Early changes in pro-inflammatory cytokine levels in neonates with encephalopathy are associated with remote epilepsy.

BackgroundNeonatal seizures are associated with adverse neurologic sequelae including epilepsy in childhood. Here we aim to determine whether levels of cytokines in neonates with brain injury are associated with acute symptomatic seizures or remote epilepsy.MethodsThis is a cohort study of term newborns with encephalopathy at UCSF between 10/1993 and 1/2000 who had dried blood spots. Maternal, perinatal/postnatal, neuroimaging, and epilepsy variables were abstracted by chart review. Logistic regression was used to compare levels of cytokines with acute seizures and the development of epilepsy.ResultsIn a cohort of 26 newborns with neonatal encephalopathy at risk for hypoxic ischemic encephalopathy with blood spots for analysis, diffuse alterations in both pro- and anti-inflammatory cytokine levels were observed between those with (11/28, 39%) and without acute symptomatic seizures. Seventeen of the 26 (63%) patients had >2 years of follow-up and 4/17 (24%) developed epilepsy. Higher levels of pro-inflammatory cytokines IL-6 and TNF-α within the IL-1β pathway were significantly associated with epilepsy.ConclusionsElevations in pro-inflammatory cytokines in the IL-1β pathway were associated with later onset of epilepsy. Larger cohort studies are needed to confirm the predictive value of these circulating biomarkers

Doctor2Vec: Dynamic Doctor Representation Learning for Clinical Trial Recruitment

Massive electronic health records (EHRs) enable the success of learning accurate patient representations to support various predictive health applications. In contrast, doctor representation was not well studied despite that doctors play pivotal roles in healthcare. How to construct the right doctor representations? How to use doctor representation to solve important health analytic problems? In this work, we study the problem on {\it clinical trial recruitment}, which is about identifying the right doctors to help conduct the trials based on the trial description and patient EHR data of those doctors. We propose doctor2vec which simultaneously learns 1) doctor representations from EHR data and 2) trial representations from the description and categorical information about the trials. In particular, doctor2vec utilizes a dynamic memory network where the doctor's experience with patients are stored in the memory bank and the network will dynamically assign weights based on the trial representation via an attention mechanism. Validated on large real-world trials and EHR data including 2,609 trials, 25K doctors and 430K patients, doctor2vec demonstrated improved performance over the best baseline by up to $8.7\%$ in PR-AUC. We also demonstrated that the doctor2vec embedding can be transferred to benefit data insufficiency settings including trial recruitment in less populated/newly explored country with $13.7\%$ improvement or for rare diseases with $8.1\%$ improvement in PR-AUC.Comment: Accepted by AAAI 202

Controlling the Chiral Inversion Reaction of the Metallopeptide Ni-Asparagine-Cysteine-Cysteine with Dioxygen

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ic301717q.Synthetically generated metallopeptides have the potential to serve a variety of roles in biotechnology applications, but the use of such systems is often hampered by the inability to control secondary reactions. We have previously reported that the NiII complex of the tripeptide LLL-asparagine-cysteine-cysteine, LLL-NiII-NCC, undergoes metal-facilitated chiral inversion to DLD-NiII-NCC, which increases the observed superoxide scavenging activity. However, the mechanism for this process remained unexplored. Electronic absorption and circular dichroism studies of the chiral inversion reaction of NiII-NCC reveal a unique dependence on dioxygen. Specifically, in the absence of dioxygen, the chiral inversion is not observed, even at elevated pH, whereas the addition of O2 initiates this reactivity and concomitantly generates superoxide. Scavenging experiments using acetaldehyde are indicative of the formation of carbanion intermediates, demonstrating that inversion takes place by deprotonation of the alpha carbons of Asn1 and Cys3. Together, these data are consistent with the chiral inversion being dependent on the formation of a NiIII-NCC intermediate from NiII-NCC and O2. The data further suggest that the anionic thiolate and amide ligands in NiII-NCC inhibit Cα–H deprotonation for the NiII oxidation state, leading to a stable complex in the absence of O2. Together, these results offer insights into the factors controlling reactivity in synthetic metallopeptides

A novel tripeptide model of nickel superoxide dismutase

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ic901828m.Nickel superoxide dismutase (Ni-SOD) catalyzes the disproportionation of superoxide to molecular oxygen and hydrogen peroxide, but the overall reaction mechanism has yet to be determined. Peptide-based models of the 2N:2S nickel coordination sphere of Ni-SOD have provided some insight into the mechanism of this enzyme. Here we show that the coordination sphere of Ni-SOD can be mimicked using the tripeptide asparagine-cysteine-cysteine (NCC). NCC binds nickel with extremely high affinity at physiological pH with 2N:2S geometry, as demonstrated by electronic absorption and circular dichroism (CD) data. Like Ni-SOD, Ni-NCC has mixed amine/amide ligation that favors metal-based oxidation over ligand-based oxidation. Electronic absorption, CD, and magnetic CD data (MCD) collected for Ni-NCC are consistent with a diamagnetic Ni(II) center bound in square planar geometry. Ni-NCC is quasi-reversibly oxidized with a midpoint potential of 0.72(2) V (versus Ag/AgCl) and breaks down superoxide in an enzyme-based assay, supporting its potential use as a model for Ni-SOD chemistry

Research and Publishing during COVID-19

This discussion will explore the impact of the COVID-19 pandemic on scholarly research and publishing. Travel restrictions, retracted funding, delayed or halted projects, and an increase in caretaker and other personal responsibilities at home compound to create unprecedented challenges for producing and publishing research. Early indicators show women, those with significant unpaid care responsibilities, and members of minoritized groups have been disproportionately impacted. For graduate students and early career faculty who depend on research and publication for promotion and tenure, the stakes are especially high. Join our panelists for a conversation about the how the COVID-19 pandemic is impacting the research landscape. Watch the video to see the discussion. Click on the download button for a list of readings and resources.https://digitalcommons.usu.edu/inter_inclusion/1001/thumbnail.jp

Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes

Sentra: a database of signal transduction proteins for comparative genome analysis

Sentra (), a database of signal transduction proteins encoded in completely sequenced prokaryotic genomes, has been updated to reflect recent advances in understanding signal transduction events on a whole-genome scale. Sentra consists of two principal components, a manually curated list of signal transduction proteins in 202 completely sequenced prokaryotic genomes and an automatically generated listing of predicted signaling proteins in 235 sequenced genomes that are awaiting manual curation. In addition to two-component histidine kinases and response regulators, the database now lists manually curated Ser/Thr/Tyr protein kinases and protein phosphatases, as well as adenylate and diguanylate cyclases and c-di-GMP phosphodiesterases, as defined in several recent reviews. All entries in Sentra are extensively annotated with relevant information from public databases (e.g. UniProt, KEGG, PDB and NCBI). Sentra's infrastructure was redesigned to support interactive cross-genome comparisons of signal transduction capabilities of prokaryotic organisms from a taxonomic and phenotypic perspective and in the framework of signal transduction pathways from KEGG. Sentra leverages the PUMA2 system to support interactive analysis and annotation of signal transduction proteins by the users

TGF-b2 induction regulates invasiveness of theileria-transformed leukocytes and disease susceptibility

Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva), or tropical theileriosis (T. annulata). Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF) cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK). We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence

Perceived Causes and Solutions to Soil Degradation in the UK and Norway

Soil quality is declining in many parts of the world, with implications for the productivity, resilience and sustainability of agri-food systems. Research suggests multiple causes of soil degradation with no single solution and a divided stakeholder opinion on how to manage this problem. However, creating socially acceptable and effective policies to halt soil degradation requires engagement with a diverse range of stakeholders who possess different and complementary knowledge, experiences and perspectives. To understand how British and Norwegian agricultural stakeholders perceived the causes of and solutions to soil degradation, we used Q-methodology with 114 respondents, including farmers, scientists and agricultural advisers. For the UK, respondents thought the causes were due to loss of soil structure, soil erosion, compaction and loss of organic matter; the perceived solutions were to develop more collaborative research between researchers and farmers, invest in training, improve trust between farmers and regulatory agencies, and reduce soil compaction. In Norway, respondents thought soils were degrading due to soil erosion, monocultures and loss of soil structure; they believed the solutions were to reduce compaction, increase rotation and invest in agricultural training. There was an overarching theme related to industrialised agriculture being responsible for declining soil quality in both countries. We highlight potential areas for land use policy development in Norway and the UK, including multi-actor approaches that may improve the social acceptance of these policies. This study also illustrates how Q-methodology may be used to co-produce stakeholder-driven policy options to address land degradation