Activation of the Syk tyrosine kinase is insufficient for downstream signal transduction in B lymphocytes

BACKGROUND: Immature B lymphocytes and certain B cell lymphomas undergo apoptotic cell death following activation of the B cell antigen receptor (BCR) signal transduction pathway. Several biochemical changes occur in response to BCR engagement, including activation of the Syk tyrosine kinase. Although Syk activation appears to be necessary for some downstream biochemical and cellular responses, the signaling events that precede Syk activation remain ill defined. In addition, the requirements for complete activation of the Syk-dependent signaling step remain to be elucidated. RESULTS: A mutant form of Syk carrying a combination of a K395A substitution in the kinase domain and substitutions of three phenylalanines (3F) for the three C-terminal tyrosines was expressed in a murine B cell lymphoma cell line, BCL(1).3B3 to interfere with normal Syk regulation as a means to examine the Syk activation step in BCR signaling. Introduction of this kinase-inactive mutant led to the constitutive activation of the endogenous wildtype Syk enzyme in the absence of receptor engagement through a 'dominant-positive' effect. Under these conditions, Syk kinase activation occurred in the absence of phosphorylation on Syk tyrosine residues. Although Syk appears to be required for BCR-induced apoptosis in several systems, no increase in spontaneous cell death was observed in these cells. Surprisingly, although the endogenous Syk kinase was enzymatically active, no enhancement in the phosphorylation of cytoplasmic proteins, including phospholipase Cγ2 (PLCγ2), a direct Syk target, was observed. CONCLUSION: These data indicate that activation of Syk kinase enzymatic activity is insufficient for Syk-dependent signal transduction. This observation suggests that other events are required for efficient signaling. We speculate that localization of the active enzyme to a receptor complex specifically assembled for signal transduction may be the missing event

Seasonal variability of the warm Atlantic Water layer in the vicinity of the Greenland shelf break

The warmest water reaching the east and west coast of Greenland is found between 200?m and 600?m. Whilst important for melting Greenland's outlet glaciers, limited winter observations of this layer prohibit determination of its seasonality. To address this, temperature data from Argo profiling floats, a range of sources within the World Ocean Database and unprecedented coverage from marine-mammal borne sensors have been analysed for the period 2002-2011. A significant seasonal range in temperature (~1-2?°C) is found in the warm layer, in contrast to most of the surrounding ocean. The phase of the seasonal cycle exhibits considerable spatial variability, with the warmest water found near the eastern and southwestern shelf-break towards the end of the calendar year. High-resolution ocean model trajectory analysis suggest the timing of the arrival of the year's warmest water is a function of advection time from the subduction site in the Irminger Basin

Evaluating the Dimensionality of First-Grade Written Composition

Purpose—We examined dimensions of written composition using multiple evaluative approaches such as an adapted 6+1 trait scoring, syntactic complexity measures, and productivity measures. We further examined unique relations of oral language and literacy skills to the identified dimensions of written composition. Method—A large sample of first grade students (N = 527) was assessed on their language, reading, spelling, letter writing automaticity, and writing in the spring. Data were analyzed using a latent variable approach including confirmatory factor analysis and structural equation modeling. Results—The seven traits in the 6+1 trait system were best described as two constructs: substantive quality, and spelling and writing conventions. When the other evaluation procedures such as productivity and syntactic complexity indicators were included, four dimensions emerged: substantive quality, productivity, syntactic complexity, and spelling and writing conventions. Language and literacy predictors were differentially related to each dimension in written composition. Conclusions—These four dimensions may be a useful guideline for evaluating developing beginning writer’s compositions

A Comparison of Components of Written Expression Abilities in Learning Disabled and Non-Learning Disabled Students at Three Grade Levels

Although written language plays a critical role in academic success, little empirical evidence exists on the normal development of processes involved in producing written products. Even less is known about the writing performance of LD children. This study empirically compared the written products of LD and normal students at three grade levels on The Test of Written Language. Results showed that LD subjects scored significantly lower than normal subjects on most written expression abilities, especially in the mechanical tasks of spelling, punctuation, and word usage.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Discovery of Novel, Orally Bioavailable, Antileishmanial Compounds Using Phenotypic Screening

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug

Breadth versus depth : cumulative risk model and continuous measure prediction of poor language and reading outcomes at 12

This study examines whether, and how, multiple risks in early childhood are associated with an increased likelihood of a poor language or literacy outcome in early adolescence. Using data from 210 participants in the longitudinal Twins Early Developmental Study, we focus on the following risk factors at age four: family risk, and poor language, speech, emergent literacy and nonverbal skills. The outcomes of interest at age 12 are language, reading fluency, and reading comprehension. We contrast a ‘cumulative risk’ model, counting the presence or absence of each risk factor (breadth), with a model that also considers the severity of the early deficits (depth). A ‘cumulative risk index’ correlated modestly but significantly with outcome (r = .32-.40). Odds ratios confirmed that having many risk factors (3-6) confers a higher probability of a poor outcome (OR 7.86-17.71) than having one or two (OR 3.65-7.28). Logistic regression models showed that predictive validity is not improved by including information about the severity of each deficit. Even with rich information on children’s risk status at age 4, we can make only a moderately accurate prediction of the likelihood of a language or literacy disorder eight years later (Area Under the Curve = .74-.84; Positive Predictive Value = .33-.55, Negative Predictive Value = .86-.91). Taken together, and consistent with the idea of ‘cumulative risk’, these results suggest that breadth of risk is a core predictor of outcome, and furthermore that severity of early deficits does not add significantly to this prediction

Perioperative mental health intervention for depression and anxiety symptoms in older adults study protocol: Design and methods for three linked randomised controlled trials

INTRODUCTION: Preoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients. METHODS AND ANALYSIS: Adults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention. ETHICS AND DISSEMINATION: The trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website. TRIAL REGISTRATION NUMBERS: NCT05575128, NCT05685511, NCT05697835, pre-results

Convergence of marine megafauna movement patterns in coastal and open oceans

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences of the United States of America 115 (2018): 3072-3077, doi:10.1073/pnas.1716137115.The extent of increasing anthropogenic impacts on large marine vertebrates partly depends on the animals’ movement patterns. Effective conservation requires identification of the key drivers of movement including intrinsic properties and extrinsic constraints associated with the dynamic nature of the environments the animals inhabit. However, the relative importance of intrinsic versus extrinsic factors remains elusive. We analyse a global dataset of 2.8 million locations from > 2,600 tracked individuals across 50 marine vertebrates evolutionarily separated by millions of years and using different locomotion modes (fly, swim, walk/paddle). Strikingly, movement patterns show a remarkable convergence, being strongly conserved across species and independent of body length and mass, despite these traits ranging over 10 orders of magnitude among the species studied. This represents a fundamental difference between marine and terrestrial vertebrates not previously identified, likely linked to the reduced costs of locomotion in water. Movement patterns were primarily explained by the interaction between species-specific traits and the habitat(s) they move through, resulting in complex movement patterns when moving close to coasts compared to more predictable patterns when moving in open oceans. This distinct difference may be associated with greater complexity within coastal micro-habitats, highlighting a critical role of preferred habitat in shaping marine vertebrate global movements. Efforts to develop understanding of the characteristics of vertebrate movement should consider the habitat(s) through which they move to identify how movement patterns will alter with forecasted severe ocean changes, such as reduced Arctic sea ice cover, sea level rise and declining oxygen content.Workshops funding granted by the UWA Oceans Institute, AIMS, and KAUST. AMMS was supported by an ARC Grant DE170100841 and an IOMRC (UWA, AIMS, CSIRO) fellowship; JPR by MEDC (FPU program, Spain); DWS by UK NERC and Save Our Seas Foundation; NQ by FCT (Portugal); MMCM by a CAPES fellowship (Ministry of Education)

Posterior fossa tumours in childhood: Associated speech and language disorders post-surgery

Six children aged between 6 and 16 years who had undergone surgery for the removal of a posterior fossa tumour were assessed at least one year postoperatively to determine the incidence and severity of any associated speech or language deficits. Five males and one female were included in the sample. The subjects were administered a battery of speech/language assessments including: a language screening test, an articulation test, a dysarthria assessment and a perceptual speech analysis. The results indicated that dysarthria and/or language impairment occurs in some cases subsequent to surgical removal of posterior fossa tumours. The occurrence of muteness immediately post-surgery would appear to indicate a poor prognosis for speech abilities. A possible link between the occurrence of long term language disabilities in these children and post-surgical radiotherapy is documented