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Previous studies have conducted time course characterization of murine colitis models through transcriptional profiling of differential expression. We characterize the transcriptional landscape of acute and chronic models of dextran sodium sulfate (DSS) and adoptive transfer (AT) colitis to derive temporal gene expression and splicing signatures in blood and colonic tissue in order to capture dynamics of colitis remission and relapse. We identify sub networks of patient-derived causal networks that are enriched in these temporal signatures to distinguish acute and chronic disease components within the broader molecular landscape of IBD. The interaction between the DSS phenotype and chronological time-point naturally defines parsimonious temporal gene expression and splicing signatures associated with acute and chronic phases disease (as opposed to ordinary time-specific differential expression/splicing). We show these expression and splicing signatures are largely orthogonal, i.e. affect different genetic bodies, and that using machine learning, signatures are predictive of histopathological measures from both blood and intestinal data in murine colitis models as well as an independent cohort of IBD patients. Through access to longitudinal multi-scale profiling from disease tissue in IBD patient cohorts, we can apply this machine learning pipeline to generation of direct patient temporal multimodal regulatory signatures for prediction of histopathological outcomes. Longitudinal changes in gene expression, splicing patterns and adaptive immune repertoire in murine models of colitis are examined and associated with histologic inflammation in mice and in patients with inflammatory bowel disease.

Polymeric-based nano drug delivery systems have been widely exploited to overcome protein instability during formulation. Presently, a diverse range of polymeric agents can be used, among which polysaccharides, such as chitosan (CS), hyaluronic acid (HA) and cyclodextrins (CDs), are included. Due to its unique biological and physicochemical properties, CS is one of the most used polysaccharides for development of protein delivery systems. However, CS has been described as potentially immunogenic. By envisaging a biosafe cytocompatible and haemocompatible profile, this paper reports the systematic development of a delivery system based on CS and derived with HA and CDs to nanoencapsulate the model human phenylalanine hydroxylase (hPAH) through ionotropic gelation with tripolyphosphate (TPP), while maintaining protein stability and enzyme activity. By merging the combined set of biopolymers, we were able to effectively entrap hPAH within CS nanoparticles with improvements in hPAH stability and the maintenance of functional activity, while simultaneously achieving strict control of the formulation process. Detailed characterization of the developed nanoparticulate systems showed that the lead formulations were internalized by hepatocytes (HepG2 cell line), did not reveal cell toxicity and presented a safe haemocompatible profile.

Human phenylalanine hydroxylase (hPAH) hydroxylates l -phenylalanine ( l -Phe) to l -tyrosine, a precursor for neurotransmitter biosynthesis. Phenylketonuria (PKU), caused by mutations in PAH that impair PAH function, leads to neurological impairment when untreated. Understanding the hPAH structural and regulatory properties is essential to outline PKU pathophysiological mechanisms. Each hPAH monomer comprises an N-terminal regulatory, a central catalytic and a C-terminal oligomerisation domain. To maintain physiological l -Phe levels, hPAH employs complex regulatory mechanisms. Resting PAH adopts an auto-inhibited conformation where regulatory domains block access to the active site. l -Phe-mediated allosteric activation induces a repositioning of the regulatory domains. Since a structure of activated wild-type hPAH is lacking, we addressed hPAH l -Phe-mediated conformational changes and report the first solution structure of the allosterically activated state. Our solution structures obtained by small-angle X-ray scattering support a tetramer with distorted P222 symmetry, where catalytic and oligomerisation domains form a core from which regulatory domains protrude, positioning themselves close to the active site entrance in the absence of l -Phe. Binding of l -Phe induces a large movement and dimerisation of regulatory domains, exposing the active site. Activated hPAH is more resistant to proteolytic cleavage and thermal denaturation, suggesting that the association of regulatory domains stabilises hPAH.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Saccades were assessed in 21 adults (age 24 years, SD = 4) and 15 children (age 11 years, SD = 1), using combined functional magnetic resonance imaging (fMRI) and eye-tracking. Subjects visually tracked a point on a horizontal line in four conditions: time and position predictable task (PRED), position predictable (pPRED), time predictable (tPRED) and visually guided saccades (SAC). Both groups in the PRED but not in pPRED, tPRED and SAC produced predictive saccades with latency below 80 ms. In task versus group comparisons, children's showed less efficient learning compared to adults for predictive saccades (adults = 48%, children = 34%, p = 0.05). In adults brain activation was found in the frontal and occipital regions in the PRED, in the intraparietal sulcus in pPRED and in the frontal eye field, posterior intraparietal sulcus and medial regions in the tPRED task. Group-task interaction was found in the supplementary eye field and visual cortex in the PRED task, and the frontal cortex including the right frontal eye field and left frontal pole, in the pPRED condition. These results indicate that, the basic visuomotor circuitry is present in both adults and children, but fine-tuning of the activation according to the task temporal and spatial demand mature late in child development.

Background Mating induces behavioral and physiological changes in the arbovirus vector Aedes aegypti , including stimulation of egg development and oviposition, increased survival, and reluctance to re-mate with subsequent males. Transferred seminal fluid proteins and peptides derived from the male accessory glands induce these changes, though the mechanism by which they do this is not known. Results To determine transcriptome changes induced by seminal proteins, we injected extract from male accessory glands and seminal vesicles (MAG extract) into females and examined female lower reproductive tract (LRT) transcriptomes 24 h later, relative to non-injected controls. MAG extract induced 87 transcript-level changes, 31 of which were also seen in a previous study of the LRT 24 h after a natural mating, including 15 genes with transcript-level changes similarly observed in the spermathecae of mated females. The differentially-regulated genes are involved in diverse molecular processes, including immunity, proteolysis, neuronal function, transcription control, or contain predicted small-molecule binding and transport domains. Conclusions Our results reveal that seminal fluid proteins, specifically, can induce gene expression responses after mating and identify gene targets to further investigate for roles in post-mating responses and potential use in vector control.

Static body equilibrium is an essential requisite for human daily life. It is known that visual and vestibular systems must work together to support equilibrium. However, the relationship between these two systems is not fully understood. In this work, we present the results of a study which identify the interaction of brain areas that are involved with concurrent visual and vestibular inputs. The visual and the vestibular systems were individually and simultaneously stimulated, using flickering checkerboard (without movement stimulus) and galvanic current, during experiments of functional magnetic resonance imaging. Twenty-four right-handed and non-symptomatic subjects participated in this study. Single visual stimulation shows positive blood-oxygen-level-dependent (BOLD) responses (PBR) in the primary and associative visual cortices. Single vestibular stimulation shows PBR in the parieto-insular vestibular cortex, inferior parietal lobe, superior temporal gyrus, precentral gyrus and lobules V and VI of the cerebellar hemisphere. Simultaneous stimulation shows PBR in the middle and inferior frontal gyri and in the precentral gyrus. Vestibular- and somatosensory-related areas show negative BOLD responses (NBR) during simultaneous stimulation. NBR areas were also observed in the calcarine gyrus, lingual gyrus, cuneus and precuneus during simultaneous and single visual stimulations. For static visual and galvanic vestibular simultaneous stimulation, the reciprocal inhibitory visual–vestibular interaction pattern is observed in our results. The experimental results revealed interactions in frontal areas during concurrent visual–vestibular stimuli, which are affected by intermodal association areas in occipital, parietal, and temporal lobes.

Background/Objective The prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving diabetic macular oedema (DME). Patients/Methods Prospective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo ( n  = 17) or levosulpiride ( n  = 17) for 8 weeks or in patients with PDR undergoing elective pars plana vitrectomy and receiving placebo ( n  = 18) or levosulpiride ( n  = 18) orally for the 1 week before vitrectomy. Results Levosulpiride improved changes from baseline in best-corrected visual acuity ( p  ≤ 0.037), central foveal thickness (CFT, p  ≤ 0.013), and mean macular volume (MMV, p  ≤ 0.002) at weeks 4, 6, and 8 compared to placebo. At 8 weeks, the proportion of eyes gaining ≥5 ETDRS letters at 4 m (41% vs. 28%), losing ≥21 μm in CFT (55% vs. 28%), and dropping ≥0.06 mm 3 in MMV (65% vs. 29%) was higher after levosulpiride than placebo. The overall grading of visual and structural parameters improved with levosulpiride ( p  = 0.029). Levosulpiride reduced VEGF ( p  = 0.025) and PlGF ( p  = 0.008) levels in the vitreous of PDR patients. No significant adverse side-effects were detected. Conclusions Oral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.

ObjectivesTo assess the prevalence of SARS-CoV-2-specific IgM and IgG antibodies among workers of the three public higher education institutions of Porto, Portugal, up to July 2020.MethodsA rapid point-of-care test for specific IgM and IgG antibodies of SARS-CoV-2 was offered to all workers (SD Biosensor STANDARD Q COVID-19 IgM/IgG Duo and STANDARD Q COVID-19 IgM/IgG Combo). Testing was performed and a questionnaire was completed by 4592 workers on a voluntary basis from 21 May to 31 July 2020. We computed the apparent IgM, IgG, and combined IgM or IgG prevalence, along with the true prevalence and 95% credible intervals (95% CrI) using Bayesian inference.ResultsWe found an apparent prevalence of 3.1% for IgM, 1.0% for IgG and 3.9% for either. The estimated true prevalence was 2.0% (95% CrI 0.1% to 4.3%) for IgM, 0.6% (95% CrI 0.0% to 1.3%) for IgG, and 2.5% (95% CrI 0.1% to 5.3%) for IgM or IgG. A SARS-CoV-2 molecular diagnosis was reported by 21 (0.5%) workers; and of these, 90.5% had a reactive IgG result. Seroprevalence was higher among those reporting contacts with confirmed cases, having been quarantined, having a previous molecular negative test or having had symptoms.ConclusionsThe seroprevalence among workers from the three public higher education institutions of Porto after the first wave of the SARS-CoV-2 infection was similar to national estimates for the same age working population. However, the estimated true seroprevalence was approximately five times higher than the reported SARS-CoV-2 infection based on a molecular test.

Mnemonic strategy training (MST) has been shown to improve cognitive performance in amnestic mild cognitive impairment (a-MCI), however, several questions remain unresolved. The goal of the present study was to replicate earlier pilot study findings using a randomized controlled design and to evaluate transfer effects and changes in brain activation. Thirty patients with a-MCI were randomized into MST or education program. At baseline, participants completed clinical and neuropsychological assessments as well as structural and functional magnetic resonance imaging (fMRI). Interventions were administered individually and comprised four sessions, over 2 weeks. MST taught patients to use a three-step process to learn and recall face-name associations. Post-treatment assessment included fMRI, a separate face-name association task, neuropsychological tests, and measures of metamemory. Behavioral (i.e., non-fMRI) measures were repeated after one and 3-months. Participants in the MST condition showed greater improvement on measures of face-name memory, and increased associative strategy use; effects that were accompanied by increased fMRI activation in the left anterior temporal lobe. While all participants reported greater contentment with their everyday memory following intervention, only the MST group reported significant improvements in their memory abilities. There was no clear indication of far-transfer effects to other neuropsychological tests. Results demonstrate that patients with a-MCI not only show stimulus specific benefits of MST, but that they appear capable of transferring training to at least some other cognitive tasks. MST also facilitated the use of brain regions that are involved in face processing, episodic and semantic memory, and social cognition, which are consonant with the cognitive processes engaged by training.