cssi/SciSciGPT-SciSciNet huggingface dataset:
Predictive scoring model of mortality in Gram-negative bloodstream infection

Abstract Mortality is a well-recognized complication of Gram-negative bloodstream infection (BSI). The aim of this study was to develop a model to predict mortality in patients with Gram-negative BSI by using the Pitt bacteraemia score (PBS) and other clinical and laboratory variables. A cohort of 683 unique adult patients who were followed for at least 28 days after admission to Mayo Clinic Hospitals with Gram-negative BSI from 1 January 2001 to 31 October 2006 and who received clinically predefined appropriate empirical antimicrobial therapy was retrospectively identified. Multivariable logistic regression was used to identify independent risk factors for 28-day all-cause mortality. Regression coefficients from a multivariable model were used to develop a risk score to predict mortality following Gram-negative BSI. Malignancy (OR 3.48, 95% CI 1.94–6.22), liver cirrhosis (OR 5.42, 95% CI 2.52–11.65), source of BSI other than urinary tract or central venous catheter infection (OR 5.54, 95% CI 2.42–12.69), and PBS (OR 1.98, 95% CI 0.92–4.25 for PBS of 2–3 and OR 6.42, 95% CI 3.11–13.24 for PBS ≥ 4) were identified as independent risk factors for 28-day mortality in patients with Gram-negative BSI. A risk-score model was created by adding points for each independent risk factor, and had a c-statistic of 0.84. Patients with risk scores of 0, 4, 8, 12 and 16 had estimated 28-day mortality rates of approximately 0%, 3%, 14%, 45%, and 81%, respectively. The Gram-negative BSI risk score described herein estimated mortality risk with high discrimination in patients with Gram-negative BSI who received clinically adequate empirical antimicrobial therapy.
A numerical characterization of the S2-ification of a Rees algebra

Let A be a local ring with maximal ideal m. For an arbitrary ideal I of A, we define the generalized Hilbert coefficients jk(I)∈Zk+1 (0⩽k⩽dimA). When the ideal I is m-primary, jk(I)=(0,…,0,(−1)kek(I)), where ek(I) is the classical kth Hilbert coefficient of I. Using these coefficients we give a numerical characterization of the homogeneous components of the S2-ification of S=A[It,t−1], extending previous results obtained by the author to not necessarily m-primary ideals.
A Micro-Fabricated Linear Array of Electrospray Emitters for Thruster Applications

This paper reports the design, fabrication, and experimental characterization of an internally fed linear array of electrospray emitters intended for space propulsion applications. The engine uses doped formamide as propellant and operates in the single-Taylor-cone droplet emission regime. The engine implements the concept of hydraulic and electrodynamic flow rate matching to achieve electrical control. The engine uses a set of meso-scaled silicon deflection springs to assemble the hydraulics to the electrodes, allowing to decouple the corresponding process flows. The micro-fabrication of the engine is described and novel technologies that were developed are reported. Experimental results that demonstrate cumulative uniform and steady operation are provided. Current-flowrate characteristics of the engine are in agreement with a reduced-order model. Experimental data demonstrating the low divergence of electrospray emitter arrays operated in the single Taylor Cone is in qualitative agreement with a reduced-order mode that assumes the absence of a thermalized tail in the plume
Robust accurate identification of peptides (RAId): deciphering MS2 data using a structured library search with de novo based statistics

Motivation: The key to MS -based proteomics is peptide sequencing. The major challenge in peptide sequencing, whether library search or de novo, is to better infer statistical significance and better attain noise reduction. Since the noise in a spectrum depends on experimental conditions, the instrument used and many other factors, it cannot be predicted even if the peptide sequence is known. The characteristics of the noise can only be uncovered once a spectrum is given. We wish to overcome such issues. Results: We designed RAId to identify peptides from their associated tandem mass spectrometry data. RAId performs a novel de novo sequencing followed by a search in a peptide library that we created. Through de novo sequencing, we establish the spectrum-specific background score statistics for the library search. When the database search fails to return significant hits, the top-ranking de novo sequences become potential candidates for new peptides that are not yet in the database. The use of spectrum-specific background statistics seems to enable RAId to perform well even when the spectral quality is marginal. Other important features of RAId include its potential in de novo sequencing alone and the ease of incorporating post-translational modifications. Availability: Programs implementing the methods described are available from the authors on request. Contact: yyu@ncbi.nlm.nih.gov Supplementary information: ftp://ftp.ncbi.nih.gov/pub/yyu/Proteomics/MSMS/RAId/MSMS_bioinfo_supp.pdf
The economic burden of incident venous thromboembolism in the United States: A review of estimated attributable healthcare costs

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is an important cause of preventable mortality and morbidity. In this study, we summarize estimates of per-patient and aggregate medical costs or expenditures attributable to incident VTE in the United States. Per-patient estimates of incremental costs can be calculated as the difference in costs between patients with and without an event after controlling for differences in underlying health status. We identified estimates of the incremental per-patient costs of acute VTEs and VTE-related complications, including recurrent VTE, post-thrombotic syndrome, chronic thromboembolic pulmonary hypertension, and anticoagulation-related adverse drug events. Based on the studies identified, treatment of an acute VTE on average appears to be associated with incremental direct medical costs of $12,000 to $15,000 (2014 US dollars) among first-year survivors, controlling for risk factors. Subsequent complications are conservatively estimated to increase cumulative costs to $18,000-23,000 per incident case. Annual incident VTE events conservatively cost the US healthcare system $7-10 billion each year for 375,000 to 425,000 newly diagnosed, medically treated incident VTE cases. Future studies should track long-term costs for cohorts of people with incident VTE, control for comorbid conditions that have been shown to be associated with VTE, and estimate incremental medical costs for people with VTE who do not survive. The costs associated with treating VTE can be used to assess the potential economic benefit and cost-savings from prevention efforts, although costs will vary among different patient groups.
A Simplified Forward Osmosis Process To Reduce The Volume Of Produced Water From Qatari Gas Fields

One of the key challenges facing the gas industry in Qatar is to reduce produced/process water (PW) volumes injected in disposal wells by a target of 50% to ensure long term reservoir sustainability. This presentation describes a simplified Forward Osmosis (FO) system design that could meet this target. In contrast with conventional FO designs, this design uses readily available seawater or thermal brine as the draw solution and then, instead of recovering water from draw solution, simply discharges the diluted draw solution to the Arabian Gulf. This eliminates entirely the expensive and technically challenging draw solution recovery step. This research addresses the water security grand challenge identified by the Qatar National Research Strategy (QNRS) and helps to foster FO in Qatar. The project is funded by NPRP grant # NPRP 6 ‐ 868 ‐ 1 ‐ 163 from the Qatar National Research Fund (a member of Qatar Foundation). Commercial flat sheet FO membranes (HTI, USA) and newly developed hollow fiber FO membranes (by Nanyang Technological University in Singapore) have been tested in various bench-scale experiments. The results show that FO can successfully treat the produced/process water from Qatari gas field to achieve the target volume reduction. The average flux, with pretreated feed, was 17 L/m2-h using a draw solution of 1M NaCl and no significant fouling was observed during the 5 hours experiment. Organics passage from the feed to the draw solution was below detection limit, which eliminate the potential concern of organics leaching into the draw solution. Appropriate pretreatment of the produced/processed water is beneficial to minimize membrane fouling. Results showed a flux decline of approximately 10% over 5 hours when the PW was processed without pretreatment. The fouling has been attributed to the organics present in the PW. Different pretreatment options were evaluated to reduce membrane fouling including: i) ceramic membrane filtration; ii) Powdered Activated Carbon (PAC); and iii) Osorb, (organically-modified silica, capable of absorbing oil and other contaminants from water). This presentation will provide highlights of the results-to-date and discuss the technical feasibility of this FO design. Results look promising and indicate that FO could be a potentially good technology to reduce produced/process water injected in gas fields.
Adeno-associated viruses: an update.

Publisher Summary The adeno-associated viruses (AAV) are the only known DNA animal viruses that are absolutely dependent upon coinfection by a second unrelated virus to undergo productive infection. They are members of the family Parvoviridae , which are among the smallest of the DNA animal viruses. The Parvoviridae genome is a linear single-stranded DNA molecule approximately 5 kb in size, which is encapsidated in a naked icosahedral particle 18–27 nm in diameter. In addition to one genus of insect viruses (densoviruses), the family contains two genera that infect a broad spectrum of vertebrates ranging from birds to humans. The parvoviruses are able to replicate autonomously in infected cells but require actively dividing cells for a productive infection. Although the dependoviruses (AAV) are structurally similar to the autonomous parvoviruses, they are absolutely defective and require coinfection with structurally unrelated adenoviruses or herpesviruses for a productive infection to occur. Adeno-associated virus does not have any structural relatedness to either of its helpers; on the other hand, the three viruses do represent all of the known vertebrate virus families with linear DNA genomes that replicate in cell nuclei.
Screening for Chemical Toxicity Using Cryopreserved Precision Cut Lung Slices.

To assess chemical toxicity, current high throughput screening (HTS) assays rely primarily on in vitro measurements using cultured cells. Responses frequently differ from in vivo results due to the lack of physical and humoral interactions provided by the extracellular matrix, cell-cell interactions, and other molecular components of the native organ. To more accurately reproduce organ complexity in HTS, we developed an organotypic assay using the cryopreserved precision cut lung slice (PCLS) from rats and mice. Compared to the never-frozen PCLS, their frozen-thawed counterpart slices showed viability or metabolic activity that is decreased to an extent comparable to that observed in other cryopreserved cells and tissues, but shows no differences in further changes in cell viability, mitochondrial integrity, and glutathione activity in response to the model toxin zinc chloride (ZnCl2). Notably, these measurements were successfully miniaturized so as to establish HTS capacity in a 96-well plate format. Finally, PCLS responses correlated with common markers of lung injury measured in lavage fluid from rats intratracheally instilled with ZnCl2. In summary, we establish that the cryopreserved PCLS is a feasible approach for HTS investigations in predictive toxicology.
Meta-analysis of Ivabradine in Patients With Stable Coronary Artery Disease With and Without Left Ventricular Dysfunction

Abstract Purpose Ivabradine is a novel I f -channel antagonist that controls heart rate and may be helpful in treating patients with left ventricular dysfunction (LVD) who are unable to tolerate β-blockers or achieve a heart rate of 70 beats/min with standard therapy. Three landmark trials were used for the approval of ivabradine in the United States. These trials tested ivabradine in addition to a standard of care (including β-blockers) in patients with stable coronary artery disease (CAD) and found modest benefit in those with established LVD unable to tolerate β-blockers. The goal of this review was to pool data from ivabradine studies in all patients with stable CAD to compare cardiovascular and safety-related outcomes. Methods Three randomized, double-blind, placebo-controlled trials of ivabradine added to standard treatment (including β-blockers) in patients with stable CAD with and without LVD were reviewed for effects on mortality, cardiovascular outcomes, and adverse events. Data were independently abstracted by 2 reviewers; the Oxford quality scoring system was used to evaluate randomization, blinding, withdrawals, and dropouts; and a Mantel-Haenszel random effects pairwise meta-analysis was used to combine data into odds ratios. Findings The initial search identified 116 trials; 3 of these trials, representing 36,524 patients with stable CAD, met inclusion criteria. According to the pooled results, ivabradine did not consistently reduce all-cause mortality (odds ratio [OR], 1.00 [95% CI, 0.91–1.11]; P = 0.98], cardiovascular death (OR, 1.02 [95% CI, 0.91–1.15]; P = 0.74), or hospitalization for worsening or new onset heart-failure in patients with stable CAD (OR, 0.94 [95% CI, 0.71–1.25]; P = 0.69). Ivabradine did not increase serious adverse drug reactions (OR, 0.99 [95% CI, 0.88–1.13]; P = 0.93) or cardiac disorders (OR, 1.03 [95% CI, 0.87–1.22]; P = 0.74). However, it was associated with drug-specific effects, including new-onset atrial fibrillation (OR, 1.35 [95% CI, 1.19–1.53]; P P P P Implications Unselective use of ivabradine in patients with stable CAD is not supported by evidence and can be associated with new-onset atrial fibrillation, bradycardia, and drug-related nuisance adverse events.
Occupational physical activity assessment for chronic disease prevention and management: A review of methods for both occupational health practitioners and researchers

Occupational physical activity (OPA) is an occupational exposure that impacts worker health. OPA is amenable to measurement and modification through the hierarchy of controls. Occupational exposure scientists have roles in addressing inadequate physical activity, as well as excessive or harmful physical activity. Occupational health researchers can contribute to the development of novel OPA exposure assessment techniques and to epidemiologic studies examining the health impacts of physical activity at work. Occupational health practitioners stand to benefit from understanding the strengths and limitations of physical activity measurement approaches, such as accelerometers in smartphones, which are already ubiquitous in many workplaces and in some worksite health programs. This comprehensive review of the literature provides an overview of physical activity monitoring for occupational exposure scientists. This article summarizes data on the public health implications of physical activity at work, highlighting complex relationships with common chronic diseases. This article includes descriptions of several techniques that have been used to measure physical activity at work and elsewhere, focusing in detail on pedometers, accelerometers, and Global Positioning System technology. Additional subjective and objective measurement strategies are described as well.
Measuring Interdisciplinarity in Science

Funding agencies and policy makers in science tout the importance of interdisciplinary and transdisciplinary research -- bring together experts from multiple domains and good things happen. But what are these good things and can they be measured? Scholarly networks are a good model system for answering these questions. Looking at millions of collaborations between scientists across disciplinary and generational boundaries, we are developing metrics and algorithms that detect the ontogeny of innovative ideas and technological breakthroughs that lead to new fields and sub-fields of science.
Use of Computational Thermodynamics in Rapid Prototyping and Infiltrating Steel Parts

The direct manufacture of metal parts by rapid prototyping often involves building a porous skeleton from a metal powder. In this work, a method termed Homogeneous Steel Infiltration has been developed for infiltrating steel skeletons to make conventional tool steel alloys. The method uses a gated infiltration route that uses as the infiltrant a steel alloy with a lower melting point than the base powder. The infiltrant liquid may use carbon and/or silicon as a melting point depressant. Premature freeze-off of the steel infiltrant is avoided by operating at a temperature where some liquid is stable at chemical equilibrium. The compositions of the skeleton and infiltrant and the infiltration temperature are selected by using computational thermodynamics. Examples of successful infiltrations using D2 and A3 tool steels as target compositions are shown. The thermodynamic design method enables suitable parameters to make other tool steels, some stainless steels and manganese steels.
Murine animal model.

Experimental animal models are available for the development of new treatment. Murine animal models have particular advantages for comparative study to evaluate the efficacy and safety of different treatment modalities because many mice can be treated at the same time with easy handling. Among several experimental models, murine renal carcinoma (Renca), which arises spontaneously in Balb/c mice, is the most frequently used for the assessment of chemotherapy, immunotherapy, and radiotherapy. Renca cells readily establish tumors in isogenic mice, producing histologically proven adenocarcinoma with a predictable growth rate to mimic the clinical situation for orthotopic growth and metastasis in a reasonable time frame. Because of its poor immunogenicity and its responsiveness to immunotherapy, the number of studies using cytokine gene-modified tumor vaccines-such as interferon-alpha or interleukin-2-in the Renca system is growing. Therefore, Renca experiments greatly contribute to the analysis of the mechanisms of antitumor immune response. In this chapter, we describe several experimental systems using this Renca model.
Antifertility effects of progestins in hamsters.

This study investigated the mechanism of antifertility action of low-dose preogestin therapy in hamsters. The method used assured that any delay induced in ovulation was registered as inhibition of ovulation. This was done to demonstrate other antifertility effects. Adult golden hamsters were given daily sc doses of megestrol acetate chlormadinone acetate norgestrel 19-nor-progesterone or nor-ethindrone through 1 estrous cycle. Mating took place on Day 4 of treatment. A group was autopsied on Day 5 and oviducts examined for eggs and sperm. Others were autopsied on Day 11 and examined for implantation sites. Ovulation was suppressed by a high dose of each of the 5 progestins. At lower doses antifertility effects were evident without inhibition of ovulation. All the progestins used except norethi ndrone showed a similar type of activity. Sperm were not found in the oviducts suggesting that sperm transport had been inhibited. Norethindrone reduced the number of implantations without affecting the number of eggs ovulated. The other progestins when given in appropriate doses completely prevented pregnancy without preventing ovulation or mating. Other effects may also exist.
The Cocktail Party of Life

During my morning writing rituals at the bakery where my creativity ebbs and flows, I often find myself totally engrossed in my writing that the only thing I am consciously aware of outside of my writing is my pumpkin muffin and occasionally the background music. Then there are those moments that my muses leave me and my writing comes to a crashing standstill. During these moments, I turn to observe other customers who frequent the bakery each morning. By allowing my mind to wander from the writing at hand, I become captivated by the social interactions of those around me.
NON-ENZYMATIC DISSOLUTION OF FIBRIN "S" BY ACIDIC DYES, SURFACTANTS, AND NAPHTHALENE SULFONATES.

SummaryNaphthalene-disulfonic acids, acidic dyes, and numerous surfactants dissolve fibrin “s” at low concentrations. Human plasma inhibits some surfactants, does not affect others, and enhances markedly the activity of a third group. Of the amphoteric surfactants, Deriphat 160-C dissolved fibrin “s” and, in contrast to other surfactants, induced enzymatic fibrinolytic activity in human plasma.
‘I’ve Learned to Love What’s Going to Pay Me’: A Culture of Despair in Higher Education during a Time of Insecurity

Based on 153 interviews at a mid-sized, commuter university, this article examines the disjuncture between students and alumni on the one hand, and faculty, academic staff and administrators on the...
Low-Density Lipoprotein (LDL) Apheresis

Low-density lipoprotein (LDL) apheresis, also referred to as lipoprotein apheresis or lipid apheresis, is a procedure that involves extracorporeal treatment of plasma to remove apoprotein (apo) B-containing lipoproteins followed by reinfusion of the processed blood. This specialized adjunctive procedure is reserved for patients who have severe refractory hypercholesterolemia after treatment with maximally tolerated LDL-lowering medications in combination with lifestyle changes, most often in the context of the genetic disorder familial hypercholesterolemia (FH). It is estimated that 2–4 % of patients with FH meet the criteria for initiating LDL apheresis, which means that about 1 in 12,500 to 1 in 50,000 individuals may be candidates for LDL apheresis. The approximately 3-h procedure acutely lowers the plasma LDL cholesterol concentration by up to 85 %, as well as lowering the concentrations of Lp(a) and remnant lipoproteins. The procedure has several documented cardiovascular benefits, including a 72 % reduction in cardiovascular events compared to standard medical therapy in a long-term open label trial.
Reassessing the role of milldams in Piedmont floodplain development and remobilization

Abstract Recent emphasis on milldams as a cause of colonial-era floodplain sediment deposits and source for modern remobilization has ignited debate in scientific and environmental policy forums, especially in the mid-Atlantic USA. Although milldams are regionally ubiquitous and visually striking, no investigation has demonstrated that they are a dominant driver of regional floodplain sediment accumulation and remobilization. Long-term analysis in Baltimore County, Maryland found that milldams were sufficient, but not necessary for historical sediment accumulation. We compared erosion from streams upstream and downstream of confirmed milldam locations, in paired segment comparisons with and without the influence of historical milldams, and pooled across 37 study segments. We found the scale of inquiry produced different interpretations regarding the role of milldams in regional erosion and sedimentation. Although local milldam sediment remobilization rates were 15% greater than those immediately downstream, neither paired nor pooled segment comparisons provided evidence that milldam deposits are contemporary dominant sources of sediment. Further comparison across drainage areas demonstrated that milldam deposits could raise local remobilization rates by augmenting sediment availability along supply-limited channels. We introduce a unifying conceptual model that explains apparently contradictory findings in the literature where, rather than the sole cause of legacy sediment deposits, some milldams are nonetheless responsible for local increases in sediment remobilization rates along portions of the stream network.
Introduction to Parkinson disease (PD) and its complications

Abstract Parkinson disease (PD) is a common neurodegenerative disorder in older adults characterized by motor and nonmotor symptoms and complications. Impulse control disorders (ICDs), such as path...
Viagra and Beyond: Where Sex Educators and Therapists Fit in From a Multidisciplinary Perspective

New understanding of medical and surgical risk factors, new methods for scientific diagnosis, and new pharmacological options for treatment are all shaping the way we approach female sexual dysfunction. Sildenafil (Viagra) and similar drugs to treat sexual function complaints are here to stay, and will provide a range of phenomenal opportunities as well as potential pitfalls. One of the major roles of sex educators and therapists in the new millennium will be to help to monitor and adjust the global application of pharmacotherapy. The issue is not the availability of medication to treat sexual complaints, but how it is applied. Sex educators and therapists will be called upon to join teams of physicians and help make comprehensive diagnoses—not only for women, but for men as well. The time has come to join forces with the physicians and release the vacuum in which these fields have existed. It is not about whose approach is better; it is about determining the best approach for each individual patient and ...
Parent–Adolescent Relationship Factors and Adolescent Outcomes Among High‐Risk Families

Using a stress-process and attachment theory framework, we identified salient aspects of the parent–adolescent relationship and tested the extent to which those aspects were longitudinally associated with depression, withdrawal, delinquency, and aggressive behavior outcomes among a sample of high-risk adolescents (N = 498). First, four dimensions of the parent–adolescent relationship were identified: emotional closeness, communication, autonomy, and conflict. Next, latent profile analyses were conducted, and four distinct parent–adolescent relationship profiles emerged: secure, avoidant, anxious, and detached. Adolescent outcomes were assessed 2 years later. Results indicated that (a) adolescents in the avoidant and anxious profiles demonstrated higher depression symptoms than did those in the secure profile, (b) higher levels of aggression were demonstrated in the avoidant profile, and (c) higher levels of delinquency were demonstrated in the detached profile. Implications for parent–adolescent relationships and family therapy interventions are provided.
Campath-IH Combined with Fludarabine/Cyclophophamide/Rituximab (FCR) as Conditioning for Unrelated Non-Myeloablative Hematopoietic Transplantation (NMT) for Non-Hodgkin’s Lymphoma (NHL): Low Mortality Rate and Lower Than Expected Incidence of Cytomegalovirus (CMV) Reactivation.

Abstract Graft-versus-host disease (GVHD) remains a significant cause for morbidity following unrelated hematopoietic transplantation. We investigated the addition of Campath-IH in vivo, at a total dose of 45 mg, to the FCR conditioning regimen for unrelated NMT for relapsed chemosensitive NHL. 25 consecutive patients (pts) with various lymphoid histologies {Follicular = 9, Mantle cell = 7, Large cell =9}were treated. Median age was 52 yrs (range, 31–64). Median # of prior chemoregimens received was 3, and 5 pts (20%) had failed a prior autologous transplant. Ten pts (40%) were in complete remission, and 15 (60%) had evidence of active disease at study entry. Pts received rituximab at 375 mg/m2 on day −8, −1, +6 and +13. Campath-IH 15 mg/iv was given daily on days −4,−3,−2. Chemotherapy was provided on the same days as the Campath-IH and consisted of fludarabine 30 mg/m2/day x 3, and cyclophosphamide 1000 mg/m2 /day x 3. Transplantation was given on day 0. Bone marrow was the source of graft in 20 pts (80%), and 5(20%) received peripheral blood. Tacrolimus (maintained at a low trough level of 5) and methotrexate were used as additional GVHD prophylaxis. Median time to recovery of an ANC>500 was 11 days (range, 9–21). Nine pts (36%) did not require any platelet transfusions. All pts engrafted donor cells (median 81%, at 30 days); 19 pts remained mixed chimera at the time of their last follow-up. Five pts required donor lymphocyte infusion (DLI) for disease progression: 3 achieved complete, one partial and one had no response. With a median follow-up time of 16 mos (range, 3–45 mos), overall survival was 90% (95%CI, 66–99), and the current progression-free survival rate was 68% at 18 mos. Acute GVHD occurred in one pt (grade 1) pre-DLI, and in 3 pts (one grade 1, one grade 2, and one grade 3) post DLI. Chronic extensive GVHD occurred in 3 pts pre-, and 2 additional pts post DLI. Two pts died: one of chronic GVHD, and one of disease progression. Seventeen of the 25 transplants had either the recipient or the donor with CMV-positive serology. CMV prevention consisted of a once daily dose of foscarnet, and twice-weekly screening using the CMV Direct Antibody Fluorescent Stain Antigenemia test. With this strategy, only 9 pts (36%) had evidence of CMV reactivation (defined as any detection of CMV cells). No pt developed or died from CMV disease. These data suggest that unrelated NMT after Campath-FCR conditioning is associated with a low incidence of GVHD and treatment-related mortality. Foscarnet prevention with bi-weekly CMV screening is associated with a lower than expected risk for CMV reactivation. The regimen is a promising approach for unrelated donor transplantation for patients with advanced lymphoma.
Abstract 189: DWORF: Discovery and Characterization of a Cardiac Micropeptide Encoded in a Putative Long Noncoding RNA

Background: Mammalian transcriptomes contain thousands of potential open reading frames (ORFs) with fewer than fifty codons. Most of these ORFs are presumed to be random and therefore noncoding, but recently several genes annotated as long noncoding RNAs (lncRNAs) were shown to encode functional micropeptides. Objective: Identify and characterize novel micropeptides encoded in cardiac-expressed lncRNAs using comparative genomics. Methods and Results: Using codon substitution frequency, a comparative genomics strategy, we identified several previously unknown small proteins, including a 34-amino acid micropeptide that we have named DWORF (Dwarf Open Reading Frame). DWORF is a tail-anchored transmembrane protein that localizes to the sarcoplasmic reticulum and is expressed only in cardiac ventricle and slow-twitch skeletal muscle by quantitative PCR. We subsequently derived a custom antibody targeting the N-terminal residues of DWORF. Western blots using this antibody revealed a 4 kDa protein that is expressed in cardiac ventricle and soleus muscle, but not other tissues. We further validated specificity of this signal by disrupting the reading frame of DWORF in mice using CRISPR/Cas9 mutagenesis, conclusively demonstrating that the mRNA encodes a small protein. Transgenic overexpression of DWORF in cardiac myocytes resulted in increased peak amplitude of Ca 2+ transients and improved Ca 2+ resequestration kinetics with no apparent adverse effects. These findings suggest that DWORF specifically enhances activity of the sarco/endoplasmic reticulum calcium ATPase (SERCA). Conclusions: Some putative lncRNAs encode micropeptides that can be identified using bioinformatics strategies. Micropeptides, though likely too small to have enzymatic activity of their own, may have modulatory functions in important cellular processes such as calcium handling, as we have demonstrated in the case of the muscle-restricted micropeptide DWORF.
Multiplexed Engineering and Analysis of Combinatorial Enhancer Activity in Single Cells

The study of enhancers has been hampered by the scarcity of methods to systematically quantify their endogenous activity. We develop Mosaic-seq to systematically perturb enhancers and measure their endogenous activities at single-cell resolution. Mosaic-seq uses a CRISPR barcoding system to jointly measure a cell's transcriptome and its sgRNA modulators, thus quantifying the effects of dCas9-KRAB-mediated enhancer repression in single cells. Applying Mosaic-seq to 71 constituent enhancers from 15 super-enhancers, our analysis of 51,448 sgRNA-induced transcriptomes finds that only a small number of constituents are major effectors of target gene expression. Binding of p300 and RNAPII are key features of these constituents. We determine two key parameters of enhancer activity in single cells: their penetrance in a population and their contribution to expression in these cells. Through combinatorial interrogation, we find that simultaneous repression of multiple weak constituents can alter super-enhancer activity in a manner greatly exceeding repression of individual constituents.
“Who is an Entrepreneur?” Is a Question Worth Asking:

This paper is a response to Gartner's critique of definitions posited by Carland, Hoy, Boulton and Carland (1984) for “entrepreneur” and “small business owner.” The paper concludes that both trait and behavioral approaches to research are necessary in order to understand the concept of entrepreneurship.
Ecological Network Inference From Long-Term Presence-Absence Data

Ecological communities are characterized by complex networks of trophic and nontrophic interactions, which shape the dy-namics of the community. Machine learning and correlational methods are increasingly popular for inferring networks from co-occurrence and time series data, particularly in microbial systems. In this study, we test the suitability of these methods for inferring ecological interactions by constructing networks using Dynamic Bayesian Networks, Lasso regression, and Pear-son’s correlation coefficient, then comparing the model networks to empirical trophic and nontrophic webs in two ecological systems. We find that although each model significantly replicates the structure of at least one empirical network, no model significantly predicts network structure in both systems, and no model is clearly superior to the others. We also find that networks inferred for the Tatoosh intertidal match the nontrophic network much more closely than the trophic one, possibly due to the challenges of identifying trophic interactions from presence-absence data. Our findings suggest that although these methods hold some promise for ecological network inference, presence-absence data does not provide enough signal for models to consistently identify interactions, and networks inferred from these data should be interpreted with caution.
Abstract 3923: Oncogenic kinase-induced PKM2 Y105 phosphorylation promotes tumorigenesis and cancer stem cell-like property

The role of pyruvate kinase M2 isoform (PKM2) in tumor progression is controversial. Previously, it was reported that PKM2 has an oncogenic function in promoting tumor growth in xenograft models; however, PKM2 was indicated non-oncogenic or even anti-oncogenic because depletion of PKM2 accelerates mammary tumor growth in the Brca1 knockout mouse model of breast cancer. Since tumors frequently harbor various abnormally activated oncogenic kinases, we hypothesized that phosphorylation of PKM2 by oncogenic kinases in tumor cells enables PKM2 to promote tumor growth, while unphosphorylated PKM2 in non-transformed cells cannot promote tumor growth. Here, we report that PKM2 proteins were largely unphosphorylated and formed tetramers in normal mammary epithelial cells (MCF10A, MCF12A). On the other hand, PKM2 proteins were phosphorylated at Y105 and formed dimers in breast cancer cells (MDA-MB-231, MDA-MB-435). Knocking down PKM2 didn’t affect normal mammary epithelial cell (MCF10A) growth but significantly decreased breast cancer cell MDA-MB-231 proliferation. In addition, introducing the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced epithelial to mesenchymal transition, increased CD44Hi/CD24Neg stem cell-like cell population, and induced colony formation in soft agar, promoted cell migration and invasion. Interestingly, PKM2-Y105D increased YAP1 protein nuclear localization in MCF10A cells, whereas inhibiting YAP1 by siRNA or a chemical inhibitor (Verteporfin) decreased PKM2-Y105D-induced cancer stem cell-like population and colony formation ability. The data indicate that YAP1 is a novel downstream target of pY105-PKM2 in promoting the stem-like property and triggering mammary tumor initiation. Next, we performed receptor tyrosine kinase array and identified several oncogenic tyrosine kinases (AXL, EPHA2, FAK, Src, JAK3 and so on) that effectively phosphorylates PKM2 at Y105. Currently, we are testing the efficacy of targeting these oncogenic tyrosine kinases in reversing the phosphorylation of PKM2 and blocking its tumor-promoting function. Together, our data indicate that oncogenic kinases-induced phospho-Y105-PKM2, but not the unphosphorylated PKM2, promotes mammary tumor initiation by increasing cancer stem cell populations. Citation Format: Zhifen Zhou, Min Li, Lin Zhang, Dihua Yu. Oncogenic kinase-induced PKM2 Y105 phosphorylation promotes tumorigenesis and cancer stem cell-like property [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3923. doi:10.1158/1538-7445.AM2017-3923
Fusion of Multirate Measurements for Nonlinear Dynamic State Estimation of the Power Systems

With the increasing availability of sensors, power system dynamic state estimation (PSDSE) is going to play a critical role in the reliable and efficient operation of power systems. The real-time measurements in today’s power grid are obtained through various types of sensors having different sampling rates, e.g., the traditional SCADA systems with low sampling rates (generally 0.5–2 samples per second), and different groups of phasor measurement units having high sampling rates (usually 30–60 samples per second). We propose a multi-rate multi-sensor data fusion -based PSDSE framework to utilize the measurements coming from sensors with two different sampling rates. The continuous time-domain nonlinear dynamical and measurement equations are discretized at appropriate sampling periods to obtain two discrete models. Two separate estimators are developed using these models. State information of the intermediate time steps of the estimation having coarser sampling period is evaluated using model-based prediction. These two estimations are optimally combined or fused using Bar–Shalom–Campo formula. The proposed algorithm tracks the dynamic states successfully during transient events such as faults. The method is demonstrated by using the standard IEEE-9, 39, 57, and 118 bus systems. The fusion -based state estimator is shown to perform better than the individual state estimators.
Feasibility, process, and outcomes of cardiovascular clinical trial data sharing: A reproduction analysis of the SMART-AF Trial

Importance Data sharing is as an expanding initiative for enhancing trust in the clinical research enterprise. Objective To evaluate the feasibility, process, and outcomes of a reproduction analysis of the THERMOCOOL SMARTTOUCH Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation (SMART-AF) trial using shared clinical trial data. Design, Setting, and Participants A reproduction analysis of the SMART-AF trial was performed using the data sets, data dictionary, case report file, and statistical analysis plan from the original trial accessed through the Yale Open Data Access Project using the SAS Clinical Trials Data Transparency platform. SMART-AF was a multicenter, single-arm trial evaluating the effectiveness and safety of an irrigated, contact force-sensing catheter for ablation of drug refractory, symptomatic paroxysmal atrial fibrillation in 172 participants recruited from 21 sites between June 2011 and December 2011. Analysis of the data was conducted between December 2016 and April 2017. Main Outcomes and Measures Effectiveness outcomes included freedom from atrial arrhythmias after ablation and proportion of participants without any arrhythmia recurrence over the 12 months of follow-up after a 3-month blanking period. Safety outcomes included major adverse device- or procedure-related events. Results The SMART AF trial participants’ mean age was 58.7 (10.8) years, and 72% were men. The time from initial proposal submission to final analysis was 11 months. Freedom from atrial arrhythmias at 12 months postprocedure was similar compared with the primary study report (74.0%; 95% CI, 66.0-82.0 vs 76.4%; 95% CI, 68.7-84.1). The reproduction analysis success rate was higher than the primary study report (65.8%; 95% CI 56.5-74.2 vs 75.6%; 95% CI, 67.2-82.5). Adverse events were minimal and similar between the 2 analyses, but contact force range or regression models could not be reproduced. Conclusions and Relevance The feasibility of a reproduction analysis of the SMART-AF trial was demonstrated through an academic data-sharing platform. Data sharing can be facilitated through incentivizing collaboration, sharing statistical code, and creating more decentralized data sharing platforms with fewer restrictions to data access.
Interlayer fracture toughness of additively manufactured unreinforced and carbon-fiber-reinforced acrylonitrile butadiene styrene

Abstract This study presents development of a test method for characterization of interlayer, mode-I fracture toughness of fused filament fabrication (FFF) materials using a modified double cantilever beam (DCB) test. This test consists of DCB specimen fabricated from using unidirectional FFF layers, an 8 μm Kapton starter crack inserted in the midplane during the printing process, and reinforcing glass/epoxy doublers to prevent DCB arm failure during loading. DCB specimens are manufactured with a commercially available 3D printer using unreinforced Acrylonitrile Butadiene Styrene (ABS) and chopped carbon-fiber-reinforced ABS (CF-ABS) filaments. To examine the effect of the FFF printing process on fracture toughness, additional ABS and CF-ABS specimens are hot-press molded using the filament material, and tested with the single end notch bend (SENB) specimen configuration. The fracture toughness data from DCB and SENB tests reveal that the FFF process significantly lowers the mode-I fracture toughness of ABS and CF-ABS. For both materials, in situ thermal imaging and post-mortem fractography shows, respectively, rapid cool-down of the rasters during filament deposition and presence of voids between adjacent raster roads; both of which serve to reduce fracture toughness. For CF-ABS specimens, fracture toughness is further reduced by inclusion of poorly wetted chopped carbon fibers. Although this study did not attempt to optimize the fracture performance of FFF specimens, the results demonstrate that the proposed methodology is suitable for design and optimization of FFF processes for improved interlayer fracture performance.
Leukotrienes in nocturnal asthma

Nocturnal worsenings of asthma affect the vast majority of the asthmatic population at some point in the course of their disease and are significant contributors both to the morbidity and mortality associated with asthma [1]. However, many of the pathophysiologic reasons for this worsening remain unknown. The advent of the leukotriene (LT)-modulating drugs has allowed the LTs to be definitively included as causative mediators in this syndrome. As with any other mediator, cytokine or cell type, the identification of their definitive role in a particular disease is dependent on the fulfillment of Koch’s postulates. These postulates were set out approximately 100 years ago by Robert Koch to identify the role of bacteria in infections, such as tuberculosis, but clearly the principles behind them are widely applicable today. In a modified format appropriate to LTs, they can be outlined as follows. The leukotrienes must (i) be able to cause the symptoms and pathophysiologic changes of nocturnal asthma, (ii) be made by the cells present in the airways of nocturnal asthmatics, (iii) be measured in asthmatics at night during symptoms and correlate with disease severity and (iv) be blocked by antagonists or inhibitors leading to improvement in the symptoms and/or physiologic changes of asthma. This chapter will outline the fulfillment of these hypotheses by the LTs, both the cysteinyl LTs and LTB4.
Oxygen Supply Dependency in the Critically Ill — A Continuing Conundrum

Although they were not the first to observe it, a seminal paper by Danek et al. (1980) ushered in a decade of concern for oxygen supply dependency in critically ill patients. That concern continues today with some urgency because of the uncertainty of what it means. The observation made by Danek et al. (1980) was that O2 uptake (VO2) varied directly with O2 delivery (DO2) even at very high delivery rates in patients that were critically ill with adult respiratory distress syndrome (ARDS). A similar linear relationship between VO2 and DO2 was not seen in another group of critically ill ventilator patients who had not been diagnosed with ARDS. In this and in the earlier studies, it appeared that O2 demand was higher than expected and was not satisfied in ARDS patients even if DO2 were raised to well above normal resting levels. The authors suggested that this was due to a possible disturbance of normal regulatory control of blood flow in the periphery as well as a possible disruption of cellular structure with mitochondrial dysfunction.
Managing interprocedural optimization

This dissertation addresses a number of important issues related to interprocedural optimization. Interprocedural optimization is an integral component in a compilation system for high-performance computing. The importance of interprocedural optimization stems from two sources: it increases the context available to the optimizing compiler, and it enables programmers to use procedure calls without the concern of hurting execution time. While important, interprocedural optimization can introduce some significant compile-time costs. When interprocedural information is used to optimize a procedure, the procedure is then dependent on those interprocedural facts. Thus, even if the procedure is not edited, it may require recompilation due to changes in the interprocedural facts. In addition to these effects on recompilation, interprocedural information can also be expensive to compute. Furthermore, interprocedural optimizations can increase program size which can in turn increase compile time. To make interprocedural optimization feasible in a compilation system, it must be possible to manage the compile-time costs. This dissertation explores some open questions in interprocedural optimization. An efficient algorithm is developed for constructing the call multigraph, the underlying program representation for interprocedural optimization. A procedure cloning algorithm is also described. This algorithm avoids the significant code growth and increased compilation time possible with cloning, while focusing optimization on the most profitable opportunities. We present results of an in-depth study of inline substitution. These results led to a new approach for interprocedural optimization, focusing on enabling only high-payoff optimizations. All of these ideas are brought together in a compilation system supporting interprocedural optimization, which significantly reduces the costs of interprocedural optimization. The compilation system is further adapted to support optimizations for enhancing parallelism.