In vivo multiphoton microscopy beyond 1 mm in the brain

The ability to visualize deep brain structures in vivo with high spatial resolution is of rising interest to investigate neuronal physiology and cerebral vasculature. Optical imaging offers non-invasive, high-resolution in vivo microscopy techniques to observe brain tissue and its surrounding environment. Two-photon fluorescence laser- scanning microscopy (2PM) can overcome depth limitations by using nonlinear excitation. The ideal approach for deep imaging in brain is to use both high energy pulses and longer excitation wavelengths. Please click Additional Files below to see the full abstract

Reliability and validity of neurobehavioral function on the Psychology Experimental Building Language test battery in young adults

Background. The Psychology Experiment Building Language (PEBL) software consists of over one-hundred computerized tests based on classic and novel cognitive neuropsychology and behavioral neurology measures. Although the PEBL tests are becoming more widely utilized, there is currently very limited information about the psychometric properties of these measures. Methods. Study I examined inter-relationships among nine PEBL tests including indices of motor-function (Pursuit Rotor and Dexterity), attention (Test of Attentional Vigilance and Time-Wall), working memory (Digit Span Forward), and executive-function (PEBL Trail Making Test, Berg/Wisconsin Card Sorting Test, Iowa Gambling Test, and Mental Rotation) in a normative sample (N = 189, ages 18–22). Study II evaluated test–retest reliability with a two-week interest interval between administrations in a separate sample (N = 79, ages 18–22). Results. Moderate intra-test, but low inter-test, correlations were observed and ceiling/floor effects were uncommon. Sex differences were identified on the Pursuit Rotor (Cohen’s d = 0.89) and Mental Rotation (d = 0.31) tests. The correlation between the test and retest was high for tests of motor learning (Pursuit Rotor time on target r = .86) and attention (Test of Attentional Vigilance response time r = .79), intermediate for memory (digit span r = .63) but lower for the executive function indices (Wisconsin/Berg Card Sorting Test perseverative errors = .45, Tower of London moves = .15). Significant practice effects were identified on several indices of executive function. Conclusions. These results are broadly supportive of the reliability and validity of individual PEBL tests in this sample. These findings indicate that the freely downloadable, open-source PEBL battery (http://pebl.sourceforge.net) is a versatile research tool to study individual differences in neurocognitive performance

Expression of Integrin-αE by Mucosal Mast Cells in the Intestinal Epithelium and Its Absence in Nematode-Infected Mice Lacking the Transforming Growth Factor-β1-Activating Integrin αvβ6

Peak intestinal mucosal mast cell (MMC) recruitment coincides with expulsion of Trichinella spiralis, at a time when the majority of the MMCs are located within the epithelium in BALB/c mice. Although expression of integrin-α(E)β(7) by MMCs has not been formally demonstrated, it has been proposed as a potential mechanism to account for the predominantly intraepithelial location of MMCs during nematode infection. Co-expression of integrin-α(E)β(7) and the MMC chymase mouse mast cell protease-1, by mouse bone marrow-derived mast cells, is strictly regulated by transforming growth factor (TGF)-β(1). However, TGF-β(1) is secreted as part of a latent complex in vivo and subsequent extracellular modification is required to render it biologically active. We now show, for the first time, that intraepithelial MMCs express integrin-α(E)β(7) in Trichinella-infected BALB/c and S129 mice. In S129 mice that lack the gene for the integrin-β(6) subunit and, as consequence, do not express the epithelial integrin-α(v)β(6), integrin-α(E) expression is virtually abolished and recruitment of MMCs into the intestinal epithelium is dramatically reduced despite significant overall augmentation of the MMC population. Because a major function of integrin-α(v)β(6) is to activate latent TGF-β(1,) these findings strongly support a role for TGF-β(1) in both the recruitment and differentiation of murine MMCs during nematode infection

Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors

Mast cells are tissue-resident cells with important functions in allergy and inflammation. Pluripotential hematopoietic stem cells in the bone marrow give rise to committed mast cell progenitors that transit via the blood to tissues throughout the body, where they mature. Knowledge is limited about the factors that release mast cell progenitors from the bone marrow or recruit them to remote tissues. Mouse femoral bone marrow cells were cultured with IL-3 for 2 wk and a range of chemotactic agents were tested on the c-kit+ population. Cells were remarkably refractory and no chemotaxis was induced by any chemokines tested. However, supernatants from activated mature mast cells induced pronounced chemotaxis, with the active principle identified as leukotriene (LT) B4. Other activation products were inactive. LTB4 was highly chemotactic for 2-wk-old cells, but not mature cells, correlating with a loss of mRNA for the LTB4 receptor, BLT1. Immature cells also accumulated in vivo in response to intradermally injected LTB4. Furthermore, LTB4 was highly potent in attracting mast cell progenitors from freshly isolated bone marrow cell suspensions. Finally, LTB4 was a potent chemoattractant for human cord blood–derived immature, but not mature, mast cells. These results suggest an autocrine role for LTB4 in regulating tissue mast cell numbers

Natural language processing to automatically extract the presence and severity of esophagitis in notes of patients undergoing radiotherapy

Radiotherapy (RT) toxicities can impair survival and quality-of-life, yet remain under-studied. Real-world evidence holds potential to improve our understanding of toxicities, but toxicity information is often only in clinical notes. We developed natural language processing (NLP) models to identify the presence and severity of esophagitis from notes of patients treated with thoracic RT. We fine-tuned statistical and pre-trained BERT-based models for three esophagitis classification tasks: Task 1) presence of esophagitis, Task 2) severe esophagitis or not, and Task 3) no esophagitis vs. grade 1 vs. grade 2-3. Transferability was tested on 345 notes from patients with esophageal cancer undergoing RT. Fine-tuning PubmedBERT yielded the best performance. The best macro-F1 was 0.92, 0.82, and 0.74 for Task 1, 2, and 3, respectively. Selecting the most informative note sections during fine-tuning improved macro-F1 by over 2% for all tasks. Silver-labeled data improved the macro-F1 by over 3% across all tasks. For the esophageal cancer notes, the best macro-F1 was 0.73, 0.74, and 0.65 for Task 1, 2, and 3, respectively, without additional fine-tuning. To our knowledge, this is the first effort to automatically extract esophagitis toxicity severity according to CTCAE guidelines from clinic notes. The promising performance provides proof-of-concept for NLP-based automated detailed toxicity monitoring in expanded domains.Comment: 17 pages, 6 tables, 1figure, submiting to JCO-CCI for revie

The institutional shaping of management: in the tracks of English individualism

Globalisation raises important questions about the shaping of economic action by cultural factors. This article explores the formation of what is seen by some as a prime influence on the formation of British management: individualism. Drawing on a range of historical sources, it argues for a comparative approach. In this case, the primary comparison drawn is between England and Scotland. The contention is that there is a systemic approach to authority in Scotland that can be contrasted to a personal approach in England. An examination of the careers of a number of Scottish pioneers of management suggests the roots of this systemic approach in practices of church governance. Ultimately this systemic approach was to take a secondary role to the personal approach engendered by institutions like the universities of Oxford and Cambridge, but it found more success in the different institutional context of the USA. The complexities of dealing with historical evidence are stressed, as is the value of taking a comparative approach. In this case this indicates a need to take religious practice as seriously as religious belief as a source of transferable practice. The article suggests that management should not be seen as a simple response to economic imperatives, but as shaped by the social and cultural context from which it emerges

Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide

Glioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype

Recommended Priorities for Research on Ecological Impacts of Ocean and Coastal Acidification in the U.S. Mid-Atlantic

The estuaries and continental shelf system of the United States Mid-Atlantic are subject to ocean acidification driven by atmospheric CO2, and coastal acidification caused by nearshore and land-sea interactions that include biological, chemical, and physical processes. These processes include freshwater and nutrient input from rivers and groundwater; tidally-driven outwelling of nutrients, inorganic carbon, alkalinity; high productivity and respiration; and hypoxia. Hence, these complex dynamic systems exhibit substantial daily, seasonal, and interannual variability that is not well captured by current acidification research on Mid-Atlantic organisms and ecosystems. We present recommendations for research priorities that target better understanding of the ecological impacts of acidification in the U. S. Mid-Atlantic region. Suggested priorities are: 1) Determining the impact of multiple stressors on our resource species as well as the magnitude of acidification; 2) Filling information gaps on major taxa and regionally important species in different life stages to improve understanding of their response to variable temporal scales and sources of acidification; 3) Improving experimental approaches to incorporate realistic environmental variability and gradients, include interactions with other environmental stressors, increase transferability to other systems or organisms, and evaluate community and ecosystem response; 4) Determining the capacity of important species to acclimate or adapt to changing ocean conditions; 5) Considering multi-disciplinary, ecosystem-level research that examines acidification impacts on biodiversity and biotic interactions; and 6) Connecting potential acidification-induced ecological impacts to ecosystem services and the economy. These recommendations, while developed for the Mid-Atlantic, can be applicable to other regions will help align research towards knowledge of potential larger-scale ecological and economic impacts