Müller glia activation in response to inherited retinal degeneration is highly varied and disease-specific

Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Δ307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Δ307, but decreased in the Prph2+/Δ307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent

Protective role of Cadherin 13 in interneuron development

Cortical interneurons are generated in the ganglionic eminences and migrate through the ventral and dorsal telencephalon before finding their final positions within the cortical plate. During early stages of migration, these cells are present in two well-defined streams within the developing cortex. In an attempt to identify candidate genes which may play a role in interneuron stream specification, we previously carried out a microarray analysis which identified a number of cadherin receptors that were differentially expressed in these streams, including Cadherin-13 (Cdh13). Expression analysis confirmed Cdh13 to be present in the preplate layer at E13.5 and, later in development, in some cortical interneurons and pyramidal cells. Analysis of Cdh13 knockout mice at E18.5, but not at E15.5, showed a reduction in the number of interneurons and late born pyramidal neurons and a concomitant increase in apoptotic cells in the cortex. These observations were confirmed in dissociated cell cultures using overexpression and short interfering RNAs (siRNAs) constructs and dominant negative inhibitory proteins. Our findings identified a novel protective role for Cdh13 in cortical neuron development

Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo

Whether neurons can restore their original connectivity patterns during circuit repair is unclear. Taking advantage of the regenerative capacity of zebrafish retina, we show here the remarkable specificity by which surviving neurons reassemble their connectivity upon regeneration of their major input. H3 horizontal cells (HCs) normally avoid red and green cones, and prefer ultraviolet over blue cones. Upon ablation of the major (ultraviolet) input, H3 HCs do not immediately increase connectivity with other cone types. Instead, H3 dendrites retract and re-extend to contact new ultraviolet cones. But, if regeneration is delayed or absent, blue-cone synaptogenesis increases and ectopic synapses are made with red and green cones. Thus, cues directing synapse specificity can be maintained following input loss, but only within a limited time period. Further, we postulate that signals from the major input that shape the H3 HC's wiring pattern during development persist to restrict miswiring after damage

The role of parental achievement goals in predicting autonomy-supportive and controlling parenting

Although autonomy-supportive and controlling parenting are linked to numerous positive and negative child outcomes respectively, fewer studies have focused on their determinants. Drawing on achievement goal theory and self-determination theory, we propose that parental achievement goals (i.e., achievement goals that parents have for their children) can be mastery, performance-approach or performance-avoidance oriented and that types of goals predict mothers' tendency to adopt autonomy-supportive and controlling behaviors. A total of 67 mothers (aged 30-53 years) reported their goals for their adolescent (aged 13-16 years; 19.4 % girls), while their adolescent evaluated their mothers' behaviors. Hierarchical regression analyses showed that parental performance-approach goals predict more controlling parenting and prevent acknowledgement of feelings, one autonomy-supportive behavior. In addition, mothers who have mastery goals and who endorse performance-avoidance goals are less likely to use guilt-inducing criticisms. These findings were observed while controlling for the effect of maternal anxiety

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

CenTime: Event-conditional modelling of censoring in survival analysis

Survival analysis is a valuable tool for estimating the time until specific events, such as death or cancer recurrence, based on baseline observations. This is particularly useful in healthcare to prognostically predict clinically important events based on patient data. However, existing approaches often have limitations; some focus only on ranking patients by survivability, neglecting to estimate the actual event time, while others treat the problem as a classification task, ignoring the inherent time-ordered structure of the events. Additionally, the effective utilisation of censored samples−data points where the event time is unknown− is essential for enhancing the model's predictive accuracy. In this paper, we introduce CenTime, a novel approach to survival analysis that directly estimates the time to event. Our method features an innovative event-conditional censoring mechanism that performs robustly even when uncensored data is scarce. We demonstrate that our approach forms a consistent estimator for the event model parameters, even in the absence of uncensored data. Furthermore, CenTime is easily integrated with deep learning models with no restrictions on batch size or the number of uncensored samples. We compare our approach to standard survival analysis methods, including the Cox proportional-hazard model and DeepHit. Our results indicate that CenTime offers state-of-the-art performance in predicting time-to-death while maintaining comparable ranking performance. Our implementation is publicly available at https://github.com/ahmedhshahin/CenTime

Neural Network Based Methods for the Survival Analysis of Idiopathic Pulmonary Fibrosis Patients from a Baseline CT Acquisition

Idiopathic pulmonary fibrosis is an interstitial lung disease that causes scarring of the lungs, leading to a decline in lung function and eventually death. Because this disease has a heterogeneous disease progression, predictive models could guide clinicians in making decisions about disease management. Some survival analysis methods, such as Cox, seek to rank participants based on their predicted survivability. However, Cox cannot directly output a survival time. DeepHit is a neural network based survival analysis method which predicts the most likely histogram bin of survival time. A disadvantage of DeepHit is that, when training, an error of one year is equivalent to an error of one hundred years. A common problem encountered is that training data is often censored, where the exact time of death is unknown except that it is past a censoring time. Here, a comparison of neural network approaches utilising five different losses is presented. Compared are; ranking based approaches (such as Cox or Cox with a memory bank of previous predictions) and death distribution based approaches (such as DeepHit and likelihood with a uniform or Gaussian distribution to sample censoring times). The input to each model is a single computed tomography volume (plus optionally clinical features) and the output is a survival time. Improvements over previous work includes; a larger model with a learned downsampling, a parameterised activation (which starts linear and becomes non-linear), a softplus output, orthogonal initialisation, an optimiser integrating weight decay, gradient accumulation, and an annealed learning rate. Evaluations used include; mean and relative absolute error, the concordance index, the Brier score, and a visual analysis of Grad-CAM results. Overall, the likelihood models performed the best, with DeepHit a close second and both Cox models a distant last. The uniform likelihood model performed marginally better than the alternative

Obesity and pronated foot type may increase the risk of chronic plantar heel pain : a matched case-control study

Background : Chronic plantar heel pain (CPHP) is one of the most common musculoskeletal disorders of the foot, yet its aetiology is poorly understood. The purpose of this study was to examine the association between CPHP and a number of commonly hypothesised causative factors.Methods : Eighty participants with CPHP (33 males, 47 females, mean age 52.3 years, S.D. 11.7) were matched by age (&plusmn; 2 years) and sex to 80 control participants (33 males, 47 females, mean age 51.9 years, S.D. 11.8). The two groups were then compared on body mass index (BMI), foot posture as measured by the Foot Posture Index (FPI), ankle dorsiflexion range of motion (ROM) as measured by the Dorsiflexion Lunge Test, occupational lower limb stress using the Occupational Rating Scale and calf endurance using the Standing Heel Rise Test.Results : Univariate analysis demonstrated that the CPHP group had significantly greater BMI (29.8 &plusmn; 5.4 kg/m2 vs. 27.5 &plusmn; 4.9 kg/m2; P &lt; 0.01), a more pronated foot posture (FPI score 2.4 &plusmn; 3.3 vs. 1.1 &plusmn; 2.3; P &lt; 0.01) and greater ankle dorsiflexion ROM (45.1 &plusmn; 7.1&deg; vs. 40.5 &plusmn; 6.6&deg;; P &lt; 0.01) than the control group. No difference was identified between the groups for calf endurance or time spent sitting, standing, walking on uneven ground, squatting, climbing or lifting. Multivariate logistic regression revealed that those with CPHP were more likely to be obese (BMI &ge; 30 kg/m2) (OR 2.9, 95% CI 1.4 &ndash; 6.1, P &lt; 0.01) and to have a pronated foot posture (FPI &ge; 4) (OR 3.7, 95% CI 1.6 &ndash; 8.7, P &lt; 0.01).Conclusion : Obesity and pronated foot posture are associated with CPHP and may be risk factors for the development of the condition. Decreased ankle dorsiflexion, calf endurance and occupational lower limb stress may not play a role in CPHP.<br /