Explore the vast range of titles available.

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases 1 – 3 . Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin 4 – 6 , which regulate aspects of social behaviour in mammals 7 . However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3 -knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3 , regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions. An autism-associated mutation in Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and altered social behavioural responses in mice, and treatment with an inhibitor of MAP kinase-interacting kinases rescues these phenotypes.

\"Our goal in this book is to describe the instruction that children need to help them transition from learning from their own experiences to learning from text and from developing listening comprehension to reading comprehension. We provide descriptions of research-validated practices that can be implemented in preschool to grade 2 classrooms so that children improve their comprehension and can articulate their understanding in both oral and written formats. Additionally, this book provides recommendations to help teachers support emergent bilinguals (children who know one language at home, but who are acquiring English at school, often called English learners), dialect speakers, and children from diverse cultural and linguistic backgrounds. We also focus on children who require something extra to overcome meaning-making hurdles\"-- Provided by publisher.

Cortical mapping: dendrites run deep Dendrites enhance the computational power of neurons by active processing of synaptic inputs but their activity, particularly in cortex, has been hard to measure. Matthew Larkum and colleagues now use a new fibre-optic method to record dendritic calcium signals in freely moving animals. They show that the strength of a sensory stimulus — a puff or air on a mouse hind leg — is gradually encoded in somatosensory cortex neurons' dendrites, under the control of local inhibitory circuitry. The findings illustrate that the representation of sensory stimuli by cortical neurons cannot be fully described by traditional integrate-and-fire models. This study uses a new fibre-optic method to record dendritic calcium signals in freely moving animals. The strength of a sensory stimulus is gradually encoded in somatosensory cortex neurons' dendrites, under the control of local inhibitory circuitry. The findings illustrate that the representation of sensory stimuli by cortical neurons cannot be fully described by traditional integrate-and-fire models. The computational power of single neurons is greatly enhanced by active dendritic conductances 1 that have a large influence on their spike activity 2 , 3 , 4 . In cortical output neurons such as the large pyramidal cells of layer 5 (L5), activation of apical dendritic calcium channels leads to plateau potentials that increase the gain of the input/output function 5 and switch the cell to burst-firing mode 6 , 7 , 8 , 9 . The apical dendrites are innervated by local excitatory and inhibitory inputs as well as thalamic 10 , 11 , 12 , 13 and corticocortical projections 14 , 15 , 16 , which makes it a formidable task to predict how these inputs influence active dendritic properties in vivo . Here we investigate activity in populations of L5 pyramidal dendrites of the somatosensory cortex in awake and anaesthetized rats following sensory stimulation using a new fibre-optic method 17 for recording dendritic calcium changes. We show that the strength of sensory stimulation is encoded in the combined dendritic calcium response of a local population of L5 pyramidal cells in a graded manner. The slope of the stimulus–response function was under the control of a particular subset of inhibitory neurons activated by synaptic inputs predominantly in L5. Recordings from single apical tuft dendrites in vitro showed that activity in L5 pyramidal neurons disynaptically coupled via interneurons directly blocks the initiation of dendritic calcium spikes in neighbouring pyramidal neurons. The results constitute a functional description of a cortical microcircuit in awake animals that relies on the active properties of L5 pyramidal dendrites and their very high sensitivity to inhibition. The microcircuit is organized so that local populations of apical dendrites can adaptively encode bottom-up sensory stimuli linearly across their full dynamic range.

To analyze whether there is improvement in adherence to inhaled treatment in patients with COPD and asthma after an educational intervention based on the teach-to-goal method. This is a prospective, non-randomized, single-group study, with intervention and before-after evaluation. The study population included 120 patients (67 females and 53 males) diagnosed with asthma (70.8%) and COPD (29.1%). The level of adherence (low and optimal) and the noncompliance behavior pattern (erratic, deliberate and unwitting) were determined by the Test of the adherence to Inhalers (TAI). This questionnaire allows you to determine the level of adherence and the types of noncompliance. Low Adherence (LowAd) was defined as a score less than 49 points. All patients received individualized educational inhaler technique intervention (IEITI). Before the IEITI, 67.5% of the patients had LowAd. Following IEITI, on week 24, LowAd was 55% (p = 0.024). Each patient can present one or more types of noncompliance. The most frequent type was forgetting to use the inhaler (erratic), 65.8%. The other types were deliberate: 43.3%, and unwitting: 57.5%. All of them had decreased on the final visit: 51.7% (p = 0.009), 25.8% (p = 0.002), 39.2% (p = 0.002). There were no significant differences in adherence between asthma and COPD patients at the start of the study. The only predicting factor of LowAd was the female gender. An individualized educational intervention, in ambulatory patients with COPD and asthma, in real-world clinical practice conditions, improves adherence to the inhaled treatment.

GABA B receptors are the most abundant inhibitory G protein–coupled receptors in the mammalian brain. Using high-resolution proteomics, the authors show that native GABA B receptors are macromolecular complexes with previously unknown complexity in subunit composition. This molecular diversity in structure and assembly encodes the diversity of GABA B physiology in the CNS. GABA B receptors, the most abundant inhibitory G protein–coupled receptors in the mammalian brain, display pronounced diversity in functional properties, cellular signaling and subcellular distribution. We used high-resolution functional proteomics to identify the building blocks of these receptors in the rodent brain. Our analyses revealed that native GABA B receptors are macromolecular complexes with defined architecture, but marked diversity in subunit composition: the receptor core is assembled from GABA B1a/b , GABA B2 , four KCTD proteins and a distinct set of G-protein subunits, whereas the receptor's periphery is mostly formed by transmembrane proteins of different classes. In particular, the periphery-forming constituents include signaling effectors, such as Cav2 and HCN channels, and the proteins AJAP1 and amyloid-β A4, both of which tightly associate with the sushi domains of GABA B1a . Our results unravel the molecular diversity of GABA B receptors and their postnatal assembly dynamics and provide a roadmap for studying the cellular signaling of this inhibitory neurotransmitter receptor.

We present the description of defensive behavior in wild Octopus vulgaris against conger eel (Conger conger) attacks based on three video sequences recorded by recreational SCUBA divers in the eastern Atlantic off the coast of Galicia (NW Spain) and in the Cantabrian Sea (NW Spain). These records document common traits in defensive behavior: (1) the octopuses enveloped the conger eel's head to obscure its view; (2) they covered the eel's gills in an attempt to suffocate it; (3) they released ink; (4) the octopuses lost some appendages because of the fight. In the third video, the octopus did not exhibit the defensive behavior described in the first two videos due to an inability to utilize its arms in defense, and the conger eel's success in capturing octopuses is discussed. Additionally, both the cost that the octopus could face by losing some arms during the fight and whether the experience it acquires can be an advantage for future encounters are analyzed. The defensive behavior exhibited by octopuses in this study highlights their ability to survive in a hostile environment and serves as an example of the extensive repertoire of anti‐predator strategies employed by these cephalopods. The first description of defensive behavior in wild Octopus vulgaris against conger eel attacks is presented from three observations made in the Atlantic Coast of Galicia (NW Spain) and Cantabrian Sea (NW Spain), which were filmed by scuba divers. The defensive behavior shown by octopuses in this work can help to understand the evolution of anti‐predator strategies in cephalopods.

In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.).

Introduction/BackgroundCervical cancer is a global public health problem. It causes significant morbidity and mortality, with more than 500,000 new cases and more than 300,000 deaths per year worldwide. In Tunisia, we do not have enough published data, so the epidemiological profile of this pathology is not well known. The objective of this work was to determine the epidemiological profile of cervical cancer in Tunisia and to specify the cost of treating the disease in order to develop an effective prevention strategy.MethodologyThis was a retrospective descriptive, multi-centric study conducted in 6 obstetrical gynecology departments over a four-year period from January 1, 2016 to December 31, 2019.ResultsThe number of all-stage cervical cancer cases in the different centers was 665 cases over a four-year period; which is equivalent to 166 cases/year. The average age of our patients was 53.5 years. Cervico-vaginal smear screening was performed in only 17.9% of cases. The average consultation time in the study population was 5.6 months. Tumors were classified according to the FIGO 2009 c: 23.5% were diagnosed at an early stage (

Journal Article

Share this book

Add to My Shelf