Investigation of hippocampal synaptic transmission and plasticity in mice deficient in the actin-binding protein Drebrin

The dynamic regulation of the actin cytoskeleton plays a key role in controlling the structure and function of synapses. It is vital for activity-dependent modulation of synaptic transmission and long-term changes in synaptic morphology associated with memory consolidation. Several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilising protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Given that a decrease in DBN levels is correlated with cognitive deficits associated with ageing and dementia, it was hypothesised that DBN protein abundance instructs the integrity and function of synapses. We created a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. Electrophysiological recordings in acute hippocampal slices and primary hippocampal neuronal cultures showed that basal synaptic transmission, and both long-term and homeostatic synaptic plasticity were unchanged, suggesting that loss of DBN is not sufficient in inducing synapse dysfunction. We propose that the overall lack of changes in synaptic function and plasticity in DBN deficient mice may indicate robust compensatory mechanisms that safeguard cytoskeleton dynamics at the synapse

Phosphorylation of the actin binding protein Drebrin at S647 and is regulated by neuronal activity and PTEN

Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse

National trends in pectus excavatum repair: patient age, facility volume, and outcomes

Background: There is limited data on the adult repair of pectus excavatum (PE). Existing literature is largely limited to single institution experiences and suggests that adults undergoing modified Nuss repair may have worse outcomes than pediatric and adolescent patients. Using a representative national database, this analysis is the first to describe trends in demographics, outcomes, charges, and facility volume for adults undergoing modified Nuss procedure. Methods: Because of a coding change associated with ICD-10, a retrospective cohort analysis using the National Inpatient Sample (NIS) for patients 12 or older undergoing modified Nuss repair between 2016-2018 was possible. Pearson\u27s χ2 and Student\u27s t-tests were utilized to compare patient, clinical, and hospital characteristics. Complications were sub-classified into major and minor categories. Facilities performing greater than the mean number of operations were categorized as high-volume. Results: Of 360 patients, 79.2% were male. There was near gender parity for patients over 30 undergoing repair (55.2% male, 44.8% female). In all age cohorts, patients were predominantly Caucasian. Rates of any postoperative complication differed by age (12-17 years: 30.6%; 18-29 years: 45.2%; 30+ years: 62.1%; P\u3c0.01); older patients had higher rates of all but two subclasses of complication. Age over 30 was associated with higher charges (12-17 years: $57,312; 18-29 years:$57,001; 30+ years: $67,014; P\u3c0.01). High-volume centers operate on older patients, had shorter lengths of stay, and comparable charges to low-volume centers. Conclusions: Women comprise nearly half of patients undergoing modified Nuss repair after 30 years of age. There are significant differences in complication rates and charges when comparing patients by age. Patients undergoing repair at high-volume facilities benefitted from shorter lengths of stay

Impaired viral infection and reduced mortality of diatoms in iron-limited oceanic regions

Diatom primary productivity is tightly coupled with carbon export through the ballasted nature of the silica-based cell wall, linking the oceanic silicon and carbon cycles. However, despite low productivity, iron (Fe)-limited regimes are considered ‘hot spots’ of diatom silica burial with enhanced carbon export efficiency, raising questions about the mechanisms driving the biogeochemistry of these regions. Marine viruses are classically recognized as catalysts of remineralization through host lysis, short-circuiting the trophic transfer of carbon and facilitating the retention of dissolved organic matter and associated elements in the surface ocean. Here we used metatranscriptomic analysis of diatoms and associated viruses, along with a suite of physiological and geochemical metrics, to study the interaction between diatoms and viruses in Fe-limited regimes of the northeast Pacific. We found low cell-associated diatom virus diversity and abundance in a chronically Fe-limited region of the subarctic northeast Pacific. In a coastal upwelling region of the California Current, transient iron limitation also substantially reduced viral replication. These observations were recapitulated in Fe-limited cultures of the bloom-forming, centric diatom, Chaetoceros tenuissimus, which exhibited delayed virus-mediated mortality in addition to reduced viral replication. We suggest Fe-limited diatoms escape viral lysis and subsequent remineralization in the surface ocean, providing an additional mechanism contributing to enhanced carbon export efficiency and silica burial in Fe-limited oceanic regimes

The Association Between Robotic Lung Cancer Resection and Esophagectomy Outcomes: A Facility-Level Analysis

Background: Within the field of robotic thoracic surgery, the association between facility surgical volume, conversion rates, and patient outcomes across multiple procedures has not been explored. This study aims to examine the potential association between robotic lung cancer resection surgical volume and conversion rates for robotic-assisted minimally invasive esophagectomy (RAMIE). Methods: A retrospective analysis of the National Cancer Database, between the years 2010–2018 was conducted. Facility-years were categorized into one of four groups based on a combination of robotic lung cancer resection surgical volume and RAMIE volumes. Cutoffs were based on previously identified surgical volume thresholds. Results: A total of 16,178 patients received robotic lung cancer resections within the included facility-years. The median age was 68 years [interquartile range (IQR): 62–74 years]. A total of 2,153 patients received RAMIEs within the included facility-years. The median age was 65 years (IQR, 58–71 years). RAMIE conversion rate was highest at facilities with high RAMIE and low robotic lung cancer resection volumes and lowest at facilities with high lung cancer resection and RAMIE volume [18 (9.0%) vs. 10 (1.8%); P\u3c0.001]. Higher 30-& 90-day mortality rates were seen among patients who required conversion during robotic lung cancer resection (30-day: 5.8% vs. 1.1%, P\u3c0.001; 90-day: 9.1% vs. 2.1%, P\u3c0.001). Conclusions: Conversion from robotic to open esophagectomy occurs more frequently at centers performing a low volume of robotic lung resections. This finding may imply that robotic operative experience might be transferable between procedures

Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients

A Pipeline Strategy for Grain Crop Domestication

In the interest of diversifying the global food system, improving human nutrition, and making agriculture more sustainable, there have been many proposals to domesticate wild plants or complete the domestication of semidomesticated orphan crops. However, very few new crops have recently been fully domesticated. Many wild plants have traits limiting their production or consumption that could be costly and slow to change. Others may have fortuitous preadaptations that make them easier to develop or feasible as high-value, albeit low-yielding, crops. To increase success in contemporary domestication of new crops, we propose a pipeline approach, with attrition expected as species advance through the pipeline. We list criteria for ranking domestication candidates to help enrich the starting pool with more preadapted, promising species. We also discuss strategies for prioritizing initial research efforts once the candidates have been selected: developing higher value products and services from the crop, increasing yield potential, and focusing on overcoming undesirable traits. Finally, we present new-crop case studies that demonstrate that wild species’ limitations and potential (in agronomic culture, shattering, seed size, harvest, cleaning, hybridization, etc.) are often only revealed during the early phases of domestication. When nearly insurmountable barriers were reached in some species, they have been (at least temporarily) eliminated from the pipeline. Conversely, a few species have moved quickly through the pipeline as hurdles, such as low seed weight or low seed number per head, were rapidly overcome, leading to increased confidence, farmer collaboration, and program expansion.Fil: DeHaan, Lee R.. The Land Institute; Estados UnidosFil: Van Tassel, David L.. The Land Institute; Estados UnidosFil: Anderson, James A.. University of Minnesota; Estados UnidosFil: Asselin, Sean R.. University of Manitoba; CanadáFil: Barnes, Richard. University of Minnesota; Estados UnidosFil: Baute, Gregory J.. University of British Columbia; CanadáFil: Cattani, Douglas J.. University of Manitoba; CanadáFil: Culman, Steve W.. Ohio State University; Estados UnidosFil: Dorn, Kevin M.. University of Minnesota; Estados UnidosFil: Hulke, Brent S.. United States Department of Agriculture. Agriculture Research Service; Estados UnidosFil: Kantar, Michael. University of British Columbia; CanadáFil: Larson, Steve. Forage and Range Research Laboratory; Estados UnidosFil: David Marks, M.. University of Minnesota; Estados UnidosFil: Miller, Allison J.. Saint Louis University; Estados UnidosFil: Poland, Jesse. Kansas State University; Estados UnidosFil: Ravetta, Damián Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Museo Paleontológico Egidio Feruglio; ArgentinaFil: Rude, Emily. University of Wisconsin; Estados UnidosFil: Ryan, Matthew R.. Cornell University; Estados UnidosFil: Wyse, Don. University of Minnesota; Estados UnidosFil: Zhang, Xiaofei. University of Minnesota; Estados Unido

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)

New WAVEs in neuronal PI3K signalling

NYAPs or ‘Neuronal tYrosine-phosphorylated Adaptor for the PI3K' are novel regulators of PI3K signalling in neurons. NYAPs link PI3K to the WAVE1 complex to regulate neuronal morphology