A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development.

EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, given that EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knock-in mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly and specifically blocked. We found that the tyrosine kinase activity of EphBs was required for axon guidance in vivo. In contrast, EphB-mediated synaptogenesis occurred normally when the kinase activity of EphBs was inhibited, suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, our data indicate that EphBs control axon guidance and synaptogenesis by distinct mechanisms and provide a new mouse model for dissecting EphB function in development and disease

Scaling predictions for radii of weakly bound triatomic molecules

The mean-square radii of the molecules $^4$He$_3$, $^4$He$_2-^6$Li, $^4$He$_2-^7$Li and $^4$He$_2-^{23}$Na are calculated using a three-body model with contact interactions. They are obtained from a universal scaling function calculated within a renormalized scheme for three particles interacting through pairwise Dirac-delta interaction. The root-mean-square distance between two atoms of mass $m_A$ in a triatomic molecule are estimated to be of de order of ${\cal C}\sqrt{\hbar^2/[m_A(E_3-E_2)]}$, where $E_2$ is the dimer and $E_3$ the trimer binding energies, and ${\cal C}$ is a constant (varying from $\sim 0.6$ to $\sim 1$) that depends on the ratio between $E_2$ and $E_3$. Considering previous estimates for the trimer energies, we also predict the sizes of Rubidium and Sodium trimers in atomic traps.Comment: 7 pages, 2 figure

A Chemical Genetic Approach Reveals Distinct Mechanisms of EphB Signaling During Brain Development

EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, as EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knockin mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly, and specifically blocked. Using these mice we demonstrate that the tyrosine kinase activity of EphBs is required for axon guidance in vivo. By contrast, EphB-mediated synaptogenesis occurs normally when the kinase activity of EphBs is inhibited suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, these experiments reveal that EphBs control axon guidance and synaptogenesis by distinct mechanisms, and provide a new mouse model for dissecting EphB function in development and disease

Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons

The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 (Slc17a7) and inhibits a GABAergic fate by repressing transcription of Gad1. In addition, we identify the axon guidance receptor EphB1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype–specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity

Secondary Bacterial Pneumonias and Bloodstream Infections in Patients Hospitalized with COVID-19

Group Name: The Emory COVID-19 Quality and Clinical Research Collaborative Background: Patients hospitalized with COVID-19 are at risk of secondary infections—10%–33% develop bacterial pneumonia and 2%–6% develop bloodstream infection (BSI). We conducted a retrospective cohort study to identify the prevalence, microbiology, and outcomes of secondary pneumonias and BSIs in patients hospitalized with COVID-19. Methods: Patients aged ≥18 years with a positive SARS-CoV-2 real-time polymerase chain reaction assay admitted to 4 academic hospitals in Atlanta, Georgia, between February 15 and May 16, 2020, were included. We extracted electronic medical record data through June 16, 2020. Microbiology tests were performed according to standard protocols. Possible ventilator-associated pneumonia (PVAP) was defined according to Centers for Disease Control and Prevention (CDC) criteria. We assessed in-hospital mortality, comparing patients with and without infections using the χ(2) test. SAS University Edition software was used for data analyses. Results: In total, 774 patients were included (median age, 62 years; 49.7% female; 66.6% black). In total, 335 patients (43.3%) required intensive care unit (ICU) admission, 238 (30.7%) required mechanical ventilation, and 120 (15.5%) died. Among 238 intubated patients, 65 (27.3%) had a positive respiratory culture, including 15 with multiple potential pathogens, for a total of 84 potential pathogens. The most common organisms were Staphylococcus aureus (29 of 84; 34.5%), Pseudomonas aeruginosa (16 of 84; 19.0%), and Klebsiella spp (14 of 84; 16.7%). Mortality did not differ between intubated patients with and without a positive respiratory culture (41.5% vs 35.3%; P = .37). Also, 5 patients (2.1%) had a CDC-defined PVAP (1.7 PVAPs per 1,000 ventilator days); none of them died. Among 536 (69.3%) nonintubated patients, 2 (0.4%) had a positive Legionella urine antigen and 1 had a positive respiratory culture (for S. aureus). Of 774 patients, 36 (4.7%) had BSI, including 5 with polymicrobial BSI (42 isolates total). Most BSIs (24 of 36; 66.7%) had ICU onset. The most common organisms were S. aureus (7 of 42; 16.7%), Candida spp (7 of 42; 16.7%), and coagulase-negative staphylococci (5 of 42; 11.9%); 12 (28.6%) were gram-negative. The most common source was central-line–associated BSI (17 of 36; 47.2%), followed by skin (6 of 36; 16.7%), lungs (5 of 36; 13.9%), and urine (4 of 36; 11.1%). Mortality was 50% in patients with BSI versus 13.8% without (p < 0.0001). Conclusions: In a large cohort of patients hospitalized with COVID-19, secondary infections were rare: 2% bacterial pneumonia and 5% BSI. The risk factors for these infections (intubation and central lines, respectively) and causative pathogens reflect healthcare delivery and not a COVID-19–specific effect. Clinicians should adhere to standard best practices for preventing and empirically treating secondary infections in patients hospitalized with COVID-19. Funding: No Disclosures: Non

Racial-Ethnic Disparities in Acute Stroke Care in the Florida-Puerto Rico Collaboration to Reduce Stroke Disparities Study

Background-Racial-ethnic disparities in acute stroke care can contribute to inequality in stroke outcomes. We examined raceethnic disparities in acute stroke performance metrics in a voluntary stroke registry among Florida and Puerto Rico Get With the Guidelines-Stroke hospitals. Methods and Results-Seventy-five sites in the Florida Puerto Rico Stroke Registry (66 Florida and 9 Puerto Rico) recorded 58 864 ischemic stroke cases (2010-2014). Logistic regression models examined racial-ethnic differences in acute stroke performance measures and defect-free care (intravenous tissue plasminogen activator treatment, in-hospital antithrombotic therapy, deep vein thrombosis prophylaxis, discharge antithrombotic therapy, appropriate anticoagulation therapy, statin use, smoking cessation counseling) and temporal trends. Among ischemic stroke cases, 63% were non-Hispanic white (NHW), 18% were non-Hispanic black (NHB), 14% were Hispanic living in Florida, and 6% were Hispanic living in Puerto Rico. NHW patients were the oldest, followed by Hispanics, and NHBs. Defect-free care was greatest among NHBs (81%), followed by NHWs (79%) and Florida Hispanics (79%), then Puerto Rico Hispanics (57%) (P \u3c 0.0001). Puerto Rico Hispanics were less likely than Florida whites to meet any stroke care performance metric other than anticoagulation. Defect-free care improved for all groups during 2010-2014, but the disparity in Puerto Rico persisted (2010: NHWs=63%, NHBs=65%, Florida Hispanics=59%, Puerto Rico Hispanics=31%; 2014: NHWs=93%, NHBs=94%, Florida Hispanics=94%, Puerto Rico Hispanics=63%). Conclusions-Racial-ethnic/geographic disparities were observed for acute stroke care performance metrics. Adoption of a quality improvement program improved stroke care from 2010 to 2014 in Puerto Rico and all Florida racial-ethnic groups. However, stroke care quality delivered in Puerto Rico is lower than in Florida. Sustained support of evidence-based acute stroke quality improvement programs is required to improve stroke care and minimize racial-ethnic disparities, particularly in resource-strained Puerto Rico

Efficient algorithms for reconstructing gene content by co-evolution

<p>Abstract</p> <p>Background</p> <p>In a previous study we demonstrated that co-evolutionary information can be utilized for improving the accuracy of ancestral gene content reconstruction. To this end, we defined a new computational problem, the Ancestral Co-Evolutionary (ACE) problem, and developed algorithms for solving it.</p> <p>Results</p> <p>In the current paper we generalize our previous study in various ways. First, we describe new efficient computational approaches for solving the ACE problem. The new approaches are based on reductions to classical methods such as linear programming relaxation, quadratic programming, and min-cut. Second, we report new computational hardness results related to the ACE, including practical cases where it can be solved in polynomial time.</p> <p>Third, we generalize the ACE problem and demonstrate how our approach can be used for inferring parts of the genomes of <it>non-ancestral</it> organisms. To this end, we describe a heuristic for finding the portion of the genome ('dominant set’) that can be used to reconstruct the rest of the genome with the lowest error rate. This heuristic utilizes both evolutionary information and co-evolutionary information.</p> <p>We implemented these algorithms on a large input of the ACE problem (95 unicellular organisms, 4,873 protein families, and 10, 576 of co-evolutionary relations), demonstrating that some of these algorithms can outperform the algorithm used in our previous study. In addition, we show that based on our approach a ’dominant set’ cab be used reconstruct a major fraction of a genome (up to 79%) with relatively low error-rate (<it>e.g.</it> 0.11). We find that the ’dominant set’ tends to include metabolic and regulatory genes, with high evolutionary rate, and low protein abundance and number of protein-protein interactions.</p> <p>Conclusions</p> <p>The <it>ACE</it> problem can be efficiently extended for inferring the genomes of organisms that exist today. In addition, it may be solved in polynomial time in many practical cases. Metabolic and regulatory genes were found to be the most important groups of genes necessary for reconstructing gene content of an organism based on other related genomes.</p

Adaptive Radiation in Mediterranean Cistus (Cistaceae)

lineage consists of 12 species primarily distributed in Mediterranean habitats and is herein subject to analysis. lineages), which display asymmetric characteristics: number of species (2 vs. 10), leaf morphologies (linear vs. linear to ovate), floral characteristics (small, three-sepalled vs. small to large, three- or five-sepalled flowers) and ecological attributes (low-land vs. low-land to mountain environments). A positive phenotype-environment correlation has been detected by historical reconstructions of morphological traits (leaf shape, leaf labdanum content and leaf pubescence). Ecological evidence indicates that modifications of leaf shape and size, coupled with differences in labdanum secretion and pubescence density, appear to be related to success of new species in different Mediterranean habitats.

Troponin Is Unrelated to Outcomes in Heart Failure Patients Discharged From the Emergency Department

Background: Prior data has demonstrated increased mortality in hospitalized patients with acute heart failure (AHF) and troponin elevation. No data has specifically examined the prognostic significance of troponin elevation in patients with AHF discharged after emergency department (ED) management. Objective: Evaluate the relationship between troponin elevation and outcomes in patients with AHF who are treated and released from the ED. Methods: This was a secondary analysis of the Get with the Guidelines to Reduce Disparities in AHF Patients Discharged from the ED (GUIDED-HF) trial, a randomized, controlled trial of ED patients with AHF who were discharged. Patients with elevated conventional troponin not due to acute coronary syndrome (ACS) were included. Our primary outcome was a composite endpoint: time to 30-day cardiovascular death and/or heart failure-related events. Results: Of the 491 subjects included in the GUIDED-HF trial, 418 had troponin measured during the ED evaluation and 66 (16%) had troponin values above the 99th percentile. Median age was 63 years (interquartile range, 54-70), 62% (n = 261) were male, 63% (n = 265) were Black, and 16% (n = 67) experienced our primary outcome. There were no differences in our primary outcome between those with and without troponin elevation (12/66, 18.1% vs 55/352, 15.6%; P = 0.60). This effect was maintained regardless of assignment to usual care or the intervention arm. In multivariable regression analysis, there was no association between our primary outcome and elevated troponin (hazard ratio, 1.00; 95% confidence interval, 0.49-2.01, P = 0.994). Conclusion: If confirmed in a larger cohort, these findings may facilitate safe ED discharge for a group of patients with AHF without ACS when an elevated troponin is the primary reason for admission

Silver Microparticle and Submicron Wire - Polylactic Acid Composites for Additive Manufacturing

This thesis explores the incorporation of silver microparticle and submicron wire additives into thermoplastic filament feedstock for fused filament fabrication (FFF) to create multifunctional three-dimensional (3D) printable composites. The impact of silver microparticle and submicron wire additives on mechanical behavior along with antibacterial effect of the silver microparticle and submicron wire additives on printed objects were assessed. Composite FFF filaments were fabricated by solution processing, granulation, and extrusion. Differential Scanning Calorimetry (DSC) was conducted to measure the glass transition and melting point temperatures of the composite filaments for 3D printing. The effect of the additive addition on the thermal properties and tensile mechanical performance was measured. Scanning Electron Microscopy (SEM) was used to analyze the composite microstructure and fracture behavior. The reduction in the growth of Escherichia coli (E. coli) was measured after exposure to FFF-printed composite test specimens with additive concentrations ranging from 0.0 to 10.0 weight percent