The effects of treatment with pimavanserin on activities of daily living in patients with Parkinson's disease psychosis: a 16-week, single-arm, open-label study.

Background: More than half of patients with Parkinson's disease will experience psychosis symptoms in the form of hallucinations or delusions at some point over the course of their disease. These symptoms can significantly impact patients' health-related quality of life, cognitive abilities, and activities of daily living (ADLs) and function. Clinical assessment of how psychosis impacts these measures is crucial; however, few studies have assessed this sufficiently, in part due to a lack of appropriate scales for comprehensively assessing function. Objective: The objective was to assess how symptoms of Parkinson's disease psychosis (PDP) impact ADLs and function, cognitive function, and health-related quality of life. Design: To address this unmet need, we utilized a modified version of the Functional Status Questionnaire (mFSQ) to measure the impact of psychosis on ADLs and function in patients with PDP treated with pimavanserin, a US Food and Drug Administration-approved medication to treat hallucinations and delusions associated with PDP. Methods: Eligible patients entered a 16-week, single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. The primary endpoint was change from baseline to Week 16 on the mFSQ. Secondary endpoints included the Movement Disorders Society-modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I and II; Schwab and England ADL; Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I), and were also measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares mean (LSM). Results: Our results in a proof-of-concept, 16-week, open-label clinical study in 29 patients demonstrated that an improvement in psychosis symptoms following treatment with pimavanserin was associated with improvements in multiple measures of ADLs and function. Notably, a significant improvement was found on the primary endpoint, change from baseline to Week 16 in mFSQ score [LSM [SE] 14.0 [2.50], n = 17; 95% CI (8.8, 19.3); p < 0.0001]. Conclusion: These findings highlight the potential for improvement in function with improvement of psychosis symptoms in patients with PDP and suggest that the mFSQ may be a measurement tool to evaluate the level of improvement in function. Trial registration: ClinicalTrials.gov Identifier: NCT04292223.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Normal Table of Xenopus development: a new graphical resource.

Normal tables of development are essential for studies of embryogenesis, serving as an important resource for model organisms, including the frog Xenopus laevis. Xenopus has long been used to study developmental and cell biology, and is an increasingly important model for human birth defects and disease, genomics, proteomics and toxicology. Scientists utilize Nieuwkoop and Faber's classic 'Normal Table of Xenopus laevis (Daudin)' and accompanying illustrations to enable experimental reproducibility and reuse the illustrations in new publications and teaching. However, it is no longer possible to obtain permission for these copyrighted illustrations. We present 133 new, high-quality illustrations of X. laevis development from fertilization to metamorphosis, with additional views that were not available in the original collection. All the images are available on Xenbase, the Xenopus knowledgebase (http://www.xenbase.org/entry/zahn.do), for download and reuse under an attributable, non-commercial creative commons license. Additionally, we have compiled a 'Landmarks Table' of key morphological features and marker gene expression that can be used to distinguish stages quickly and reliably (https://www.xenbase.org/entry/landmarks-table.do). This new open-access resource will facilitate Xenopus research and teaching in the decades to come.

TrkB-Targeted Therapy for Mucoepidermoid Carcinoma.

The brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) pathway was previously associated with key oncogenic outcomes in a number of adenocarcinomas. The aim of our study was to determine the role of this pathway in mucoepidermoid carcinoma (MEC). Three MEC cell lines (UM-HMC-2, H253 and H292) were exposed to Cisplatin, the TrkB inhibitor, ANA-12 and a combination of these drugs. Ultrastructural changes were assessed through transmission electron microscopy; scratch and Transwell assays were used to assess migration and invasion; and a clonogenic assay and spheroid-forming assay allowed assessment of survival and percentage of cancer stem cells (CSC). Changes in cell ultrastructure demonstrated Cisplatin cytotoxicity, while the effects of ANA-12 were less pronounced. Both drugs, used individually and in combination, delayed MEC cell migration, invasion and survival. ANA-12 significantly reduced the number of CSC, but the Cisplatin effect was greater, almost eliminating this cell population in all MEC cell lines. Interestingly, the spheroid forming capacity recovered, following the combination therapy, as compared to Cisplatin alone. Our studies allowed us to conclude that the TrkB inhibition, efficiently impaired MEC cell migration, invasion and survival in vitro, however, the decrease in CSC number, following the combined treatment of ANA-12 and Cisplatin, was less than that seen with Cisplatin alone; this represents a limiting factor.

Screening for vulnerable older people: Is the Probability of Repeated Admission scale an accurate tool?

AIM: To evaluate the Probability of Repeated Admission (Pra) scale performance in predicting healthcare utilization and death in a community sample of Rio de Janeiro city, Brazil. METHODS: This was a prospective longitudinal study. The sample was composed of community-dwelling older people who participated in the research network Frailty in Brazilian Older People Study, Rio de Janeiro section. It analyzed data from the baseline and the follow up. At the baseline, 764 older adults were stratified by the Pra, and, 3 years later, data on health services utilization and survival status were collected. The Pra accuracy, obtained by the area under the curve, the sensitivity and the specificity to predict hospitalization in 3 years; visits to the emergency department; and death were determined. Cox regression estimated the survival curves, according to the risk strata. RESULTS: The accuracy, the sensitivity and the specificity of Pra were 62% (95% CI 57-68%), 8.8% and 95.4% for hospitalization in 3 years; 59% (95% CI 53-64%), 8.3% and 94.8% for emergency room visits; 66% (95% CI 59-74%) and 68% (95% CI 63-73%), 15.0% and 96.0% for death. Survival curves showed that high-risk individuals were more likely to die compared with the low-risk individuals, adjusted to covariables (P < 0.001). CONCLUSIONS: The Pra presented low accuracy, low sensitivity and high specificity for all outcomes observed, indicating a poor performance to screen vulnerable older adults in Brazil. Therefore, this tool should not be used alone, as a case-finding instrument. Geriatr Gerontol Int 2020; 20: 360-365.

Ulnar neuropathy at the elbow: Reappraisal of the wrist-upper arm latency difference between ulnar and median nerves.

OBJECTIVES: To evaluate the sensitivity and specificity of the latency difference (DLat) between ulnar and median nerves of the arm after stimulation at the wrist; one of the easiest techniques proposed for recognizing ulnar neuropathy at the elbow (UNE). As latency difference is not a standardized technique, we set up a multicenter study to recruit large numbers of normal subjects and patients with UNE or generalized neuropathy. METHODS: Six centers participated in the study with data obtained from three groups of participants, controls (CTRLs), patients with UNE and patients with generalized neuropathy (GNP). We first verified the anatomical superposition of the ulnar and median nerves in cadaver examination. The optimal recording site for these two nerves was found to be 10 cm above the medial epicondyle. We then standardized the position of the arm with full extension of the elbow and stimulated first the median and then the ulnar nerves at the wrist. CTRLs were examined on both arms at two consecutive visits. RESULTS: We recorded 32 idiopathic UNE cases, 44 GNP patients and 62 controls. We demonstrated that a DLat cut-off value of 0.69 ms brings a sensitivity of 0.86 and specificity of 0.89 to discriminate CTRLs from UNE. We also validated that intra-examiner reproducibility was good. CONCLUSION: We report a lower normal value for DLat than reported in several non-standardized studies and CTRL and UNE groups have clearly separated DLat values. SIGNIFICANCE: Due to its high sensitivity, our standardized technique could be used as a first-line diagnostic tool when UNE is suspected.

Spiking Neural Networks applied to the classification of motor tasks in EEG signals.

Motivated by the recent progress of Spiking Neural Network (SNN) models in pattern recognition, we report on the development and evaluation of brain signal classifiers based on SNNs. The work shows the capabilities of this type of Spiking Neurons in the recognition of motor imagery tasks from EEG signals and compares their performance with other traditional classifiers commonly used in this application. This work includes two stages: the first stage consists of comparing the performance of the SNN models against some traditional neural network models. The second stage, compares the SNN models performance in two input conditions: input features with constant values and input features with temporal information. The EEG signals employed in this work represent five motor imagery tasks: i.e. rest, left hand, right hand, foot and tongue movements. These EEG signals were obtained from a public database provided by the Technological University of Graz (Brunner et al., 2008). The feature extraction stage was performed by applying two algorithms: power spectral density and wavelet decomposition. Likewise, this work uses raw EEG signals for the second stage of the problem solution. All of the models were evaluated in the classification between two motor imagery tasks. This work demonstrates that with a smaller number of Spiking neurons, simple problems can be solved. Better results are obtained by using patterns with temporal information, thereby exploiting the capabilities of the SNNs.

Xenbase: deep integration of GEO & SRA RNA-seq and ChIP-seq data in a model organism database.

Xenbase (www.xenbase.org) is a knowledge base for researchers and biomedical scientists that employ the amphibian Xenopus as a model organism in biomedical research to gain a deeper understanding of developmental and disease processes. Through expert curation and automated data provisioning from various sources Xenbase strives to integrate the body of knowledge on Xenopus genomics and biology together with the visualization of biologically significant interactions. Most current studies utilize next generation sequencing (NGS) but until now the results of different experiments were difficult to compare and not integrated with other Xenbase content. Xenbase has developed a suite of tools, interfaces and data processing pipelines that transforms NCBI Gene Expression Omnibus (GEO) NGS content into deeply integrated gene expression and chromatin data, mapping all aligned reads to the most recent genome builds. This content can be queried and visualized via multiple tools and also provides the basis for future automated 'gene expression as a phenotype' and gene regulatory network analyses.

Matrix stiffness mechanically conditions EMT and migratory behavior of oral squamous cell carcinoma.

Tumors are composed of heterogeneous phenotypes, each having different sensitivities to the microenvironment. One microenvironment characteristic - matrix stiffness - helps to regulate malignant transformation and invasion in mammary tumors, but its influence on oral squamous cell carcinoma (OSCC) is unclear. We observed that, on stiff matrices, a highly invasive OSCC cell line (SCC25) comprising a low E-cad to N-cad ratio (InvH/E:NL; SCC25) had increased migration velocity and decreased adhesion strength compared to a less invasive OSCC cell line (Cal27) with high E-cad to N-cad ratio (InvL/E:NH; Cal27). However, InvL/E:NH cells acquire a mesenchymal signature and begin to migrate faster when exposed to prolonged time on a stiff niche, suggesting that cells can be mechanically conditioned. Owing to increased focal adhesion assembly, InvL/E:NH cells migrated faster, which could be reduced when increasing integrin affinity with high divalent cation concentrations. Mirroring these data in human patients, we observed that collagen organization, an indicator of matrix stiffness, was increased with advanced disease and correlated with early recurrence. Consistent with epithelial tumors, our data suggest that OSCC cells are mechanically sensitive and that their contribution to tumor progression is mediated in part by this sensitivity.This article has an associated First Person interview with the first author of the paper.

Analysis of different anthropometric indicators in the detection of high blood pressure in school adolescents: a cross-sectional study with 8295 adolescents.

BACKGROUND: High blood pressure is strongly associated with obesity in different populations. However, it is unclear whether different anthropometric indicators of obesity can satisfactorily predict high blood pressure in the school setting. OBJECTIVES: This study evaluated the sensitivity and specificity of body mass index, waist circumference, and waist to height ratio in the detection of high blood pressure in adolescents. METHODS: The sample consisted of 8295 adolescents aged 10-17 years. Weight was measured using a digital scale, height with a stadiometer, and waist circumference using a tape measure. Blood pressure was measured by an automatic blood pressure measuring device. ROC curves were used for the analysis of sensitivity and specificity of the three anthropometric indices in identifying high blood pressure. Binary Logistic Regression was used to assess the association of body mass index, waist circumference, and waist to height ratio with high blood pressure. RESULTS: Low values of sensitivity were observed for body mass index (0.35), waist circumference (0.37), and waist to height ratio (0.31) and high values of specificity for body mass index (0.86), waist circumference (0.82), and waist to height ratio (0.83) in the detection of high blood pressure. An association was observed between adolescents classified with high body mass index (OR=3.57 [95% CI=3.10-4.10]), waist cirumference (OR=3.24 [95% CI=2.83-3.72]), and waist to height ratio (OR=2.94 [95% CI=2.54-3.40]) with high blood pressure. CONCLUSIONS: Body mass index, waist circumference, and waist to height ratio presented low sensitivity to identify adolescents with high blood pressure. However, adolescents classified with high body mass index, waist circumference, and waist to height ratio demonstrated a high association of presenting high blood pressure.

Intraoperative test stimulation versus stereotactic accuracy as a surgical end point: a comparison of essential tremor outcomes after ventral intermediate nucleus deep brain stimulation.

OBJECTIVE Ventral intermediate nucleus deep brain stimulation (DBS) for essential tremor is traditionally performed with intraoperative test stimulation and conscious sedation, without general anesthesia (GA). Recently, the authors reported retrospective data on 17 patients undergoing DBS after induction of GA with standardized anatomical coordinates on T1-weighted MRI sequences used for indirect targeting. Here, they compare prospectively collected data from essential tremor patients undergoing DBS both with GA and without GA (non-GA). METHODS Clinical outcomes were prospectively collected at baseline and 3-month follow-up for patients undergoing DBS surgery performed by a single surgeon. Stereotactic, euclidean, and radial errors of lead placement were calculated. Functional (activities of daily living), quality of life (Quality of Life in Essential Tremor [QUEST] questionnaire), and tremor severity outcomes were compared between groups. RESULTS Fifty-six patients underwent surgery: 16 without GA (24 electrodes) and 40 with GA (66 electrodes). The mean baseline functional scores and QUEST summary indices were not different between groups (p = 0.91 and p = 0.59, respectively). Non-GA and GA groups did not differ significantly regarding mean postoperative percentages of functional improvement (non-GA, 47.9% vs GA, 48.1%; p = 0.96) or QUEST summary indices (non-GA, 79.9% vs GA, 74.8%; p = 0.50). Accuracy was comparable between groups (mean radial error 0.9 ± 0.3 mm for non-GA and 0.9 ± 0.4 mm for GA patients) (p = 0.75). The mean euclidean error was also similar between groups (non-GA, 1.1 ± 0.6 mm vs GA, 1.2 ± 0.5 mm; p = 0.92). No patient had an intraoperative complication, and the number of postoperative complications was not different between groups (non-GA, n = 1 vs GA, n = 10; p = 0.16). CONCLUSIONS DBS performed with the patient under GA to treat essential tremor is as safe and effective as traditional DBS surgery with intraoperative test stimulation while the patient is under conscious sedation without GA.

UV-Vis and CIELAB Based Chemometric Characterization of Manihot esculenta Carotenoid Contents.

Vitamin A deficiency is a prevalent health problem in many areas of the world, where cassava genotypes with high pro-vitamin A content have been identified as a strategy to address this issue. In this study, we found a positive correlation between the color of the root pulp and the total carotenoid contents and, importantly, showed how CIELAB color measurements can be used as a non-destructive and fast technique to quantify the amount of carotenoids in cassava root samples, as opposed to traditional methods. We trained several machine learning models using UV-visible spectrophotometry data, CIELAB data and a low-level data fusion of the two. Best performance models were obtained for the total carotenoids contents calculated using the UV-visible dataset as input, with R2 values above 90 %. Using CIELAB and fusion data, values around 60 % and above 90 % were found. Importantly, these results demonstrated how data fusion can lead to a better model performance for prediction when comparing to the use of a single data source. Considering all these findings, the use of colorimetric data associated with UV-visible and HPLC data through statistical and machine learning methods is a reliable way of predicting the content of total carotenoids in cassava root samples.

Parkinson's disease outcomes after intraoperative CT-guided "asleep" deep brain stimulation in the globus pallidus internus.

OBJECTIVE: Recent studies show that deep brain stimulation can be performed safely and accurately without microelectrode recording ortest stimulation but with the patient under general anesthesia. The procedure couples techniques for direct anatomical targeting on MRI with intraoperative imaging to verify stereotactic accuracy. However, few authors have examined the clinical outcomes of Parkinson's disease (PD) patients after this procedure. The purpose of this study was to evaluate PD outcomes following "asleep" deep brain stimulation in the globus pallidus internus (GPi). METHODS: The authors prospectively examined all consecutive patients with advanced PD who underwent bilateral GPi electrode placement while under general anesthesia. Intraoperative CT was used to assess lead placement accuracy. The primary outcome measure was the change in the off-medication Unified Parkinson's Disease Rating Scale motor score 6 months after surgery. Secondary outcomes included effects on the 39-Item Parkinson's Disease Questionnaire (PDQ-39) scores, on-medication motor scores, and levodopa equivalent daily dose. Lead locations, active contact sites, stimulation parameters, and adverse events were documented. RESULTS: Thirty-five patients (24 males, 11 females) had a mean age of 61 years at lead implantation. The mean radial error off plan was 0.8 mm. Mean coordinates for the active contact were 21.4 mm lateral, 4.7 mm anterior, and 0.4 mm superior to the midcommissural point. The mean off-medication motor score improved from 48.4 at baseline to 28.9 (40.3% improvement) at 6 months (p < 0.001). The PDQ-39 scores improved (50.3 vs 42.0; p = 0.03), and the levodopa equivalent daily dose was reduced (1207 vs 1035 mg; p = 0.004). There were no significant adverse events. CONCLUSIONS: Globus pallidus internus leads placed with the patient under general anesthesia by using direct anatomical targeting resulted in significantly improved outcomes as measured by the improvement in the off-medication motor score at 6 months after surgery.

Xenbase, the Xenopus model organism database; new virtualized system, data types and genomes.

Xenbase (http://www.xenbase.org), the Xenopus frog model organism database, integrates a wide variety of data from this biomedical model genus. Two closely related species are represented: the allotetraploid Xenopus laevis that is widely used for microinjection and tissue explant-based protocols, and the diploid Xenopus tropicalis which is used for genetics and gene targeting. The two species are extremely similar and protocols, reagents and results from each species are often interchangeable. Xenbase imports, indexes, curates and manages data from both species; all of which are mapped via unique IDs and can be queried in either a species-specific or species agnostic manner. All our services have now migrated to a private cloud to achieve better performance and reliability. We have added new content, including providing full support for morpholino reagents, used to inhibit mRNA translation or splicing and binding to regulatory microRNAs. New genomes assembled by the JGI for both species and are displayed in Gbrowse and are also available for searches using BLAST. Researchers can easily navigate from genome content to gene page reports, literature, experimental reagents and many other features using hyperlinks. Xenbase has also greatly expanded image content for figures published in papers describing Xenopus research via PubMedCentral.

Implementation of the "Saúde na Boa" intervention: process evaluation and characteristics of participants and dropouts / Implementação da intervenção "Saúde na Boa": avaliação de processo e características dos estudantes permanecentes e não permanecentes

School-based interventions have been evaluated to examine its implementation quality and to identify the characteristics of successful participants. The objective was to analyze the process evaluation of the "Saúde na Boa" intervention and to test differences between successful participants and dropouts. Twenty schools were randomly selected to receive the intervention (n= 10) or the control (n= 10), in Recife-PE and Florianopolis-SC. The process evaluation was performed in the intervention schools using a checklist of items from five domains (knowledge, visibility, environment, Physical Education classes and extracurricular activities). The operational intervention quality was classified using the median score from each domain (median from 0.0 to 1.0= low, from 1.1 to 2.0= moderate, and from 2.1 to 3.0= high). Student characteristics were assessed at baseline (March 2006) and were compared between the participants who successfully completed the intervention (n= 989) and the dropouts (n= 1,166). We verified moderate to high operational quality of the intervention for knowledge (median= 2.0), fruit distribution and bike rack installation (median= 1.5), acquisition of materials (median= 3.0) and distribution of journals (median= 2.0). Students who dropped out were significantly more frequent in male (47.8% vs. 40.3%), in workers students (49.2% vs. 44.2%), those who smoked (21.8% vs. 13.6%) and consumed alcoholic beverages (57.4% vs. 49.5%), and slept ≥8 h/day (19.5% vs. 27.3%), than participants who did not drop out. Therefore, the "Saúde na Boa" intervention was of moderate operational quality. Participants and dropout students differed according to their gender, work status and use of licit drugs.

Intervenções no ambiente escolar têm sido avaliadas para analisar a qualidade da implementação de suas ações e o perfil dos participantes envolvidos. O objetivo deste estudo foi analisar os resultados da avaliação de processo da intervenção "Saúde na Boa"; e testar diferenças entre estudantes permanecentes e não permanecentes até o final da intervenção. Das vinte escolas selecionadas, dez foram sorteadas para a condição "intervenção" e dez compuseram o grupo "controle", em Recife/PE, e Florianópolis/SC. A avaliação de processo foi realizada nestas escolas, considerando cinco eixos (conhecimento, visibilidade, ambiente, aulas de Educação Física e atividades extraclasse), classificando-se a qualidade operacional da intervenção conforme a mediana do escore em cada um destes fatores (Mediana= 0,0 a 1,0: baixa; 1,1 a 2,0: moderada; 2,1 a 3,0: elevada). As características dos estudantes na linha de base (março de 2006) foram comparadas entre os permanecentes (n= 989) e não permanecentes (n= 1166). Verificou-se qualidade operacional moderada à elevada da intervenção para os itens conhecimento da intervenção (Mediana= 2,0), distribuição de frutas e instalação de bicicletários (Mediana= 1,5), aquisição de materiais (Mediana= 3,0) e distribuição de boletins (Mediana= 2,0). O grupo de não permanecentes apresentou significativamente maior frequência de rapazes (47,8% vs. 40,3%), de jovens que trabalhavam (49,2% vs. 44,2), que consumiam cigarros (21,8% vs. 13,6%) e bebidas alcoólicas (57,4% vs. 49,5%), e dormiam ≥8 h/dia (19,5% vs. 27,3%) do que os permanecentes. Portanto, a intervenção apresentou qualidade operacional moderada, e o perfil do abandono diferiu com relação ao sexo, ocupação e consumo de drogas lícitas.

Crim1 maintains retinal vascular stability during development by regulating endothelial cell Vegfa autocrine signaling.

Angiogenesis defines the process in which new vessels grow from existing vessels. Using the mouse retina as a model system, we show that cysteine-rich motor neuron 1 (Crim1), a type I transmembrane protein, is highly expressed in angiogenic endothelial cells. Conditional deletion of the Crim1 gene in vascular endothelial cells (VECs) causes delayed vessel expansion and reduced vessel density. Based on known Vegfa binding by Crim1 and Crim1 expression in retinal vasculature, where angiogenesis is known to be Vegfa dependent, we tested the hypothesis that Crim1 is involved in the regulation of Vegfa signaling. Consistent with this hypothesis, we showed that VEC-specific conditional compound heterozygotes for Crim1 and Vegfa exhibit a phenotype that is more severe than each single heterozygote and indistinguishable from that of the conditional homozygotes. We further showed that human CRIM1 knockdown in cultured VECs results in diminished phosphorylation of VEGFR2, but only when VECs are required to rely on an autocrine source of VEGFA. The effect of CRIM1 knockdown on reducing VEGFR2 phosphorylation was enhanced when VEGFA was also knocked down. Finally, an anti-VEGFA antibody did not enhance the effect of CRIM1 knockdown in reducing VEGFR2 phosphorylation caused by autocrine signaling, but VEGFR2 phosphorylation was completely suppressed by SU5416, a small-molecule VEGFR2 kinase inhibitor. These data are consistent with a model in which Crim1 enhances the autocrine signaling activity of Vegfa in VECs at least in part via Vegfr2.

Enhanced XAO: the ontology of Xenopus anatomy and development underpins more accurate annotation of gene expression and queries on Xenbase.

BACKGROUND: The African clawed frogs Xenopus laevis and Xenopus tropicalis are prominent animal model organisms. Xenopus research contributes to the understanding of genetic, developmental and molecular mechanisms underlying human disease. The Xenopus Anatomy Ontology (XAO) reflects the anatomy and embryological development of Xenopus. The XAO provides consistent terminology that can be applied to anatomical feature descriptions along with a set of relationships that indicate how each anatomical entity is related to others in the embryo, tadpole, or adult frog. The XAO is integral to the functionality of Xenbase (http://www.xenbase.org), the Xenopus model organism database. RESULTS: We significantly expanded the XAO in the last five years by adding 612 anatomical terms, 2934 relationships between them, 640 synonyms, and 547 ontology cross-references. Each term now has a definition, so database users and curators can be certain they are selecting the correct term when specifying an anatomical entity. With developmental timing information now asserted for every anatomical term, the ontology provides internal checks that ensure high-quality gene expression and phenotype data annotation. The XAO, now with 1313 defined anatomical and developmental stage terms, has been integrated with Xenbase expression and anatomy term searches and it enables links between various data types including images, clones, and publications. Improvements to the XAO structure and anatomical definitions have also enhanced cross-references to anatomy ontologies of other model organisms and humans, providing a bridge between Xenopus data and other vertebrates. The ontology is free and open to all users. CONCLUSIONS: The expanded and improved XAO allows enhanced capture of Xenopus research data and aids mechanisms for performing complex retrieval and analysis of gene expression, phenotypes, and antibodies through text-matching and manual curation. Its comprehensive references to ontologies across taxa help integrate these data for human disease modeling.

The Xenbase literature curation process.

Xenbase (www.xenbase.org) is the model organism database for Xenopus tropicalis and Xenopus laevis, two frog species used as model systems for developmental and cell biology. Xenbase curation processes centre on associating papers with genes and extracting gene expression patterns. Papers from PubMed with the keyword 'Xenopus' are imported into Xenbase and split into two curation tracks. In the first track, papers are automatically associated with genes and anatomy terms, images and captions are semi-automatically imported and gene expression patterns found in those images are manually annotated using controlled vocabularies. In the second track, full text of the same papers are downloaded and indexed by a number of controlled vocabularies and made available to users via the Textpresso search engine and text mining tool.

Xenbase: expansion and updates of the Xenopus model organism database.

Xenbase (http://www.xenbase.org) is a model organism database that provides genomic, molecular, cellular and developmental biology content to biomedical researchers working with the frog, Xenopus and Xenopus data to workers using other model organisms. As an amphibian Xenopus serves as a useful evolutionary bridge between invertebrates and more complex vertebrates such as birds and mammals. Xenbase content is collated from a variety of external sources using automated and semi-automated pipelines then processed via a combination of automated and manual annotation. A link-matching system allows for the wide variety of synonyms used to describe biological data on unique features, such as a gene or an anatomical entity, to be used by the database in an equivalent manner. Recent updates to the database include the Xenopus laevis genome, a new Xenopus tropicalis genome build, epigenomic data, collections of RNA and protein sequences associated with genes, more powerful gene expression searches, a community and curated wiki, an extensive set of manually annotated gene expression patterns and a new database module that contains data on over 700 antibodies that are useful for exploring Xenopus cell and developmental biology.