Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the ...membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.
Chemical named entity recognition (NER) has traditionally been dominated by conditional random fields (CRF)-based approaches but given the success of the artificial neural network techniques known as ...“deep learning” we decided to examine them as an alternative to CRFs. We present here several chemical named entity recognition systems. The first system translates the traditional CRF-based idioms into a deep learning framework, using rich per-token features and neural word embeddings, and producing a sequence of tags using bidirectional long short term memory (LSTM) networks—a type of recurrent neural net. The second system eschews the rich feature set—and even tokenisation—in favour of character labelling using neural character embeddings and multiple LSTM layers. The third system is an ensemble that combines the results of the first two systems. Our original BioCreative V.5 competition entry was placed in the top group with the highest F scores, and subsequent using transfer learning have achieved a final F score of 90.33% on the test data (precision 91.47%, recall 89.21%).
Purpose To determine the prevalence of ocular and systemic abnormalities in a group of subjects with aniridia. Methods Survey forms developed by Aniridia Foundation International were sent to all ...members prior to the 2010 AFI member conference. An additional form was provided for completion by physicians caring for patients. Forms were then collected from all members who attended the meeting. Results A total of 155 surveys were distributed, of which 83 (53%) were completed. The mean age was 25.4 ± 18.4 years, with 65% sporadic and 35% familial cases, and 2.4% with WAGR (Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome. Ocular abnormalities included nystagmus (83%), cataract (71%), dry eye (53%), glaucoma (46%), keratopathy (45%), foveal hypoplasia (41%), strabismus (31%), and retinal disease (5%). The mean age at diagnosis of aniridia was 22.1 months (median, 1.5 months) and glaucoma was 13.6 years (median, 8.5 years). Of 38 subjects with aniridia and glaucoma, 76% were treated medically, and 58% had been treated surgically. In subjects with glaucoma, the mean number (± SD) of glaucoma medications was 1.8 ± 1.3, and number of surgical procedures was 1.7 ± 2.0. Developmental delay was reported in 17%. The mean body mass index and the prevalence of obesity in subjects with aniridia was significantly greater ( P = 0.003) than in siblings without aniridia. Conclusions In this study, aniridia was associated with nystagmus and other motility problems, cataract, glaucoma, and keratopathy. Systemic abnormalities included increased average body mass index and obesity, which appeared to occur not only in WAGR syndrome but more broadly in aniridia.
Hydrogen sulfide (H
S) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification ...through which H
S acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functions. Voltage-gated K
channels, including Kv2.1, are fundamental components of neuronal excitability. Here, we show that both recombinant and native rat Kv2.1 channels are inhibited by the H
S donors, NaHS and GYY4137. Biochemical investigations revealed that NaHS treatment leads to S-sulfhydration of the full length wild type Kv2.1 protein which was absent (as was functional regulation by H
S) in the C73A mutant form of the channel. Functional experiments utilising primary rat hippocampal neurons indicated that NaHS augments action potential firing and thereby increases neuronal excitability. These studies highlight an important role for H
S in shaping cellular excitability through S-sulfhydration of Kv2.1 at C73 within the central nervous system.
Hypoxia and Neurodegeneration Peers, Chris; Dallas, Mark L.; Boycott, Hannah E. ...
Annals of the New York Academy of Sciences,
October 2009, Letnik:
1177, Številka:
1
Journal Article
Recenzirano
Periods of chronic hypoxia, which can arise from numerous cardiorespiratory disorders, predispose individuals to the development of dementias, particularly Alzheimer's disease (AD). AD is ...characterized in part by the increased production of amyloid β peptide (Aβ), which forms the extracellular plaques by which the disease can be identified post mortem. Numerous studies have now shown that hypoxia, even in vitro, can increase production of Aβ in different cell types. Evidence has been produced to indicate hypoxia alters both expression of the Aβ precursor, APP, and also the expression of the secretase enzymes, which cleave Aβ from APP. Other studies implicate reduced Aβ degradation as a possible means by which hypoxia increases Aβ levels. Such variability may be attributable to cell‐specific responses to hypoxia. Further evidence indicates that some, but not all of the cellular adaptations to chronic hypoxia (including alteration of Ca2+ homeostasis) require Aβ formation. However, other aspects of hypoxic remodeling of cell function appear to occur independently of this process. The molecular and cellular responses to hypoxia contribute to our understanding of the clinical association of hypoxia and increased incidence of AD. However, it remains to be determined whether inhibition of one or more of the effects of hypoxia may be of benefit in arresting the development of this neurodegenerative disease.
Cytoscape is a general network visualization, data integration, and analysis software package. Its development and use has been focused on the modeling requirements of systems biology, though it has ...been used in other fields. Cytoscape's flexibility has encouraged many users to adopt it and adapt it to their own research by using the plugin framework offered to specialize data analysis, data integration, or visualization. Plugins represent collections of community-contributed functionality and can be used to dynamically extend Cytoscape functionality. This community of users and developers has worked together since Cytoscape's initial release to improve the basic project through contributions to the core code and public offerings of plugin modules. This chapter discusses what Cytoscape does, why it was developed, and the extensions numerous groups have made available to the public. It also describes the development of a plugin used to investigate a particular research question in systems biology and walks through an example analysis using Cytoscape.
Now that severe combined immune deficiency (SCID) has been added to newborn screening panels in all 50 states in the U.S., there is a need to develop and disseminate well-designed educational ...materials to parents who need information to make informed decisions about treatment and care for identified infants. SCID Compass was designed to address this gap. We summarize the results of two needs assessment activities for parents-a journey mapping exercise and online survey-which will inform the development of a website and new resources.
We conducted in-depth interviews with seven parents of children with SCID identified through newborn screening. Participants were asked to complete a journey map to describe key timepoints related to SCID, starting at diagnosis through present day. This qualitative information informed an online survey that was completed by 76 parents who had a child with SCID. All participants were from the United States.
Analysis of journey maps revealed five distinct stages that parents experience: (1) Diagnosis, (2) Pre-Treatment, (3) Treatment, (4) Post-Treatment, and (5) The New Normal. At each stage, parents described unique emotions, challenges, contextual factors that can make a difference in their experience, and information and resource needs. Survey results indicated the highest-rated information needs for parents were understanding available treatment options and what to expect across the SCID lifespan. Emotional support needs included dealing with uncertainty about child's future and additional opportunities to connect with other families. Parents preferred receiving new materials from their healthcare provider or other families, and preferred materials in print, from social media, or online. Several differences were found among subgroups of parents, including those whose child had been identified through newborn screening as well as those considered medically underserved.
Findings about unmet parent needs and informational preferences will serve as the foundation for creating a suite of resources for those who have a child with SCID. The materials will be tailored to specific stages of the journey. By using a family-centered approach, we will help to ensure that the materials designed and developed as part of SCID Compass will be understandable, comprehensive, and useful.
Evidence of the ability of the gasotransmitter hydrogen sulfide (H(2)S) to serve as a regulator of many physiological functions, including control of blood pressure, regulation of cardiac function, ...protection of neurons, and cardiomyocytes against apoptosis, and in pain sensation is accumulating. However, the mechanisms accounting for its many actions are not yet well understood.
Following the pioneering studies of the regulation of N-methyl-d-aspartate receptors and ATP-sensitive K(+) channels by H(2)S, data continue to emerge indicating that H(2)S modulates other ion channel types. This article reviews the numerous, yet diverse, types of ion channels now reported to be regulated by H(2)S.
Currently, a critical issue within this field is to determine the mechanisms by which H(2)S regulates ion channels, as well as other target proteins. Mechanisms to account for regulation include direct channel protein sulfhydration, channel redox modulation, effects mediated by interactions with other gasotransmitters (carbon monoxide and nitric oxide), and indirect effects, such as modulation of channel-regulating kinases. Through such modulation of ion channels, novel roles for H(2)S are emerging as important factors in both physiological and pathological processes.
Increasing current awareness and understanding of the roles and mechanisms of action of ion channel regulation by H(2)S will open opportunities for therapeutic intervention with clear clinical benefits, and inform future therapies. In addition, more sensitive methods for detecting relevant physiological concentrations of H(2)S will allow for clarification of specific ion channel regulation with reference to physiological or pathophysiological settings.
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