When it Pays to Rush: Interpreting Morphogen Gradients Prior to Steady-State

During development, morphogen gradients precisely determine the position of gene expression boundaries despite the inevitable presence of fluctuations. Recent experiments suggest that some morphogen gradients may be interpreted prior to reaching steady-state. Theoretical work has predicted that such systems will be more robust to embryo-to-embryo fluctuations. By analysing two experimentally motivated models of morphogen gradient formation, we investigate the positional precision of gene expression boundaries determined by pre-steady-state morphogen gradients in the presence of embryo-to-embryo fluctuations, internal biochemical noise and variations in the timing of morphogen measurement. Morphogens that are direct transcription factors are found to be particularly sensitive to internal noise when interpreted prior to steady-state, disadvantaging early measurement, even in the presence of large embryo-to-embryo fluctuations. Morphogens interpreted by cell-surface receptors can be measured prior to steady-state without significant decrease in positional precision provided fluctuations in the timing of measurement are small. Applying our results to experiment, we predict that Bicoid, a transcription factor morphogen in Drosophila, is unlikely to be interpreted prior to reaching steady-state. We also predict that Activin in Xenopus and Nodal in zebrafish, morphogens interpreted by cell-surface receptors, can be decoded in pre-steady-state.Comment: 18 pages, 3 figure

DNA transport by a micromachined Brownian ratchet device

We have micromachined a silicon-chip device that transports DNA with a Brownian ratchet that rectifies the Brownian motion of microscopic particles. Transport properties for a DNA 50mer agree with theoretical predictions, and the DNA diffusion constant agrees with previous experiments. This type of micromachine could provide a generic pump or separation component for DNA or other charged species as part of a microscale lab-on-a-chip. A device with reduced feature size could produce a size-based separation of DNA molecules, with applications including the detection of single nucleotide polymorphisms.Comment: Latex: 8 pages, 4 figure

NeuroBridge ontology: computable provenance metadata to give the long tail of neuroimaging data a FAIR chance for secondary use

Background Despite the efforts of the neuroscience community, there are many published neuroimaging studies with data that are still not findable or accessible. Users face significant challenges in reusing neuroimaging data due to the lack of provenance metadata, such as experimental protocols, study instruments, and details about the study participants, which is also required for interoperability. To implement the FAIR guidelines for neuroimaging data, we have developed an iterative ontology engineering process and used it to create the NeuroBridge ontology. The NeuroBridge ontology is a computable model of provenance terms to implement FAIR principles and together with an international effort to annotate full text articles with ontology terms, the ontology enables users to locate relevant neuroimaging datasets. Methods Building on our previous work in metadata modeling, and in concert with an initial annotation of a representative corpus, we modeled diagnosis terms (e.g., schizophrenia, alcohol usage disorder), magnetic resonance imaging (MRI) scan types (T1-weighted, task-based, etc.), clinical symptom assessments (PANSS, AUDIT), and a variety of other assessments. We used the feedback of the annotation team to identify missing metadata terms, which were added to the NeuroBridge ontology, and we restructured the ontology to support both the final annotation of the corpus of neuroimaging articles by a second, independent set of annotators, as well as the functionalities of the NeuroBridge search portal for neuroimaging datasets. Results The NeuroBridge ontology consists of 660 classes with 49 properties with 3,200 axioms. The ontology includes mappings to existing ontologies, enabling the NeuroBridge ontology to be interoperable with other domain specific terminological systems. Using the ontology, we annotated 186 neuroimaging full-text articles describing the participant types, scanning, clinical and cognitive assessments. ConclusionThe NeuroBridge ontology is the first computable metadata model that represents the types of data available in recent neuroimaging studies in schizophrenia and substance use disorders research; it can be extended to include more granular terms as needed. This metadata ontology is expected to form the computational foundation to help both investigators to make their data FAIR compliant and support users to conduct reproducible neuroimaging research

Neutronic Design and Measured Performance of the Low Energy Neutron Source (LENS) Target Moderator Reflector Assembly

The Low Energy Neutron Source (LENS) is an accelerator-based pulsed cold neutron facility under construction at the Indiana University Cyclotron Facility (IUCF). The idea behind LENS is to produce pulsed cold neutron beams starting with ~MeV neutrons from (p,n) reactions in Be which are moderated to meV energies and extracted from a small solid angle for use in neutron instruments which can operate efficiently with relatively broad (~1 msec) neutron pulse widths. Although the combination of the features and operating parameters of this source is unique at present, the neutronic design possesses several features similar to those envisioned for future neutron facilities such as long-pulsed spallation sources (LPSS) and very cold neutron (VCN) sources. We describe the underlying ideas and design details of the target/moderator/reflector system (TMR) and compare measurements of its brightness, energy spectrum, and emission time distribution under different moderator configurations with MCNP simulations. Brightness measurements using an ambient temperature water moderator agree with MCNP simulations within the 20% accuracy of the measurement. The measured neutron emission time distribution from a solid methane moderator is in agreement with simulation and the cold neutron flux is sufficient for neutron scattering studies of materials. We describe some possible modifications to the existing design which would increase the cold neutron brightness with negligible effect on the emission time distribution.Comment: This is a preprint version of an article which has been published in Nuclear Instruments and Methods in Physics Research A 587 (2008) 324-341. http://dx.doi.org/10.1016/j.nima.2007.12.04

Innovative solutions to novel drug development in mental health

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

NeuroBridge: a prototype platform for discovery of the long-tail neuroimaging data

Introduction Open science initiatives have enabled sharing of large amounts of already collected data. However, significant gaps remain regarding how to find appropriate data, including underutilized data that exist in the long tail of science. We demonstrate the NeuroBridge prototype and its ability to search PubMed Central full-text papers for information relevant to neuroimaging data collected from schizophrenia and addiction studies. Methods The NeuroBridge architecture contained the following components: (1) Extensible ontology for modeling study metadata: subject population, imaging techniques, and relevant behavioral, cognitive, or clinical data. Details are described in the companion paper in this special issue; (2) A natural-language based document processor that leveraged pre-trained deep-learning models on a small-sample document corpus to establish efficient representations for each article as a collection of machine-recognized ontological terms; (3) Integrated search using ontology-driven similarity to query PubMed Central and NeuroQuery, which provides fMRI activation maps along with PubMed source articles. Results The NeuroBridge prototype contains a corpus of 356 papers from 2018 to 2021 describing schizophrenia and addiction neuroimaging studies, of which 186 were annotated with the NeuroBridge ontology. The search portal on the NeuroBridge website https://neurobridges.org/ provides an interactive Query Builder, where the user builds queries by selecting NeuroBridge ontology terms to preserve the ontology tree structure. For each return entry, links to the PubMed abstract as well as to the PMC full-text article, if available, are presented. For each of the returned articles, we provide a list of clinical assessments described in the Section “Methods” of the article. Articles returned from NeuroQuery based on the same search are also presented. Conclusion The NeuroBridge prototype combines ontology-based search with natural-language text-mining approaches to demonstrate that papers relevant to a user’s research question can be identified. The NeuroBridge prototype takes a first step toward identifying potential neuroimaging data described in full-text papers. Toward the overall goal of discovering “enough data of the right kind,” ongoing work includes validating the document processor with a larger corpus, extending the ontology to include detailed imaging data, and extracting information regarding data availability from the returned publications and incorporating XNAT-based neuroimaging databases to enhance data accessibility

Identification and Replication of Loci Involved in Camptothecin-Induced Cytotoxicity Using CEPH Pedigrees

To date, the Centre d'Etude Polymorphism Humain (CEPH) cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL) related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1±2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response

Combining Computational Prediction of Cis-Regulatory Elements with a New Enhancer Assay to Efficiently Label Neuronal Structures in the Medaka Fish

The developing vertebrate nervous system contains a remarkable array of neural cells organized into complex, evolutionarily conserved structures. The labeling of living cells in these structures is key for the understanding of brain development and function, yet the generation of stable lines expressing reporter genes in specific spatio-temporal patterns remains a limiting step. In this study we present a fast and reliable pipeline to efficiently generate a set of stable lines expressing a reporter gene in multiple neuronal structures in the developing nervous system in medaka. The pipeline combines both the accurate computational genome-wide prediction of neuronal specific cis-regulatory modules (CRMs) and a newly developed experimental setup to rapidly obtain transgenic lines in a cost-effective and highly reproducible manner. 95% of the CRMs tested in our experimental setup show enhancer activity in various and numerous neuronal structures belonging to all major brain subdivisions. This pipeline represents a significant step towards the dissection of embryonic neuronal development in vertebrates