Inositol pentakisphosphate isomers bind PH domains with varying specificity and inhibit phosphoinositide interactions

<p>Abstract</p> <p>Background</p> <p>PH domains represent one of the most common domains in the human proteome. These domains are recognized as important mediators of protein-phosphoinositide and protein-protein interactions. Phosphoinositides are lipid components of the membrane that function as signaling molecules by targeting proteins to their sites of action. Phosphoinositide based signaling pathways govern a diverse range of important cellular processes including membrane remodeling, differentiation, proliferation and survival. <it>Myo-</it>Inositol phosphates are soluble signaling molecules that are structurally similar to the head groups of phosphoinositides. These molecules have been proposed to function, at least in part, by regulating PH domain-phosphoinositide interactions. Given the structural similarity of inositol phosphates we were interested in examining the specificity of PH domains towards the family of <it>myo-</it>inositol pentakisphosphate isomers.</p> <p>Results</p> <p>In work reported here we demonstrate that the C-terminal PH domain of pleckstrin possesses the specificity required to discriminate between different <it>myo-</it>inositol pentakisphosphate isomers. The structural basis for this specificity was determined using high-resolution crystal structures. Moreover, we show that while the PH domain of Grp1 does not possess this high degree of specificity, the PH domain of protein kinase B does.</p> <p>Conclusions</p> <p>These results demonstrate that some PH domains possess enough specificity to discriminate between myo-inositol pentakisphosphate isomers allowing for these molecules to differentially regulate interactions with phosphoinositides. Furthermore, this work contributes to the growing body of evidence supporting <it>myo</it>-inositol phosphates as regulators of important PH domain-phosphoinositide interactions. Finally, in addition to expanding our knowledge of cellular signaling, these results provide a basis for developing tools to probe biological pathways.</p

Significance of high sensitivity C-reactive protein and D-dimer in evaluating intracardiac thrombus and spontaneous echo contrast in patients referred for transesophageal echocardiography: A prospective study

Background: Intra-cardiac thrombus (ICT) and spontaneous echo contrast (SEC) are considered hypercoagulable and inflammatory conditions. We aimed to determine if high sensitivity C-reactive protein (CRP) and D-dimer (DD), in combination with variables of lower thrombotic risk (normal ejection fraction [NEF], sinus rhythm [NSR]), may predict the absence of ICT/SEC. Methods and Results: Consecutive patients referred for transesophageal echocardiogram (TEE) for evaluation of cardioembolic source were prospectively enrolled. CRP and DD levels were determined at the time of TEE. 124 patients were enrolled, of whom 21 had ICT/SEC. The combination of NSR/NEF had a negative predictive value (NPV) of 98.6% for absence of ICT/SEC. The NPVs of CRP and DD were 93.6% and 85%, respectively. Adding either CRP or DD to NSR/NEF combination increased the NPV to 100%. Log CRP was significantly associated with ICT/SEC. Conclusions: The presence of NSR and NEF may defer the need for TEE for ICT/SEC evaluation. CRP association with ICT/SEC suggests that inflammation plays a role in ICT/SEC formation. Whether CRP and DD should become routine in the triage process of TEE for ICT/SEC evaluation requires further large scale prospective studies

Impact of urban expansion on potential flooding, storage and water harvesting in the city of Sharjah, United Arab Emirates

The work presented in this article is an extension of an earlier study [1] in which runoff in the city of Sharjah, United Arab Emirates (UAE), was assessed for the period 1967–2010. In this study, the impacts of urban expansion on potential flooding, storage and water harvesting were assessed for the period 1976–2016 using rainfall data recorded during the same period. Sharjah is a generally a flat coastal city that is located in a dry hot region average rainfall of approximately 100 mm/y. Remote sensing and GIS techniques were used to assess the expansion of built areas in the city using multi-temporal Landsat satellite images. The built areas in the city increased during the study period by approximately four folds while the population increased by more than 10 folds. The study results demonstrate the historical increase in runoff potential, flooding potential and runoff coefficient and decline in water storage potential. The results are consistent with the observed incidence of significant local flooding episodes in urban areas during rainfall events. Furthermore, an assessment of potential urban water harvesting based on expansion of built areas in the city is provided and appropriate urban storm water management practices for the city are recommended

School-Based Intervention in Ongoing Crisis: Lessons from a Psychosocial and Trauma-Focused Approach in Gaza Schools

It is a complex challenge to design education in emergencies responses that meet local needs, are sensitive to local culture, build on international guidelines for best practice, and use research-based methods. This paper presents lessons learned from the implementation of the Better Learning Program, a school-based response in Gaza that combined psychosocial and trauma-focused approaches, and discusses how international guidelines were incorporated. The Better Learning Program intervention was designed as a partially manualized, multi-level approach to help teachers, school counselors, and parents empower schoolchildren with strategies for calming and self-regulation. The stepwise approach first targeted all pupils, then pupils who reported having nightmares and sleep disturbances. The goal was to help these students regain lost learning capacity and strengthen resilience within the school community. The intervention was implemented in 40 schools over two and a half years, with a target group of 35,000 pupils. Teachers and school counselors reported that the combined psychosocial and trauma-focused approach was compatible with their educational perspectives. The approach appeared to enable teachers to be more proactive when teaching pupils affected by war. This paper concludes with reflections and lessons learned

Solving 1d plasmas and 2d boundary problems using Jack polynomials and functional relations

The general one-dimensional ``log-sine'' gas is defined by restricting the positive and negative charges of a two-dimensional Coulomb gas to live on a circle. Depending on charge constraints, this problem is equivalent to different boundary field theories. We study the electrically neutral case, which is equivalent to a two-dimensional free boson with an impurity cosine potential. We use two different methods: a perturbative one based on Jack symmetric functions, and a non-perturbative one based on the thermodynamic Bethe ansatz and functional relations. The first method allows us to compute explicitly all coefficients in the virial expansion of the free energy and the experimentally-measurable conductance. Some results for correlation functions are also presented. The second method provides in particular a surprising fluctuation-dissipation relation between the free energy and the conductance.Comment: 19 page

Concussion-related disruptions to hub connectivity in the default mode network are related to symptoms and cognition

Concussions present with a myriad of symptomatic and cognitive concerns; however, the relationship between these functional disruptions and the underlying changes in the brain are not yet well understood. Hubs, or brain regions that are connected to many different functional networks, may be specifically disrupted after concussion. Given the implications in concussion research, we quantified hub disruption within the default mode network (DMN) and between the DMN and other brain networks. We collected resting-state functional magnetic resonance imaging data from collegiate student-athletes (n = 44) at three timepoints: baseline (prior to beginning their athletic season), acute post-injury (approximately 48 hours after a diagnosed concussion), and recovery (after starting return-to-play progression, but prior to returning to contact). We used self-reported symptoms and computerized cognitive assessments collected across similar timepoints to link these functional connectivity changes to clinical outcomes. Concussion resulted in increased connectivity between regions within the DMN compared to baseline and recovery, and this post-injury connectivity was more positively related to symptoms and more negatively related to visual memory performance compared to baseline and recovery. Further, concussion led to decreased connectivity between DMN hubs and visual network non-hubs relative to baseline and recovery, and this post-injury connectivity was more negatively related to somatic symptoms and more positively related to visual memory performance compared to baseline and recovery. Relationships between functional connectivity, symptoms, and cognition were not significantly different at baseline versus recovery. These results highlight a unique relationship between self-reported symptoms, visual memory performance and acute functional connectivity changes involving DMN hubs after concussion in athletes. This may provide evidence for a disrupted balance of within- and between-network communication highlighting possible network inefficiencies after concussion. These results aid in our understanding of the pathophysiological disruptions after concussion and inform our understanding of the associations between disruptions in brain connectivity and specific clinical presentations acutely post-injury

Time-delayed model of immune response in plants

In the studies of plant infections, the plant immune response is known to play an essential role. In this paper we derive and analyse a new mathematical model of plant immune response with particular account for post-transcriptional gene silencing (PTGS). Besides biologically accurate representation of the PTGS dynamics, the model explicitly includes two time delays to represent the maturation time of the growing plant tissue and the non-instantaneous nature of the PTGS. Through analytical and numerical analysis of stability of the steady states of the model we identify parameter regions associated with recovery and resistant phenotypes, as well as possible chronic infections. Dynamics of the system in these regimes is illustrated by numerical simulations of the model