HIHISIV: a database of gene expression in HIV and SIV host immune response.

In the battle of the host against lentiviral pathogenesis, the immune response is crucial. However, several questions remain unanswered about the interaction with different viruses and their influence on disease progression. The simian immunodeficiency virus (SIV) infecting nonhuman primates (NHP) is widely used as a model for the study of the human immunodeficiency virus (HIV) both because they are evolutionarily linked and because they share physiological and anatomical similarities that are largely explored to understand the disease progression. The HIHISIV database was developed to support researchers to integrate and evaluate the large number of transcriptional data associated with the presence/absence of the pathogen (SIV or HIV) and the host response (NHP and human). The datasets are composed of microarray and RNA-Seq gene expression data that were selected, curated, analyzed, enriched, and stored in a relational database. Six query templates comprise the main data analysis functions and the resulting information can be downloaded. The HIHISIV database, available at  https://hihisiv.github.io , provides accurate resources for browsing and visualizing results and for more robust analyses of pre-existing data in transcriptome repositories.

Pitolisant 40 mg for excessive daytime sleepiness in obstructive sleep apnea patients treated or not by CPAP: Randomised phase 3 study.

Obstructive sleep apnea (OSA) syndrome commonly leads to excessive daytime sleepiness (EDS). Pitolisant, a selective histamine-3 receptor antagonist, is efficacious at doses up to 20 mg once daily in OSA treated or not with continuous positive airway pressure (CPAP). We assessed the efficacy and safety of pitolisant at doses up to 40 mg once daily in patients with moderate to severe OSA treated or not with CPAP therapy. In this phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial, patients with OSA were assigned 2:1 to receive pitolisant (according to an individual up-titration scheme, 10, 20 or 40 mg once daily) or placebo for 12 weeks. The primary endpoint was a change in the Epworth Sleepiness Scale (ESS) score from baseline to week 12. Secondary endpoints included a change in reaction time using the Oxford Sleep Resistance test (OSleR), Clinical Global Impression of Change (CGI-C), and Patient's Global Opinion of the Effect (PGOE) of study treatment. Overall, 361 patients (mean age 52.4 years, 77.3% male; mean apnea-hypopnea index [AHI] 27.0 events/h) were randomised to receive pitolisant (n = 242; 50% received CPAP) or placebo (n = 119; 48.7% CPAP). After the dose-adjustment phase (week 3), 88.8% of patients received pitolisant 40 mg. Compared with placebo, pitolisant produced a significant reduction in the ESS score at week 12 (least square mean difference -2.6 (95% CI: -3.4; -1.8; p < 0.001)) irrespective of CPAP use; and improved the reaction time on OSleR, CGI-C, and PGOE at week 12. Pitolisant was well tolerated; no new safety signals were identified. In conclusion, pitolisant up to 40 mg once daily was an effective treatment for EDS in patients with moderate to severe OSA irrespective of CPAP use.

Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations.

AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. RESULTS: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.

SubcellulaRVis: a web-based tool to simplify and visualise subcellular compartment enrichment.

Cells contain intracellular compartments, including membrane-bound organelles and the nucleus, and are surrounded by a plasma membrane. Proteins are localised to one or more of these cellular compartments; the correct localisation of proteins is crucial for their correct processing and function. Moreover, proteins and the cellular processes they partake in are regulated by relocalisation in response to various cellular stimuli. High-throughput 'omics experiments result in a list of proteins or genes of interest; one way in which their functional role can be understood is through the knowledge of their subcellular localisation, as deduced through statistical enrichment for Gene Ontology Cellular Component (GOCC) annotations or similar. We have designed a bioinformatics tool, named SubcellulaRVis, that compellingly visualises the results of GOCC enrichment for quick interpretation of the localisation of a group of proteins (rather than single proteins). We demonstrate that SubcellulaRVis precisely describes the subcellular localisation of gene lists whose locations have been previously ascertained. SubcellulaRVis can be accessed via the web (http://phenome.manchester.ac.uk/subcellular/) or as a stand-alone app (https://github.com/JoWatson2011/subcellularvis). SubcellulaRVis will be useful for experimental biologists with limited bioinformatics expertise who want to analyse data related to protein (re)localisation and location-specific modules within the intracellular protein network.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 µg auto-injector in healthy volunteers.

AIMS: Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 µg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 µg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females. METHODS: In this exploratory open-label, single-centre study, 54 healthy volunteers aged 18-50 years received a single 500 µg adrenaline injection (Anapen auto-injector) in the thigh (antero-lateral middle third [18 males] or antero-inferior third [36 females]). Assessments included depot depth (ultrasonography), plasma adrenaline levels (liquid chromatography-tandem mass spectrometry) and heart rate (HR; ECG Holter monitor). RESULTS: Ultrasonography showed that 82.4% of normal weight males received intramuscular injections; all overweight and obese females received subcutaneous injections. Anapen injection produced rapid increases in circulating adrenaline levels and significant increases in systolic blood pressure (SBP) and HR. Second peak plasma adrenaline concentrations (Cmax2 ) were reduced, and time to Cmax2 increased in overweight and obese females compared with males with normal body mass index; area under the curve (0-240 min) (AUC(0-240) ) was increased in overweight and obese females. Obese females had reduced maximal SBP values compared with normal weight males or overweight females; overweight and obese females had markedly different HR time courses compared with normal weight males. CONCLUSION: A 500 µg adrenaline injection via Anapen produced rapid PK/PD changes in normal weight, overweight and obese subjects, irrespective of intramuscular or subcutaneous injection, and was well tolerated.

Speakers are able to categorize vowels based on tongue somatosensation.

Auditory speech perception enables listeners to access phonological categories from speech sounds. During speech production and speech motor learning, speakers' experience matched auditory and somatosensory input. Accordingly, access to phonetic units might also be provided by somatosensory information. The present study assessed whether humans can identify vowels using somatosensory feedback, without auditory feedback. A tongue-positioning task was used in which participants were required to achieve different tongue postures within the /e, ε, a/ articulatory range, in a procedure that was totally nonspeech like, involving distorted visual feedback of tongue shape. Tongue postures were measured using electromagnetic articulography. At the end of each tongue-positioning trial, subjects were required to whisper the corresponding vocal tract configuration with masked auditory feedback and to identify the vowel associated with the reached tongue posture. Masked auditory feedback ensured that vowel categorization was based on somatosensory feedback rather than auditory feedback. A separate group of subjects was required to auditorily classify the whispered sounds. In addition, we modeled the link between vowel categories and tongue postures in normal speech production with a Bayesian classifier based on the tongue postures recorded from the same speakers for several repetitions of the /e, ε, a/ vowels during a separate speech production task. Overall, our results indicate that vowel categorization is possible with somatosensory feedback alone, with an accuracy that is similar to the accuracy of the auditory perception of whispered sounds, and in congruence with normal speech articulation, as accounted for by the Bayesian classifier.

Transcriptional Profile of the Industrial Hybrid Saccharomyces pastorianus Reveals Temperature-Dependent Allele Expression Bias and Preferential Orthologous Protein Assemblies.

Saccharomyces pastorianus is a natural yeast evolved from different hybridization events between the mesophilic S. cerevisiae and the cold-tolerant S. eubayanus. This complex aneuploid hybrid carries multiple copies of the parental alleles alongside specific hybrid genes and encodes for multiple protein isoforms which impart novel phenotypes, such as the strong ability to ferment at low temperature. These characteristics lead to agonistic competition for substrates and a plethora of biochemical activities, resulting in a unique cellular metabolism. Here, we investigated the transcriptional signature of the different orthologous alleles in S. pastorianus during temperature shifts. We identified temperature-dependent media-independent genes and showed that 35% has their regulation dependent on extracellular leucine uptake, suggesting an interplay between leucine metabolism and temperature response. The analysis of the expression of ortholog parental alleles unveiled that the majority of the genes expresses preferentially one parental allele over the other and that S. eubayanus-like alleles are significantly over-represented among the genes involved in the cold acclimatization. The presence of functionally redundant parental alleles may impact on the nature of protein complexes established in the hybrid, where both parental alleles are competing. Our expression data indicate that the majority of the protein complexes investigated in the hybrid are likely to be either exclusively chimeric or unispecific and that the redundancy is discouraged, a scenario that fits well with the gene balance hypothesis. This study offers the first overview of the transcriptional pattern of S. pastorianus and provides a rationalization for its unique industrial traits at the expression level.

Cytosolic fumarase acts as a metabolic fail-safe for both high and low temperature acclimation of Arabidopsis thaliana.

Plants acclimate their photosynthetic capacity (Pmax) in response to changing environmental conditions. In Arabidopsis thaliana, photosynthetic acclimation to cold requires the accumulation of the organic acid fumarate, catalysed by a cytosolically localized fumarase, FUM2. However, the role of this accumulation is currently unknown. Here, we use an integrated experimental and modelling approach to examine the role of FUM2 and fumarate across the physiological temperature range. We have studied three genotypes: Col-0; a fum2 mutant in a Col-0 background; and C24, an accession with reduced FUM2 expression. While low temperature causes an increase in Pmax in the Col-0 plants, this parameter decreases following exposure of plants to 30 °C for 7 d. Plants in which fumarate accumulation is partially (C24) or completely (fum2) abolished show a reduced acclimation of Pmax across the physiological temperature range (i.e. Pmax changes less in response to changing temperature). To understand the role of fumarate accumulation, we have adapted a reliability engineering technique, Failure Mode and Effect Analysis (FMEA), to formalize a rigorous approach for ranking metabolites according to the potential risk that they pose to the metabolic system. FMEA identifies fumarate as a low-risk metabolite, while its precursor, malate, is shown to be high risk and liable to cause system instability. We propose that the role of FUM2 is to provide a fail-safe in order to control malate concentration, maintaining system stability in a changing environment. We suggest that FMEA is a technique that is not only useful in understanding plant metabolism but can also be used to study reliability in other systems and synthetic pathways.

Combinatorial mathematical modelling approaches to interrogate rear retraction dynamics in 3D cell migration.

Cell migration in 3D microenvironments is a complex process which depends on the coordinated activity of leading edge protrusive force and rear retraction in a push-pull mechanism. While the potentiation of protrusions has been widely studied, the precise signalling and mechanical events that lead to retraction of the cell rear are much less well understood, particularly in physiological 3D extra-cellular matrix (ECM). We previously discovered that rear retraction in fast moving cells is a highly dynamic process involving the precise spatiotemporal interplay of mechanosensing by caveolae and signalling through RhoA. To further interrogate the dynamics of rear retraction, we have adopted three distinct mathematical modelling approaches here based on (i) Boolean logic, (ii) deterministic kinetic ordinary differential equations (ODEs) and (iii) stochastic simulations. The aims of this multi-faceted approach are twofold: firstly to derive new biological insight into cell rear dynamics via generation of testable hypotheses and predictions; and secondly to compare and contrast the distinct modelling approaches when used to describe the same, relatively under-studied system. Overall, our modelling approaches complement each other, suggesting that such a multi-faceted approach is more informative than methods based on a single modelling technique to interrogate biological systems. Whilst Boolean logic was not able to fully recapitulate the complexity of rear retraction signalling, an ODE model could make plausible population level predictions. Stochastic simulations added a further level of complexity by accurately mimicking previous experimental findings and acting as a single cell simulator. Our approach highlighted the unanticipated role for CDK1 in rear retraction, a prediction we confirmed experimentally. Moreover, our models led to a novel prediction regarding the potential existence of a 'set point' in local stiffness gradients that promotes polarisation and rapid rear retraction.

XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease.

The unfolded protein response (UPR) is a conserved cellular response to the accumulation of proteinaceous material in endoplasmic reticulum (ER), active both in health and disease to alleviate cellular stress and improve protein folding. Multiple epiphyseal dysplasia (EDM5) is a genetic skeletal condition and a classic example of an intracellular protein aggregation disease, whereby mutant matrilin-3 forms large insoluble aggregates in the ER lumen, resulting in a specific 'disease signature' of increased expression of chaperones and foldases, and alternative splicing of the UPR effector XBP1. Matrilin-3 is expressed exclusively by chondrocytes thereby making EDM5 a perfect model system to study the role of protein aggregation in disease. In order to dissect the role of XBP1 signalling in aggregation-related conditions we crossed a p.V194D Matn3 knock-in mouse model of EDM5 with a mouse line carrying a cartilage specific deletion of XBP1 and analysed the resulting phenotype. Interestingly, the growth of mice carrying the Matn3 p.V194D mutation compounded with the cartilage specific deletion of XBP1 was severely retarded. Further phenotyping revealed increased intracellular retention of amyloid-like aggregates of mutant matrilin-3 coupled with dramatically decreased cell proliferation and increased apoptosis, suggesting a role of XBP1 signalling in protein accumulation and/or degradation. Transcriptomic analysis of chondrocytes extracted from wild type, EDM5, Xbp1-null and compound mutant lines revealed that the alternative splicing of Xbp1 is crucial in modulating levels of protein aggregation. Moreover, through detailed transcriptomic comparison with a model of metaphyseal chondrodysplasia type Schmid (MCDS), an UPR-related skeletal condition in which XBP1 was removed without overt consequences, we show for the first time that the differentiation-state of cells within the cartilage growth plate influences the UPR resulting from retention of a misfolded mutant protein and postulate that modulation of XBP1 signalling pathway presents a therapeutic target for aggregation related conditions in cells undergoing proliferation.

Accuracy Assessment of Percutaneous Pedicle Screw Placement Using Cone Beam Computed Tomography with Metal Artifact Reduction.

Metal artifact reduction (MAR) algorithms are used with cone beam computed tomography (CBCT) during augmented reality surgical navigation for minimally invasive pedicle screw instrumentation. The aim of this study was to assess intra- and inter-observer reliability of pedicle screw placement and to compare the perception of baseline image quality (NoMAR) with optimized image quality (MAR). CBCT images of 24 patients operated on for degenerative spondylolisthesis using minimally invasive lumbar fusion were analyzed retrospectively. Images were treated using NoMAR and MAR by an engineer, thus creating 48 randomized files, which were then independently analyzed by 3 spine surgeons and 3 radiologists. The Gertzbein and Robins classification was used for screw accuracy rating, and an image quality scale rated the clarity of pedicle screw and bony landmark depiction. Intra-class correlation coefficients (ICC) were calculated. NoMAR and MAR led to similarly good intra-observer (ICC > 0.6) and excellent inter-observer (ICC > 0.8) assessment reliability of pedicle screw placement accuracy. The image quality scale showed more variability in individual image perception between spine surgeons and radiologists (ICC range 0.51−0.91). This study indicates that intraoperative screw positioning can be reliably assessed on CBCT for augmented reality surgical navigation when using optimized image quality. Subjective image quality was rated slightly superior for MAR compared to NoMAR.

Using Multilayer Heterogeneous Networks to Infer Functions of Phosphorylated Sites.

Mass spectrometry-based quantitative phosphoproteomics has become an essential approach in the study of cellular processes such as signaling. Commonly used methods to analyze phosphoproteomics datasets depend on generic, gene-centric annotations such as Gene Ontology terms, which do not account for the function of a protein in a particular phosphorylation state. Analysis of phosphoproteomics data is hampered by a lack of phosphorylated site-specific annotations. We propose a method that combines shotgun phosphoproteomics data, protein-protein interactions, and functional annotations into a heterogeneous multilayer network. Phosphorylation sites are associated to potential functions using a random walk on the heterogeneous network (RWHN) algorithm. We validated our approach against a model of the MAPK/ERK pathway and functional annotations from PhosphoSitePlus and were able to associate differentially regulated sites on the same proteins to their previously described specific functions. We further tested the algorithm on three previously published datasets and were able to reproduce their experimentally validated conclusions and to associate phosphorylation sites with known functions based on their regulatory patterns. Our approach provides a refinement of commonly used analysis methods and accurately predicts context-specific functions for sites with similar phosphorylation profiles.

Mechanical loading activates the YAP/TAZ pathway and chemokine expression in the MLO-Y4 osteocyte-like cell line.

Osteocytes are mechanosensitive cells that control bone remodeling in response to mechanical loading. To date, specific signaling pathways modulated by mechanical loading in osteocytes are not well understood. Yes associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the main effectors of the Hippo pathway, are reported to play a role in mechanotransduction and during osteoblastogenesis. Here, we hypothesized that YAP/TAZ signaling mediates osteocyte mechanosensing to target genes of the bone remodeling process. We aimed to investigate the contribution of YAP/TAZ in modulating the gene expression in an osteocyte-like cell line MLO-Y4. We developed a 3D osteocyte compression culture model from an MLO-Y4 osteocyte cell line embedded in concentrated collagen hydrogel. 3D-mechanical loading led to the increased expression of mechanosensitive genes and a subset of chemokines, including M-csf, Cxcl1, Cxcl2, Cxcl3, Cxcl9, and Cxcl10. The transcription regulators YAP and TAZ translocated to the nucleus and upregulated their target genes and proteins. RNAseq analysis revealed that YAP/TAZ knockdown mediated the regulation of several genes including osteocyte dendrite formation. Use of YAP/TAZ knockdown partially blunted the increase in M-csf and Cxcl3 levels in response to MLO-Y4 compression. These findings demonstrate that YAP/TAZ signaling is required for osteocyte-like cell mechano-transduction, regulates the gene expression profiles and controls chemokine expression.

Metabolic flux from the chloroplast provides signals controlling photosynthetic acclimation to cold in Arabidopsis thaliana.

Photosynthesis is especially sensitive to environmental conditions, and the composition of the photosynthetic apparatus can be modulated in response to environmental change, a process termed photosynthetic acclimation. Previously, we identified a role for a cytosolic fumarase, FUM2 in acclimation to low temperature in Arabidopsis thaliana. Mutant lines lacking FUM2 were unable to acclimate their photosynthetic apparatus to cold. Here, using gas exchange measurements and metabolite assays of acclimating and non-acclimating plants, we show that acclimation to low temperature results in a change in the distribution of photosynthetically fixed carbon to different storage pools during the day. Proteomic analysis of wild-type Col-0 Arabidopsis and of a fum2 mutant, which was unable to acclimate to cold, indicates that extensive changes occurring in response to cold are affected in the mutant. Metabolic and proteomic data were used to parameterize metabolic models. Using an approach called flux sampling, we show how the relative export of triose phosphate and 3-phosphoglycerate provides a signal of the chloroplast redox state that could underlie photosynthetic acclimation to cold.

Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment.Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns.Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Word segmentation based on prosody in Parkinson's Disease.

While Parkinson's Disease (PD) impacts the production of prosody and may lead to dysprosody, its effect on the perception of prosody is less clear. In the current study, we investigated how people with PD (PwPD) segment continuous speech using prosodic cues. We used phonemically identical and prosodically different sequences in French. Twenty-three PwPD and 30 controls took part in the study. PwPD showed similar performance to controls (mean difference in terms of correct responses = 2%, 95% confidence interval = [-4%; 8%]). Using Bayesian statistics, our data is 3.6 times more in favour of the null model compared to the alternative model (i.e. difference between PwPD and controls). It thus seems unlikely that PD impacts the perception of prosody systematically. Furthermore, the cognitive performance of PwPD predicted their performance in our segmentation task. This suggests interesting pathways for future research on the mechanisms underlying the impact of PD on speech processing. Clinically, our findings suggest that adequate evaluation of the cognitive capacity of PwPD would help speech and language therapists in assessing speech processing skills in PwPD and in managing their speech impairments.

SkeletalVis: an exploration and meta-analysis data portal of cross-species skeletal transcriptomics data.

MOTIVATION: Skeletal diseases are prevalent in society, but improved molecular understanding is required to formulate new therapeutic strategies. Large and increasing quantities of available skeletal transcriptomics experiments give the potential for mechanistic insight of both fundamental skeletal biology and skeletal disease. However, no current repository provides access to processed, readily interpretable analysis of this data. To address this, we have developed SkeletalVis, an exploration portal for skeletal gene expression experiments. RESULTS: The SkeletalVis data portal provides an exploration and comparison platform for analysed skeletal transcriptomics data. It currently hosts 287 analysed experiments with 739 perturbation responses with comprehensive downstream analysis. We demonstrate its utility in identifying both known and novel relationships between skeletal expression signatures. SkeletalVis provides users with a platform to explore the wealth of available expression data, develop consensus signatures and the ability to compare gene signatures from new experiments to the analysed data to facilitate meta-analysis. AVAILABILITY AND IMPLEMENTATION: The SkeletalVis data portal is freely accessible at http://phenome.manchester.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

From empirical to theoretical models of light response curves - linking photosynthetic and metabolic acclimation.

Light response curves (LRCs) describe how the rate of photosynthesis varies as a function of light. They provide information on the maximum photosynthetic capacity, quantum yield, light compensation point and leaf radiation use efficiency of leaves. Light response curves are widely used to capture photosynthetic phenotypes in response to changing environmental conditions. However, models describing these are predominantly empirical and do not attempt to explain behaviour at a mechanistic level. Here, we use modelling to understand the metabolic changes required for photosynthetic acclimation to changing environmental conditions. Using a simple kinetic model, we predicted LRCs across the physiological temperature range of Arabidopsis thaliana and confirm these using experimental data. We use our validated metabolic model to make novel predictions about the metabolic changes of temperature acclimation. We demonstrate that NADPH utilization are enhanced in warm-acclimated plants, whereas both NADPH and CO2 utilization is enhanced in cold-acclimated plants. We demonstrate how different metabolic acclimation strategies may lead to the same photosynthetic response across environmental change. We further identify that certain metabolic acclimation strategies, such as NADPH utilization, are only triggered when plants are moved beyond a threshold high or low temperature.

Why COVID-19 models should incorporate the network of social interactions.

The global spread of coronavirus disease 2019 (COVID-19) is overwhelming many health-care systems. As a result, epidemiological models are being used to inform policy on how to effectively deal with this pandemic. The majority of existing models assume random diffusion but do not take into account differences in the amount of interactions between individuals, i.e. the underlying human interaction network, whose structure is known to be scale-free. Here, we demonstrate how this network of interactions can be used to predict the spread of the virus and to inform policy on the most successful mitigation and suppression strategies. Using stochastic simulations in a scale-free network, we show that the epidemic can propagate for a long time at a low level before the number of infected individuals suddenly increases markedly, and that this increase occurs shortly after the first hub is infected. We further demonstrate that mitigation strategies that target hubs are far more effective than strategies that randomly decrease the number of connections between individuals. Although applicable to infectious disease modelling in general, our results emphasize how network science can improve the predictive power of current COVID-19 epidemiological models.

Evaluating the Potential Gain of Auditory and Audiovisual Speech-Predictive Coding Using Deep Learning.

Sensory processing is increasingly conceived in a predictive framework in which neurons would constantly process the error signal resulting from the comparison of expected and observed stimuli. Surprisingly, few data exist on the accuracy of predictions that can be computed in real sensory scenes. Here, we focus on the sensory processing of auditory and audiovisual speech. We propose a set of computational models based on artificial neural networks (mixing deep feedforward and convolutional networks), which are trained to predict future audio observations from present and past audio or audiovisual observations (i.e., including lip movements). Those predictions exploit purely local phonetic regularities with no explicit call to higher linguistic levels. Experiments are conducted on the multispeaker LibriSpeech audio speech database (around 100 hours) and on the NTCD-TIMIT audiovisual speech database (around 7 hours). They appear to be efficient in a short temporal range (25-50 ms), predicting 50% to 75% of the variance of the incoming stimulus, which could result in potentially saving up to three-quarters of the processing power. Then they quickly decrease and almost vanish after 250 ms. Adding information on the lips slightly improves predictions, with a 5% to 10% increase in explained variance. Interestingly the visual gain vanishes more slowly, and the gain is maximum for a delay of 75 ms between image and predicted sound.