundaries11-20. CTCF blocks loop extrusion in an orientation dependent manner, with both experimental and in-silico studies assuming that a single site of static CTCF binding is sufficient to create a stable TAD boundary21-24. Here, we report that most TAD boundaries in mouse cells are modular entities where CTCF binding clusters within extended genomic intervals. Optimized ChIP-seq analysis reveals that this clustering of CTCF binding does not only occur among peaks but also frequently within those peaks. Using a newly developed multi-contact Nano-C assay, we confirm that individual CTCF binding sites additively contribute to TAD separation. This clustering of CTCF binding may counter against the dynamic DNA-binding kinetics of CTCF25-27, which urges a re-evaluation of current models for the blocking of loop extrusion21-23. Our work thus reveals an unanticipatedly complex code of CTCF binding at TAD boundaries that expands the regulatory potential for TAD structure and function and can help to explain how distant non-coding structural variation influences gene regulation, DNA replication, recombination and repair5,28-34.


title: Image processing and genome-wide association studies in sunflower identify loci associated with seed-coat characteristics

abstract: Sunflower seeds (technically achenes) are characterized by a wide spectrum of sizes, shapes, and colors. These traits are genetically correlated with the branching plant architecture loci, which were introgressed into restorer lines to facilitate efficient hybrid production. To break this genetic correlation between branching and seed traits, high resolution mapping of the genes that regulate seed traits is necessary. Recent progress in genomics permits acquisition of comprehensive genotyping data for a large diversity panel, yet a major constraint for exploring the genetic basis of important phenotypes across large diversity panels is the ability to screen and characterize them efficiently. Here, we implement a cost-effective image analysis pipeline to phenotype seed characteristics in a large sunflower diversity panel comprised of 287 individuals that represents most of the genetic variation in cultivated sunflower. A genome-wide association analysis was performed for seed-coat size and shape traits and significant signals were identified around genes regulating phytohormone activity. In addition, significant seed-coat color QTLs were identified and candidate genes that effect pigmentation were detected including a phytomelanin regulating gene on chromosome 17. Finally, QTLs associated with the seed-coat striped pattern were identified and phytohormone regulating candidate genes were detected. The implementation of image analysis phenotyping for GWAS allowed efficient screening of a large diversity panel and identification of valuable genetic factors effecting seed characteristics at the finest resolution to date.


title: Genome-Wide Association Studies and Genomic Selection for Grain Protein Content Stability in a Nested Association Mapping Population of Spring Wheat

abstract: Grain protein content (GPC) is controlled by complex genetic systems and their interactions, and is an important quality determinant for hard spring wheat as it has a positive effect on bread and pasta quality. GPC is variable among genotypes and strongly influenced by environment. Thus, understanding the genetic control of wheat GPC and identifying genotypes with improved stability is an important breeding goal. The objectives of this research were to identify genetic backgrounds with less variation for GPC across environments and identify quantitative trait loci (QTLs) controlling the stability of GPC. A spring wheat nested association mapping (NAM) population of 650 recombinant inbred lines (RIL) derived from 26 diverse founder parents crossed to one common parent,  Berkut, was phenotyped over three years of field trials (2014-2016). Genomic selection models were developed and compared based on prediction of GPC and GPC stability. After observing variable genetic control of GPC within the NAM population, seven RIL families displaying reduced marker-by-environment interaction were selected based on a stability index derived from Finlay-Wilkinson regression. A genome-wide association study identified seven significant QTLs for GPC stability with a Bonferroni-adjusted P value <0.05. This study also demonstrated that genome-wide prediction of GPC with ridge regression best linear unbiased estimates reached up to r = 0.69. Genomic selection can be used to apply selection pressure for GPC and improve genetic gain for GPC.

category: genomics


title: The dominant axes of lifetime behavioral variation in honey bees

abstract: Insect colonies are decentralized systems that employ task allocation, whereby individuals undertake different roles to fulfil colony needs, such as honey bee "nurses", "nest workers", and "foragers". However, the extent to which individuals can be well-classified by discrete "roles", how they change behavior from day-to-day, over entire lifetimes, and with environmental conditions, is poorly understood. Using long-term automated tracking of over 4,200 individually-identified bees Apis mellifera, we use behavioral metrics to quantify and compare behavior. We show that individuals exhibit behavioral variation along two dominant axes that represent nest substrate use and movement within the nest. Across lifetimes, we find that individuals differ in foraging onset, and that certain bees exhibit lifelong consistencies in their movement patterns. Furthermore, we examine a period of sudden nectar availability where the honey stores tripled over 6 days, and see that the colony exhibits a distributed shift in activity that did not require a large-scale colony reorganization. Our quantitative approach shows how collective units differ over days and lifetimes, and how sources of variation and variability contribute to the colonys robust yet flexible response.

category: animal behavior and cognition


title: Albumin-binding Aptamer Chimeras for Improved siRNA Bioavailability

abstract: Short interfering RNAs (siRNAs) are potent nucleic acid-based drugs designed to target disease driving genes that may otherwise be undruggable with small molecules. However, the potential of administering therapeutic siRNA in vivo is limited by poor pharmacokinetic properties, including rapid renal clearance and nuclease degradation. Nanocarriers have traditionally been explored as means to overcome these challenges, but they have intrinsic downsides such as dose-limiting toxicity and synthetic complexity. Backpacking on natural carriers such as albumin, which is present at high concentration and has a long half-life in serum, is an effective way to modify pharmacokinetics of biologic drugs that otherwise have poor bioavailability. In this work, we sought to develop albumin-binding aptamer-siRNA chimeras to improve the bioavailability of siRNA. We used a Systematic Evolution of Ligands through Exponential Enrichment (SELEX) approach to obtain RNA aptamers with modified bases that bind albumin with high affinity. We then fused the aptamers directly to an siRNA to generate the chimera structure. These aptamer-siRNA chimeras are stable in serum, exhibit potent gene knockdown capabilities in vitro, and display extended circulation time in vivo. We suggest that this albumin-binding aptamersiRNA chimera approach is a promising strategy for drug delivery applications.

category: bioengineering


title: CoolBox: A flexible toolkit for visual analysis of genomics data

abstract: We developed CoolBox, an open source toolkit for visual analysis of genomics data, which is highly compatible with the Python ecosystem, easy to use and highly customizable with a well-designed user interface. It can be used in various visualization situations like a Swiss army knife, for example, to produce high-quality genome track plots or fetch common used genomic data files with a Python script or command line, interactively explore genomic data within Jupyter environment or web browser. Moreover, owing to the highly extensible API design, users can customize their own tracks without difficulty, which can greatly facilitate analytical, comparative genomic data visualization tasks.


title: A curated collection of human vaccination response signatures

abstract: Recent advances in high-throughput experiments and systems biology approaches have resulted in hundreds of publications identifying "immune signatures". Unfortunately, these are often described within text, figures, or tables in a format not amenable to computational processing, thus severely hampering our ability to fully exploit this information. Here we present a data model to represent immune signatures, along with the Human Immunology Project Consortium (HIPC) Dashboard (www.hipc-dashboard.org), a web-enabled application to facilitate signature access and querying. The data model captures the biological response components (e.g., genes, proteins, cell types or metabolites) and metadata describing the context under which the signature was identified using standardized terms from established resources (e.g., HGNC, Protein Ontology, Cell Ontology). We have manually curated a collection of >600 immune signatures from >60 published studies profiling human vaccination responses for the current release. The system will aid in building a broader understanding of the human immune response to stimuli by enabling researchers to easily access and interrogate published immune signatures.


title: A soil-binding polysaccharide complex released from root hairs functions in rhizosheath formation

abstract:
To elucidate factors involved in rhizosheath formation, wild type (WT) barley (Hordeum vulgare L. cv. Pallas) and a root hairless mutant, bald root barley (brb), were investigated with a combination of physiological, biochemical and immunochemical assays. When grown in soil, WT barley roots bound [~]5-fold more soil than brb per unit root length. High molecular weight (HMW) polysaccharide exudates of brb roots had less soil-binding capacity than those of WT root exudates. Carbohydrate and glycan monoclonal antibody analyses of HMW polysaccharide exudates indicated differing glycan profiles. Relative to WT plants, root exudates of brb had reduced signals for arabinogalactan-protein (AGP), extensin and heteroxylan epitopes than brb. In contrast, the brb root exudate contained [~]25-fold more detectable xyloglucan epitope relative to WT. Epitope detection chromatography indicated that the increased detection of xyloglucan in brb exudates was due to enhanced abundance of a neutral polymer. Exudate preparations from brb had decreased amounts of an acidic form of xyloglucan associated with root-hair located glycoprotein and heteroxylan epitopes and with soil-binding properties. Therefore, in addition to physically structuring soil particles, root hairs facilitate rhizosheath formation by releasing a soil-binding polysaccharide complex.

One sentence summaryThe root exudate of a root hairless mutant of barley, relative to wild type, has an altered pattern of polysaccharide epitopes and lesser amounts of an acidic soil-binding polysaccharide complex.


title: Evolving the Olfactory System with Machine Learning

abstract: The convergent evolution of the fly and mouse olfactory system led us to ask whether the anatomic connectivity and functional logic of olfactory circuits would evolve in artificial neural networks trained to perform olfactory tasks. Artificial networks trained to classify odor identity recapitulate the connectivity inherent in the olfactory system. Input units are driven by a single receptor type, and units driven by the same receptor converge to form a glomerulus. Glomeruli exhibit sparse, unstructured connectivity to a larger, expansion layer of Kenyon cells. When trained to both classify odor identity and to impart innate valence onto odors, the network develops independent pathways for identity and valence classification. Thus, the defining features of fly and mouse olfactory systems also evolved in artificial neural networks trained to perform olfactory tasks. This implies that convergent evolution reflects an underlying logic rather than shared developmental principles.


title: A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory

abstract: The storage of information by the hippocampus in long-term memory is thought to involve two distinct but related processes. First, the hippocampus determines whether a given stimulus is novel or familiar; next, the hippocampus stores the novel information in long-term memory. To date, the neural circuits that detect novelty and their relation to the circuits that store information of a specific memory are poorly understood. Here we address this question by examining the circuits by which the CA2 region of the hippocampus, which is essential for social memory, both detects social novelty and stores social memory. CA2, like the more thoroughly studied CA1 region, receives its major excitatory input from the entorhinal cortex through both a direct monosynaptic and indirect trisynaptic pathway. We find that the direct inputs to CA2 from the lateral entorhinal cortex, but not the indirect trisynaptic inputs, provide social information that is required for social memory. However, these direct inputs fail to discriminate a novel from a familiar animal. Thus, social novelty and social identity signals are likely conveyed through separate pathways, with the entorhinal cortex providing specific multisensory information about an animals identity and novelty detection requiring a local computation within CA2.


title: A Scribble-E-cadherin complex controls daughter cell patterning by multiple mechanisms

abstract: The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate patterning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble, links E-cadherin to NuMA and Arp2/3 signalling for sequential roles in daughter positioning. First Scribble transmits cues from E-cadherin localised in retraction fibres to control orientation of the mitotic spindle. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter-daughter junction, generation of filopodia and subsequent cell patterning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell division to orient the mitotic spindle and control placement of the daughter cells after cell division.


title: Diversity of vaccination-induced immune responses can prevent the spread of vaccine escape mutants

abstract: Pathogens that are resistant against drug treatment are widely observed. In contrast, pathogens that escape the immune response elicited upon vaccination are rare. Previous studies showed that the prophylactic character of vaccines, the multiplicity of epitopes to which the immune system responds within a host, and their diversity between hosts delay the evolution and emergence of escape mutants in a vaccinated population. By extending previous mathematical models, we find that, depending on the cost of the escape mutations, there even exist critical levels of immune response diversity that completely prevent vaccine escape. Furthermore, to quantify the potential for vaccine escape below these critical levels, we propose a concept of escape depth which measures the fraction of escape mutants that can spread in a vaccinated population. Determining this escape depth for a vaccine could help to predict its sustainability in the face of pathogen evolution.


title: MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting Nuclear Factor I/B (NFIB)

abstract:
BackgroundMedulloblastoma (MB), the most frequent malignant pediatric brain tumor, is subdivided into four primary subgroups, wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-Myc amplification distinguish high-risk group 3 tumors associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212-3p, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB.

MethodsWe first determined miR-212-3p expression in group 3 MB using several publicly-available datasets with confirmatory studies in vitro. We then identified epigenetic regulation by studying methylation and HDAC modifications along the promoter region. We used two systems for expression restoration, i.e. transient transfection or stable induction, to delineate miR-212-3ps tumor suppressive and biochemical properties via assays assessing cancer proliferation, migration, invasion, colony formation, along with cell cycle and apoptosis analyses. We then compared MB and miR target databases to isolate a putative target whose biochemical and oncogenic properties were similarly elucidated using either transient silencing of target expression or stable induction of miR-212-3p.

ResultsRNA expression analyses revealed dramatically reduced miR-212-3p levels in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications. Restoring miR-212-3p expression reduced in vitro cancer cell proliferation, migration, colony formation, and wound healing. Elevated miR-212-3p levels shifted c-Myc phosphorylation (from serine-62 to threonine-58), triggering destabilization and degradation; concurrently, its pro-apoptotic binding partners, i.e., Bin-1 and P19ARF, were upregulated with subsequent elevated apoptotic signals. Using a combination of transcriptomic data and dual luciferase assay, we isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high-expressing patients. Transient NFIB silencing in vitro reduced cancer cell proliferation, colony formation, migration, and invasion. Concurrently, in group 3 MB cells, reduced medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133) were noted.

ConclusionThese results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and provide a potential therapeutic oncogenic target implicated in metastasis and tumor recurrence.


title: Phylogeny Reveals Novel HipA-Homologous Kinase Families and Toxin - Antitoxin Gene Organizations

abstract:
Toxin - Antitoxin modules function in the genetic stability of mobile genetic elements, bacteriophage defense, and antibiotic tolerance. A gain-of-function mutation of the Escherichia coli K-12 hipBA module can induce antibiotic tolerance in a subpopulation of bacterial cells, a phenomenon known as persistence. HipA is a Ser/Thr kinase that phosphorylates and inactivates glutamyl tRNA synthetase, inhibiting cellular translation and inducing the stringent response. Additional characterized HipA homologues include HipT from pathogenic E. coli O127 and YjjJ of E. coli K-12, which are encoded by tri-cistronic hipBST and monocistronic operons, respectively. The apparent diversity of HipA homologues in bacterial genomes inspired us to investigate overall phylogeny. Here we present a comprehensive phylogenetic analysis of the Hip kinases in bacteria and archaea that expands on this diversity by revealing seven novel kinase families. Kinases of one family, encoded by monocistronic operons, consist of an N-terminal core kinase domain, a HipS-like domain and a HIRAN (HIP116 Rad5p N-terminal) domain. HIRAN domains bind single or double-stranded DNA ends. Moreover, five types of bicistronic kinase operons encode putative antitoxins with HipS-HIRAN, HipS, {gamma}{delta}-resolvase or Stl repressor-like domains. Finally, our analysis indicates that reversion of hipBA gene-order happened independently several times during evolution.

ImportanceBacterial multidrug tolerance and persistence are problems of increasing scientific and medical significance. The first gene discovered to confer persistence was hipA, encoding the kinase toxin of the hipBA toxin-antitoxin (TA) module of E. coli. HipA-homologous kinases phosphorylate and thereby inactivate specific tRNA synthetases, thus inhibiting protein translation and cell proliferation. Here, we present a comprehensive phylogenetic analysis of bacterial Hip kinases and discover seven new families with novel operon structures and domains. Overall, Hip kinases are encoded by TA modules with at least 10 different genetic organizations, seven of which have not been described before. These results open up exciting avenues for the experimental analysis of the superfamily of Hip kinases.


title: Living to the high extreme: unraveling the composition, structure, and functional insights of bacterial communities thriving in the arsenic-rich Salar de Huasco - Altiplanic ecosystem.

abstract:
Microbial communities inhabiting extreme environments like Salar de Huasco (SH) are adapted to thrive while exposed to several abiotic pressures and the presence of toxic elements like arsenic (As). Hence, we aimed to uncover the role of arsenic in shaping bacterial composition, structure, and functional potential in five different sites in this Altiplanic wetland using a shotgun metagenomic approach. The sites exhibit wide gradients of arsenic (9 to 321 mg/kg), and our results showed highly diverse communities and a clear dominance exerted by the Proteobacteria and Bacteroidetes phyla. Functional potential analyses showed broadly convergent patterns, contrasting with their great taxonomic variability. Arsenic-related metabolism is different among the five communities, as well as other functional categories like those related to the CH4 and S cycles. Particularly, we found that the distribution and abundance of As-related genes increase, following along the As concentration gradient. Approximately 75% of the detected genes for As-metabolism belong to expulsion mechanisms, being arsJ and arsP pumps related to sites with higher As concentrations and present almost exclusively in Proteobacteria. Furthermore, taxonomic diversity and functional potential are reflected in the 12 reconstructed high-quality MAGs (Metagenome Assembled Genomes) belonging to the Bacteroidetes (5), Proteobacteria (5), Cyanobacteria (1) and Gemmatimonadota (1) phyla. We conclude that SH microbial communities are diverse and possess a broad genetic repertoire to thrive under extreme conditions, including increasing concentrations of the highly toxic As. Finally, this environment represents a reservoir of unknown and undescribed microorganisms, with a great metabolic versatility, which needs further study.

IMPORTANCEMicrobial communities inhabiting extreme environments are fundamental for maintaining the ecosystems; however, little is known about their potential functions and interactions among them. We sampled the microbial communities in Salar de Huasco (SH) in the Chilean Altiplano, a fragile and complex environment that comprises several stresses. We found that microbes in SH are taxonomically diverse; nonetheless, their functional potential seems to have an important convergence degree, suggesting high adaptation levels. Particularly, arsenic metabolism showed differences associated with increasing concentrations of the metalloid throughout the area, and it is effectively exerting a clear and significant pressure over these organisms. Thus, this researchs significance is that we described highly specialized communities thriving in little-explored environments under several pressures, considered analogous of early Earth and other planets, and can have the potential for unraveling technologies to face climate change repercussions in many areas of interest.


title: The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells

abstract: Transcription factors (TFs) control gene expression by direct binding to regulatory regions of target genes but also by impacting chromatin landscapes and thereby modulating DNA accessibility for other TFs. To date, the global TF reservoir in plasmacytoid dendritic cells (pDCs), a cell type with the unique capacity to produce unmatched amounts of type I interferons, has not been fully characterized. To fill this gap, we have performed a comprehensive analysis in naive and TLR9-activated pDCs in a time course study covering early timepoints after stimulation (2h, 6h, 12h) integrating gene expression (RNA-Seq), chromatin landscape (ATAC-Seq) and Gene Ontology studies. We found that 70% of all described TFs are expressed in pDCs for at least one stimulation time point and that activation predominantly "turned on" the chromatin regions associated with TF genes. We hereby define the complete set of TLR9-regulated TFs in pDCs. Further, this study identifies the AP-1 family of TFs as potentially important but so far less well characterized regulators of pDC function.

category: molecular biology


title: Establishment of locally advantageous allele and local adaptation in partly self-fertilizing populations

abstract: Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to swamp locally adapted alleles. Conditions for the establishment of a locally advantageous allele have been studied in randomly mating populations. However, many species reproduce, at least partially, through self-fertilization, and how selfing affects local adaptation remains unclear and debated. Using a two-patch branching process formalism, we obtained a closed-form approximation under weak selection for the probability of establishment of a locally advantageous allele (P) for arbitrary selfing rate and dominance level, where selection is allowed to act on viability or fecundity, and migration can occur via seed or pollen dispersal. This solution is compared to diffusion approximation and used to investigate the consequences of a shift in a mating system on P, and the establishment of protected polymorphism. We find that selfing can either increase or decrease P, depending on the patterns of dominance in the two patches, and has conflicting effects on local adaptation. Globally, selfing favors local adaptation when locally advantageous alleles are (partially) recessive, when selection between patches is asymmetrical and when migration occurs through pollen rather than seed dispersal. These results establish a rigorous theoretical background to study heterogeneous selection and local adaptation in partially selfing species.


title: Establishment of local adaptation in partly self-fertilizing populations


title: A multiscale model predicts the sensitivity of Chlorella vulgaris to light and nitrogen levels in photobioreactors

abstract: The maximization of lipid productivity in microalgae is crucial for the biofuel industry, and it can be achieved by manipulating their metabolism. However, little efforts have been made to apply metabolic models in a dynamic framework to predict possible outcomes to scenarios observed at an industrial scale. Here, we present a dynamic framework for the simulation of large-scale photobioreactors. The framework was generated by merging the genome-scale metabolic model of Chlorella vulgaris (iCZ843) with reactor-scale parameters, thus yielding a multiscale model. This multiscale model was employed to predict the sensitivity of growth and composition variation of C. vulgaris on light and nitrogen levels. Simulations of lipid accumulation quantified the tradeoff between growth and lipid biosynthesis under nitrogen limitation. Moreover, our modeling approach quantitatively predicted the dependence of microalgal metabolism on light intensity and circadian oscillations. Finally, we use the model to design a reactor irradiance profile that maximized lipid accumulation, thus achieving a lipid productivity increase of 46% at a constant intensity of 966 E m-2 s-1. Our modeling framework elucidated how metabolism and external factors can be combined to predict optimized parameters for industrial applications.


title: Inter-Subject EEG Correlation Reflects Time-Varying Engagement with Natural Music

abstract: Musical engagement can be conceptualized through various activities, modes of listening, and listener states--among these a state of focused engagement. Recent research has reported that this state can be indexed by the inter-subject correlation (ISC) of EEG responses to a shared naturalistic stimulus. While statistically significant ISC has been reported during music listening, these reports have considered only correlations computed across entire excerpts and do not provide insights into time-varying engagement. Here we present the first EEG-ISC investigation of time-varying engagement within a musical work. From a sample of 23 adult musicians who listened to a cello concerto movement, we find varying levels of ISC throughout the excerpt. In particular, significant ISC is observed during periods of musical tension that build to climactic highpoints, but not at the highpoints themselves. In addition, we find that a control stimulus retaining envelope characteristics of the intact music, but little other temporal structure, also elicits significant neural correlation, though to a lesser extent than the original excerpt. In all, our findings shed light on temporal dynamics of listener engagement during music listening, establish connections between salient musical events and EEG ISC, and clarify specific listener states that are indexed by this measure.


title: The neural bases of program comprehension: a coordinate-based fMRI meta-analysis

abstract: The understanding of brain activity during program comprehension have advanced thanks to noninvasive neuroimaging techniques, such as functional magnetic resonance imaging (fMRI). However, individual neuroimaging studies of program comprehension often provided inconsistent results and made it difficult to identify the neural bases. To identify the essential brain regions, this study performed a small meta-analysis on recent fMRI studies of program comprehension using multilevel kernel density analysis (MKDA). Our analysis identified a set of brain regions consistently activated in various program comprehension tasks. These regions consisted of three clusters, each of which centered at the left inferior frontal gyrus pars triangularis (IFG Tri), posterior part of middle temporal gyrus (pMTG), and right middle frontal gyrus (MFG). Additionally, subsequent analyses revealed relationships among the activation patterns in the previous studies and multiple cognitive functions. These findings suggest that program comprehension mainly recycles the language-related networks and partially employs other domain-general resources in the human brain.


title: Organization and priming of long-term memory representations with two-phase plasticity

abstract: Synaptic tagging and capture (STC) is a molecular mechanism that accounts for the consolidation of synaptic changes induced by plasticity. To link this mechanism to long-term memory and thereby to the level of behavior, its dynamics on the level of recurrent networks have to be understood. To this end, we employ a biologically detailed neural network model of spiking neurons featuring STC, which models the learning and consolidation of long-term memory representations. Using this model, we investigate the effects of different organizational paradigms of multiple memory representations, and demonstrate a proof of principle for priming on long timescales. We examine these effects considering the spontaneous activation of memory representations as the network is driven by background noise. Our first finding is that the order in which the memory representations are learned significantly biases the likelihood of spontaneous activation towards more recently learned memory representations. Secondly, we find that hub-like structures counter this learning order effect for representations with less overlaps. We show that long-term depression is the mechanism underlying these findings, and that intermediate consolidation in between learning the individual representations strongly alters the described effects. Finally, we employ STC to demonstrate the priming of a long-term memory representation on a timescale of minutes to hours. As shown by these findings, our model provides a mechanistic synaptic and neuronal basis for known behavioral effects.


title: Analyzing Brain Morphology in Alzheimer's Disease Using Discriminative and Generative Spiral Networks

abstract:
Several patterns of atrophy have been identified and strongly related to Alzheimers disease (AD) pathology and its progression. Morphological changes in brain shape have been identified up to ten years before clinical diagnoses of AD, making its early detection more relevant. We propose novel geometric deep learning frameworks for the analysis of brain shape in the context of neurodegeneration caused by AD. Our deep neural networks learn low-dimensional shape descriptors of multiple neuroanatomical structures, instead of handcrafted features for each structure. A discriminative network using spiral convolution on 3D meshes is constructed for the in-vivo binary classification of AD from healthy controls (HCs) using a fast and efficient "spiral" convolution operator on 3D triangular mesh surfaces of human brain subcortical structures extracted from T1-weighted magnetic resonance imaging (MRI). Our network architecture consists of modular learning blocks using residual connections to improve overall classifier performance.

In this work: (1) a discriminative network is used to analyze the efficacy of disease classification using input data from multiple brain structures and compared to using a single hemisphere or a single structure. It also outperforms prior work using spectral graph convolution on the same the same tasks, as well as alternative methods that operate on intermediate point cloud representations of 3D shapes. (2) Additionally, visual interpretations for regions on the surface of brain structures that are associated to true positive AD predictions are generated and fall in accordance with the current reports on the structural localization of pathological changes associated to AD. (3) A conditional generative network is also implemented to analyze the effects of phenotypic priors given to the model (i.e. AD diagnosis) in generating subcortical structures. The generated surface meshes by our model indicate learned morphological differences in the presence of AD that agrees with the current literature on patterns of atrophy associated to the disease. In particular, our inference results demonstrate an overall reduction in subcortical mesh volume and surface area in the presence of AD, especially in the hippocampus. The low-dimensional shape descriptors obtained by our generative model are also evaluated in our discriminative baseline comparisons versus our discriminative network and the alternative shape-based approaches.


title: Arabidopsis CALMODULIN-BINDING PROTEIN 60b plays dual roles in plant immunity

abstract:
Arabidopsis SYSTEMIC ACQUIRED RESISTANCE DEFICIENT 1 (SARD1) and CALMODULIN-BINDING PROTEIN 60g (CBP60g) are two master transcription factors that regulate many defense-related genes in plant immunity. They are required for immunity downstream of the receptor-like protein SUPPRESSOR OF NPR1-1, CONSTITUTIVE 2 (SNC2). Constitutive defense responses in the gain-of-function autoimmune snc2-1D mutant are modestly affected by either sard1 or cbp60g single mutants, but completely suppressed by the sard1 cbp60g double mutant. Here we report that CBP60b, another member of the CBP60 family, also functions as a positive regulator of SNC2-mediated immunity. Loss-of-function mutations of CBP60b suppress the constitutive expression of SARD1 and enhanced disease resistance in cbp60g-1 snc2-1D, whereas over-expression of CBP60b leads to elevated SARD1 expression and constitutive defense responses. In addition, transient expression of CBP60b in Nicotiana benthamiana activates the expression of the pSARD1::luciferase reporter gene. Chromatin immunoprecipitation assay further showed that CBP60b is recruited to the promoter region of SARD1, suggesting that it directly regulates SARD1 expression. Interestingly, knocking out CBP60b in the wild type background leads to ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1)-dependent autoimmunity, suggesting that CBP60b is required for the expression of a guardee/decoy or a negative regulator in immunity mediated by receptors carrying an N-terminal TIR (Toll-interleukin-1 receptor-like) domain.

Significance statementArabidopsis SARD1 serves as a master transcription factor in plant immunity. In this study, we showed that CBP60b positively regulates SARD1 expression, and TIR signaling is activated when CBP60b is inactivated.


title: Increased pattern similarity in two major olfactory cortices despite higher sparseness levels

abstract:
Pattern separation is a fundamental process that enhances discrimination of similar stimuli and can be achieved by sparsening the neural activity and expanding the coding space. Odor stimuli evoke patterns of activity in the olfactory bulb (OB) and these activity patterns are projected to several cortical regions that contain larger numbers of neurons and show sparser activity levels. However, whether these projected patterns are better separated is still unclear. Here we compared odor responses in the OB, anterior piriform cortex (aPC) and anterior olfactory nucleus (AON) to the exact same odor stimuli. We found that odor representations are more similar, noisier and less distinctive in aPC and AON than in the OB. The increase in similarity was observed for both similar and dissimilar odors. Modeling odor transformation from the OB to the olfactory cortex using simulated as well as actual OB odor responses as inputs, demonstrates that the observed rise in odor representation similarity can be explained by assuming biologically plausible variation in the number of OB inputs each cortical neuron receives. We discuss the possible advantages of our findings to odor processing in the aPC and AON.

HighlightsO_LIOdor representations in the aPC and AON are more correlated despite increase in sparseness levels.
C_LIO_LIOdor identity is best represented in the OB.
C_LIO_LIVariance in the number of inputs from OB can explain the reduction in odor separation.
C_LI


title: Hippocampal theta sequences in REM sleep during spatial learning

abstract: Rapid eye movement (REM) sleep is known to play a role in hippocampally-dependent memory, yet the activity and development of hippocampal neuronal ensembles during this state is not well understood. Here we investigated patterning of CA1 place cell activity by theta oscillations, a shared electrophysiological hallmark of both waking behavior and REM sleep, in male rats learning a spatial memory task. We report the existence of REM theta sequences, sequential reactivations of place cells in REM theta that parallel waking theta sequences. REM and wake theta sequences develop rapidly with experience, recapitulating behavioral sequences of compressed space in forward and reverse directions throughout learning. REM sleep exhibited a balance of forward and reverse sequences in contrast to predominantly forward wake theta sequences. Finally, we found that a CA1 neuronal population known to shift preferred theta phases in REM exhibited differential participation in wake and REM theta sequences. In particular, this phase-shifting population showed an increased contribution to REM theta sequence representations after behavioral performance asymptotes and the task is learned, supporting a previously hypothesized role in depotentiation. These findings suggest a role for REM associated theta sequences in state dependent memory functions of the hippocampal circuit, providing evidence that REM sleep is associated with sequence reactivation that can support consolidation of representations necessary for memory guided behavior.


title: Odor induces characteristic time courses of theta, beta and gamma oscillations in human olfactory cortex

abstract: Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and in particular, whether stimulus-driven high frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that three key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: odor induces theta, beta and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.


title: Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity


title: Does powder averaging remove dispersion bias in diffusion MRI diameter estimates within real 3D axonal architectures?

abstract: Noninvasive estimation of axon diameter with diffusion MRI holds potential to investigate the dynamic properties of the brain network and pathology of neurodegenerative diseases. Recent methods use powder averaging to account for complex white matter architectures, such as fibre crossing regions, but these have not been validated for real axonal geometries. Here, we present 120 - 313 m long segmented axons from X-ray nano-holotomography volumes of a splenium and crossing fibre region of a vervet monkey brain. We show that the axons in the complex crossing fibre region, which contains callosal, association, and corticospinal connections, are larger and exhibit a wider distribution than those of the splenium region. To accurately estimate the axon diameter in these regions, therefore, sensitivity to a wide range of diameters is required. We demonstrate how the q-value, b-value, signal-to-noise ratio and the assumed intra-axonal parallel diffusivity influence the range of measurable diameters with powder average approaches. Furthermore, we show how Gaussian distributed noise results in a wider range of measurable diameter at high b-values than Rician distributed noise, even at high signal-to-noise ratios of 100. The number of gradient directions is also shown to impose a lower bound on measurable diameter. Our results indicate that axon diameter estimation can be performed with only few b-shells, and that additional shells do not improve the accuracy of the estimate. Through Monte Carlo simulations of diffusion, we show that powder averaging techniques succeed in providing accurate estimates of axon diameter across a range of sequence parameters and diffusion times, even in complex white matter architectures. At sufficiently low b-values, the acquisition becomes sensitive to axonal microdispersion and the intra-axonal parallel diffusivity shows time dependency at both in vivo and ex vivo intrinsic diffusivities.


title: Dopaminergic but not Cholinergic Neurodegeneration is Correlated with Gait Disturbances in PINK1 Knockout Rats

abstract: Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by gait dysfunction in later stages of the disease. PD hallmarks include a decrease in stride length, run speed, and swing time; an increase in stride time, stance time, and base of support; dopaminergic degeneration in the basal ganglia; and cholinergic degeneration in the pedunculopontine nucleus (PPN). A progressive animal model of PD is needed to identify treatments for gait dysfunction. The goal of this study was to quantify progressive gait degeneration in PTEN-induced putative kinase 1 knockout (P1KO) rats and investigate neurodegeneration as potential underlying mechanisms. Gait analysis was performed in male P1KO and wild-type rats at 5 and 8 months of age and immunohistochemical analysis at 8 months. Multiple parameters of volitional gait were measured using a runway system. P1KO rats exhibited significant gait deficits at 5 months, but not 8 months. Gait abnormalities improved over time suggesting compensation during behavioral testing. At 8 months a 15% loss of tyrosine hydroxylase (TH) in the striatum, a 27% loss of TH-positive cells in the substantia nigra pars compacta, and no significant loss of choline acetyltransferase-positive cells in the PPN was found. Dopaminergic cell loss may contribute to gait deficits in the P1KO model, but not cholinergic cell loss. The P1KO rat with the greatest dopamine loss exhibited the most pronounced PD-like gait deficits, highlighting variability within the model. Further analysis is required to determine the suitability of the P1KO rat as a progressive model of gait abnormalities in PD.


title: Behavioral clusters revealed by end-to-end decoding from microendoscopic imaging

abstract: In vivo calcium imaging using head-mounted miniature microscopes enables tracking activity from neural populations over weeks in freely behaving animals. Previous studies focus on inferring behavior from a population of neurons, yet it is challenging to extract neuronal signals given out-of-focus fluorescence in endoscopic data. Existing analysis pipelines include regions of interest (ROIs) identification, which might lose relevant information from false negatives or introduce unintended bias from false positives. Moreover, these methods often require prior knowledge for parameter tuning and are time-consuming for implementation. Here, we develop an end-to-end decoder to predict the behavioral variables directly from the raw microendoscopic images. Our framework requires little user input and outperforms existing decoders that need ROI extraction. We show that neuropil/background residuals carry additional behaviorally relevant information. Video analysis further reveals an optimal decoding window and dynamics between residuals and cells. Critically, saliency maps reveal the emergence of video-decomposition across our decoder, and identify distinct clusters representing different behavioral aspects. Together, we present a framework that is efficient for decoding behavior from microendoscopic imaging, and may help discover functional clustering for a variety of imaging studies.


title: The green peach aphid, Myzus persicae, transcriptome in response to a circulative, nonpropagative polerovirus, Potato leafroll virus.

abstract: Viruses in the Luteoviridae family, such as Potato leafroll virus (PLRV), are transmitted by aphids in a circulative and nonpropagative mode. This means the virions enter the aphid body through the gut when they feed from infected plants and then the virions circulate through the hemolymph to enter the salivary glands before being released into the saliva. Although these viruses do not replicate in their insect vectors, previous studies have demonstrated viruliferous aphid behavior is altered and the obligate symbiont of aphids, Buchnera aphidocola, may be involved in transmission. Here we provide the transcriptome of green peach aphids (Myzus persicae) carrying PLRV and virus-free control aphids using Illumina sequencing. Over 150 million paired-end reads were obtained through Illumina sequencing, with an average of 19 million reads per library. The comparative analysis identified 134 differentially expressed genes (DEGs) between the M. persicae transcriptomes, including 64 and 70 genes that were down- and up-regulated in aphids carrying PLRV, respectively. Using functional classification in the GO databases, 80 of the DEGs were assigned to 391 functional subcategories at category level 2. The most highly up-regulated genes in aphids carrying PLRV were cytochrome p450s, genes related to cuticle production, and genes related to development, while genes related to histone and histone modification were the most down-regulated. PLRV aphids had reduced Buchnera titer and lower abundance of several Buchnera transcripts related to stress responses and metabolism. These results suggest carrying PLRV may reduce both aphid and Buchnera genes in response to stress. This work provides valuable basis for further investigation into the complicated mechanisms of circulative and nonpropogative transmission.


title: Targeting circPTPN12/1 miR-21-5p/ΔNp63α pathway as a therapeutic strategy for human endometrial fibrosis

abstract: Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5p to inhibit miR-21-5p expression and activity, which in turn results in upregulation of {Delta}Np63 to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT. Our findings reveal the novel mechanism in the pathogenesis of endometrium fibrosis and the potential therapeutic strategy for endometrium fibrosis via targeting circPTPN12/miR-21-5p/{Delta}Np63 pathway.