cssi/SciSciGPT-SciSciNet huggingface dataset:
Residues flanking scissile bonds in Factor VIII modulate rates of cleavage and proteolytic activation catalyzed by Factor Xa

Factor Xa (FXa) proteolytically activates Factor VIII (FVIII) by cleaving P1 residues Arg372, Arg740, and Arg1689. The Arg372 site represents the rate-limiting step for procofactor activation, whereas cleavage at Arg740 is a fast step. FXa also catalyzes inactivating cleavages that occur on a slower time scale than the activating ones. To assess the role of sequences flanking the Arg372 and Arg740 sites, recombinant FVIII variants in which P3–P3′ sequences were swapped individually or in combination were prepared. Replacing the Arg372 flanking sequence with that from the Arg740 site increased the rate of cleavage at Arg372, as judged by the ∼5-fold increased rate in A1 subunit generation, and reduced the FVIIIa-dependent lag time for in situ FXa generation. The reciprocal swap yielded a nearly 2-fold increase in the rate of Arg372 cleavage, while the combined double-swap variant showed a 10-fold rate increase at that site, consistent with the individual effects being additive. Although this cleavage repre...
Surface Modification of Melt Extruded Poly(ε-caprolactone)Nanofibers: Toward a New Scalable Biomaterial Scaffold

A photochemical modification of melt-extruded polymeric nanofibers is described. A bioorthogonal functional group is used to decorate fibers made exclusively from commodity polymers, covalently attach fluorophores and peptides, and direct cell growth. Our process begins by using a layered coextrusion method, where poly(e-caprolactone) (PCL) nanofibers are incorporated within a macroscopic poly(ethylene oxide) (PEO) tape through a series of die multipliers within the extrusion line. The PEO layer is then removed with a water wash to yield rectangular PCL nanofibers with controlled cross-sectional dimensions. The fibers can be subsequently modified using photochemistry to yield a “clickable” handle for performing the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction on their surface. We have attached fluorophores, which exhibit dense surface coverage when using ligand-accelerated CuAAC reaction conditions. In addition, an RGD peptide motif was coupled to the surface of the fibers. Subsequent cell...
O-81 Honouring the hopes of parents with children with life-limiting conditions

Background Family-centred advance care planning (ACP) discussions support parents’ need for honest and open communication regarding the future complications their child with life-limiting conditions may incur. Parents find that such conversations offer opportunities for shared decision making, peace of mind, and trusting relationships with healthcare providers—opportunities that ultimately ensure that the best care is provided for their child. One component of family-centred ACP conversations is the exploration of hope. There are many barriers and challenges when exploring hope, especially for parents with children with life-limiting illness. Aim This presentation will review the value and importance of exploring the multi-dimensional concept of hope. A video demonstration of a “hope conversation” with Heather and Greg—parents with a child with a life-limiting condition—will identify how exploring the multiple layers of hope can be healing and can offer opportunities to create strategies to help parents achieve some of their goals for their seriously ill child. Discussion The exploration of hope for individuals with life-limiting illness requires skill, understanding, and compassion. Healthcare providers experience a variety of challenges when exploring hope, such as fear that the conversation will “take away” hope or cause anxiety and stress. These barriers often thwart the ability of healthcare providers to facilitate effective conversations and deepen their understanding of hope and its many layers. Hope has many dimensions, ranging from those that may be considered wishful thinking (e.g., hope for a cure) to more practical tasks (e.g., hope to control pain). Healthcare providers who understand this concept will continue to probe individuals’ hopes to gain a more comprehensive understanding of their goals and values. Exploring the concept of hope with parents with children with life-limiting illnesses is particularly challenging since such discussions are often accompanied by emotion and anticipatory grief. However, the exploration of hope also empowers individuals to become more aware of their goals and values and to, eventually, learn to prioritise the ones that are most important. It is possible for some hopes to be achieved through creative strategies and planning. The skillful exploration and management of hopes can have a direct impact on healthcare decision making and the end of life experience.
Eicosanoid Regulation of Tumor Cell-Platelet and -Endothelium Interaction During Arrest and Extravasation

Cell transformation from normalcy to malignancy is a sequential process. A nascent neoplastic clone is usually generated by a series of somatic and/or inherited mutations. Those genetic changes allow cells to bypass programmed cell death, avoid the need for growth factors (positive regulators), ignore restraining signals (negative regulators), escape from immunological surveillance, stimulate the formation of their own blood supply (angiogenesis), breach surrounding tissues (invasion), and often colonize distant sites (metastasis). With the advance of biochemistry, human genetics and powerful molecular techniques, more than 60 oncoproteins and at least 6 suppressor proteins have been characterized (1,2). These proteins are important positive or negative mediators of the signal transduction cascade, localized from exterior of cell (growth factors), membrane and cytoplasm (cell surface receptors, G proteins, protein kinases) to nucleus (transcription factors) (3).
The first application of site-directed mutagenesis using oligonucleotides for studying the function of a protein.

• I review how the method for oligonucleotide-directed mutagenesis was developed and applied to the study of the signal peptide
Telescope Observations of Interstellar and Circumstellar Ices: Successes of and Need for Laboratory Simulations

Ices play a key role in the formation of simple and complex molecules in dense molecular clouds and in the envelopes and protoplanetary disks surrounding young stars. Some fraction of the interstellar ices may become building blocks of comets, and thus be delivered to the early Earth. Laboratory simulations have proven to be crucial in the derivation of ice abundances, in quantifying reaction rates on cold grain surfaces, in determining the thermal and energetic processing history of the ices, and in understanding the interaction between the ices and the underlying refractory grain surfaces. In this invited topical paper I will review possible ways forward in improving our knowledge of the composition of the ices, as many signatures in the interstellar spectra are still poorly identified. I will also emphasize the observed importance of thermal processing of the ices (crystallization, segregation), which likely affects the chemistry after the initial dominance of grain surface reactions. Continued laboratory work is warranted in view of the upcoming observational data from, for example, the James Webb Space Telescope (JWST), which is ideally suited for ices studies. For an exhaustive review on this topic I refer to Boogert, Gerakines & Whittet (2015).
Image registration with artificial neural networks using spatial and frequency features

Image registration has been widely used in many fields such as medical imaging, remote sensing, and computer vision. It transforms multiple images of the same subject that are taken either at different times or from different points of view to the same coordinate system. In this study, two novel neural network based approaches are investigated for the registration of magnetic resonance images (MRI). They combine features in spatial domain (with scale invariant feature transform) and frequency domain (with discrete cosine transform or discrete wavelet transform) together to provide more robust feature extraction methods for image registration. Besides, the learning ability and nonlinear mapping ability of artificial neural network provide a flexible and intelligent tool for data fusion on feature matching and parameter estimation. The performances of the proposed approaches are studied and compared with other methods via computer simulations.
Muddy conditions reduce hygiene and lying time in dairy cattle and increase time spent on concrete

Dairy cattle spend less time lying and show signs of increased stress when housed in rainy and windy conditions, but no work has separated the effects of exposure to inclement weather from muddy conditions underfoot. Our objective was to evaluate the effects of muddy conditions alone on lying behavior, hygiene, and physiological responses. We housed pairs of pregnant, nonlactating dairy cattle (n = 12; 6 primigravid heifers, 6 multiparous cows) in enclosed pens with dirt floors and a concrete feed apron. Cattle were exposed to 3 levels of soil moisture: 90 (dry), 74 (muddy), or 67% (very muddy) dry matter for 5 d each in a replicated 3 × 3 Latin square design. Lying time was measured on all days with data loggers, and lying locations and postures were recorded on the final day of each treatment. Before and after each treatment, blood samples were collected, and the percentage of dirty surface area was measured on the udder, hind leg, and side of each animal. Cattle spent less time lying down in muddier conditions, especially in the first 24 h of exposure, when cows and heifers spent only 3.2 and 5.8 h, respectively, lying down in the muddiest treatment compared with 12.5 and 12.7 h on dry soil. When the soil was dry, cattle never chose to lie down on concrete, but in muddier conditions they spent a greater proportion of their lying time on concrete (mean ± SE: 56 ± 14 and 10 ± 8% in the very muddy and muddy treatments, respectively). The shift in lying location was more marked for heifers, and all 6 spent ≥87% of their lying time on concrete in the muddiest treatment. When cattle chose to lie down on wetter soil, they limited the surface area exposed to their surroundings by tucking their legs beneath their bodies (mean ± SE: 30 ± 11, 15 ± 4, and 5 ± 2% of lying observations in the very muddy, muddy, and dry treatments, respectively). Despite cattle spending less time on wetter soil, all 3 measured body parts became dirtier in muddier conditions (1.4-, 1.6-, and 1.8-fold more on the leg, udder, and side, respectively, in the muddiest compared with the driest treatment). In addition, higher soil moisture levels resulted in greater reductions in white blood cell counts relative to baseline levels (−0.95, −0.43, and 0.34 × 109/L relative to baseline levels in the very muddy, muddy, and dry treatments). Muddy conditions, even in the absence of wind or rain, are aversive for cattle and have negative implications for their welfare.
Hepatobiliary phase MRI: impact on planning image-guided liver tumor ablations

To assess the impact of hepatobiliary phase images obtained during intravenous gadoxetate disodium-enhanced liver MRI in the planning of image-guided liver tumor ablations. This institutional review board-approved retrospective study included 34 patients (21 men, 13 women, ages 25–80) who underwent 36 liver MRI examinations with gadoxetate disodium within 12 weeks prior to image-guided thermal ablation of 62 liver tumors during 36 procedures. Visibility of bile ducts, subdivided by branch order, on hepatobiliary phase images was compared to standard MRI sequence images by an attending abdominal radiologist and fellow. Interventional decision making (whether or not to ablate and technical plan) using hepatobiliary phase images was compared with standard MRI sequences by the ablationists. The technical success and adverse events of ablation procedures were noted. Bile duct visibility was significantly increased by at least one branch order in 18/36 (50%) examinations (p < 0.0001). Interventional decisions were significantly impacted in 15 (41.7%) of 36 ablation procedures (p < 0.0001), including changes to the technical plan in six (16.7%) of these procedures (p = 0.005). Technical success was achieved for 60/62 (97%) of tumors. Mild (grade 1) adverse events occurred in 4/36 (11%) procedures; no biliary complications occurred. Use of hepatobiliary phase images obtained during gadoxetate disodium-enhanced liver MRI impacted both when and how to perform image-guided liver tumor ablations in our practice.
Determining the Effect of External Stressors on Laparoscopic Skills and Performance Between Obstetrics and Gynecology Residents.

Study Objective To evaluate the effect of stress on laparoscopic skills between obstetrics and gynecology residents. Design Observational prospective cohort study. Design Classification Prospective cohort. Setting Urban teaching university hospital. Participants (Patients) Thirty-one obstetrics and gynecology residents, postgraduate years 1 to 4. Intervention We assessed 4 basic laparoscopic skills at 2 sessions. The first session was the baseline; 6 months later the same skills were assessed under audiovisual stressors. We compared the effect of stress on accuracy and efficiency between the 2 sessions. Measurements and Main Results A linear model was used to analyze time. Under stress, residents were more efficient in 3 of the 4 modules. Ring transfer (hand-eye coordination and bimanual dexterity), p = 0.0304. Ring of fire (bimanual dexterity and measure of depth perception), p = 0.0024 and dissection glove (respect of delicate tissue planes), p = 0.0002. Poisson regression was used to analyze the total number of penalties. Residents were more likely to acquire penalties under stress. Ring transfer, p = 0.0184 and cobra (hand-to-hand coordination), p = 0.0487 yielded a statistically significant increase in penalties in the presence of stressors. Dissection glove p = 0.0605 yielded a nonsignificant increase in penalties. Conclusion Our work confirmed that while under stress residents were more efficient, this translated into their ability to complete tasks faster in all the tested skills. Efficiency, however, came at the expense of accuracy.
FRAMEWORKS OF AMERICAN FINANCIAL ACCOUNTING THOUGHT: AN HISTORICAL PERSPECTIVE TO 1973

The debate among accounting theoreticians as to the content and usefulness of the Financial Accounting Standards Board's concept statements and its conceptual framework project can better be understood if a perspective of prior “framework” efforts is used. This paper interprets the principal prior efforts to produce a comprehensive conceptual framework for financial reports down to the time the FASB was formed in 1972. It shows that previous efforts were slow to evolve, and to respond to environmental changes. There is also evidence that a continuing “dynamic tension” has existed between the patterns proposed by practitioner groups and those of groups of academics.
Linkage: Medical Students and Pregnant Teens

Abstract Pregnant and parenting teen classes were presented in coordination with perinatal care at a health maintenance organization. A course for first year medical students was linked with the classes pairing medical students and adolescents as partners in the learning process. The medical students had the opportunity to develop an understanding for the broad and complex social, cultural and behavioral needs of urban adolescents during a critical period in their development. A team of health care providers underscored consistent health care messages. The team provided support and educational classes to medical students and the teenage patients. Meeting the needs of the two learning groups was challenging. The curriculum remained fluid to address and adjust to current health priorities and issues identified by providers and participants. Games and hands on learning modules were developed. Supportive and mentoring relationships were formed during the school year. Sample characteristics of the pregnant teens were 74% between the ages of 16 and 18, 50% entered prenatal care in the second trimester, 85% were in school at their entry to prenatal care, 34% had documentation of nutrition education and 51% were at the acceptable BMI range. (N=41)
Progress in development of synthetic erythrocytes made by encapsulation of hemoglobin.

Synthetic Erythrocytes (SE) are an example of the application of liposome technology to a medical product, large quantities of which are infused into a human patient.
Laminar Air Flow Unit for Patients Undergoing Cancer Chemotherapy

Several investigators have demonstrated that one type of protected environment, the Life Island unit*, can be used for patients undergoing cancer chemotherapy. Several disadvantages have been noted with this type of unit. The patient is confined to the bed and a small adjacent area. Bathing and toilet facilities must be provided from outside of the unit. Patient procedures are time-consuming since they must be performed though plastic sleeves on the side of the unit. Because there is turbulent air flow, organisms may disseminate in the unit from sites of contamination on the patient.
Fungal Infections, Systemic

Systemic fungal infections have increased markedly in frequency and importance in recent decades, primarily because advances in the treatment of serious diseases and the ongoing human immunodeficiency virus (HIV) epidemic have expanded the population of people with abnormal host defenses against infections. Key aspects of host defenses against fungal infection include anatomical barriers such as the skin and mucosal surfaces, innate and adoptive immune responses, and nutritional immunity. Recent advances in our understanding of fungal pathogenesis include the discovery of mating systems in several pathogenic fungi, development of molecular genetic tools for deleting genes or regulating their expression, the sequencing of the genomes of several pathogenic fungi, and the use of newer nucleic acid sequencing technologies to analyze and quantify global gene expression. Blastomyces , Coccidioides , Histoplasma , Paracoccidioides , and Sporothrix are true pathogens that can cause disease in people with normal or abnormal host defenses. In contrast, Aspergillus , Candida , Cryptococcus , Penicillium , Pneumocystis , and the zygomycetes are opportunistic pathogens that tend to cause serious disease only in people with abnormal host defenses. The key properties of each of these fungi are reviewed, along with the epidemiology, pathogenesis, clinical features, methods for diagnosis, and treatment of the corresponding fungal diseases.
Comparative effectiveness of commonly used devices for carotid artery stenting: an NCDR Analysis (National Cardiovascular Data Registry).

Objectives This study sought to characterize usage and outcomes of carotid stenting platforms. Background A variety of stents and embolic protection devices (EPDs) are used for carotid artery stenting. Little is known about current usage patterns and differences in outcomes with these devices. Methods We analyzed 12,135 consecutive carotid stent procedures in the NCDR (National Cardiovascular Data Registry) CARE (Carotid Artery Revascularization and Endarterectomy) registry performed between January 1, 2007 and March 31, 2012. We compared baseline characteristics and crude and multivariable-adjusted rates of in-hospital combined death/stroke among patients treated with Acculink/Accunet (Abbott Laboratories, Abbott Park, Illinois), Xact/Emboshield (Abbott), and Precise/Angioguard (Cordis Corporation, Bridgewater, New Jersey) stent/EPD combinations. Results In 78.2% of cases, stents were used in conjunction with their specific, corresponding U.S. Food and Drug Administration–approved EPD. The Acculink/Accunet (n = 2,617, 21.6%), Xact/Emboshield (n = 3,507, 28.9%), and Precise/Angioguard (n = 2,696, 22.2%) stent/EPD combinations were used in 72.7% of all cases. The Protege/SpiderFx (ev3 Endovascular Inc., Plymouth, Minnesota) (n = 453, 3.7%) and Wallstent/Filterwire (Boston Scientific, Natick, Massachusetts) (n = 213, 1.8%) devices were used in a minority of cases. In unadjusted analyses, the Precise/Angioguard system was associated with higher rates of the primary outcome than were the Acculink/Accunet (2.5% vs. 1.8%; p = 0.058) and Xact/Emboshield (2.5% vs. 1.9%; p = 0.14) systems that were not statistically different. In adjusted analyses, differences between Precise/Angioguard and Accunet/Acculink (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 0.89 to 2.47; p = 0.065), Precise/Angioguard and Xact/Emboshield (OR: 1.16, 95% CI: 0.77 to 1.76; p = 0.38), and Xact/Emboshield and Accunet/Acculink (OR: 1.28, 95% CI: 0.82 to 1.97; p = 0.18) remained nonsignificant. Conclusions In modern U.S. practice, the Acculink/Accunet, Xact/Emboshield, and Precise/Angioguard carotid stenting systems are used in most cases and are associated with similarly low rates of adverse events.
Dopamine and ESB Reward

In this chapter, we explore the role(s) that dopamine systems might play in ESB and other rewards, principally through the study of pharmacological evidence. Again, our discussion is concerned with the problem of behavior-physiology linkage. Although here the problem seems particularly subtle and complex. There are multiple components to be considered in the structure and function of dopamine systems. Difficult questions arise about the effects of dopamine on behavior, such as the separation of motor arousal and reward, or even the adequacy of these terms to describe dopamine’s actions. Additionally, research in this area spans a broad range of techniques and methods. It is problematic to know how to compare studies as different from each other as the attenuation of ESB self-stimulation by dopamine blockade, dopamine agonist self-administration, food reward extinction induced by dopamine blockade, open field locomotion, or akinesia and catalepsy induced by dopamine lesions. These techniques may reveal different facets of dopamine function, each of which may be fundamentally related or independent.
Variable impact of prior cancer history on the survival of lung cancer patients.

Abstract Introduction Non-Small Cell Lung Cancer (NSCLC) is commonly diagnosed in patients who have survived a prior malignancy. However, it is currently unclear whether NSCLC patient survival is impacted by the potential for previously-treated malignancies to recur. Understanding the impact of a prior cancer history on NSCLC survival could not only enhance decision making but could affect eligibility for NSCLC studies. Methods The National Cancer Database (NCDB) was queried for NSCLC patients (stage I–IV) diagnosed between 2004–2014. Kaplan-Meier survival curves and multivariable Cox proportional hazards regression models were estimated to analyze overall survival across a variety of treatment approaches and stages in the presence and absence of a prior cancer history. Results A total of 821,323 patients with a newly diagnosed NSCLC were identified including 179,512 (21.9%) with a prior history of cancer. The unadjusted 5-year overall survival of patients with a prior cancer history (9.8%) was slightly better to those without a cancer history (9.5%, 95% CI 11.76–11.84, P Conclusions The association between prior cancer history and survival of newly diagnosed NSCLC patients is highly variable and to some degree reflects a patient’s potential for cure.
A Graphical Processing Unit Accelerated NORmal to Anything Algorithm for High Dimensional Multivariate Simulation

Many complex real world systems can be represented as correlated high dimensional vectors (up to 20,501 in this paper). While univariate analysis is simpler, it does not account for correlations between variables. This omission often misleads researchers by producing results based on unrealistic assumptions. As the generation of large correlated data sets is time consuming and resource heavy, we propose a graphical processing unit (GPU) accelerated version of the established NORmal To Anything (NORTA) algorithm. NORTA involves many independent and parallelizeable operations—sparking our interest to deploy a Compute Unified Device Architecture (CUDA) implementation for use on Nvidia GPUs. NORTA begins by simulating independent standard normal vectors and transforms them into correlated vectors with arbitrary marginal distributions (heterogenous random variables). In our benchmark studies using a Tesla Nvidia card, the speedup obtained over a sequential NORTA coded in R (R-NORTA) peaks at 19.6× for 2000 simulated random vectors with dimension 5000. Moreover, the speedup obtained for GPU-NORTA over a commonly used R package for multivariate simulation (the copula package) was 2093× for 2000 simulated random vectors with dimension 20,501. Our study serves as a preliminary proof of concept with opportunities for further optimization, implementation, and additional features.
Optimal Network Control with Adversarial Uncontrollable Nodes

The effectiveness of many well-known network control algorithms (e.g., MaxWeight) relies on the premise that all of the nodes are fully controllable. However, these algorithms may yield poor performance in a partially-controllable network where a subset of nodes are uncontrollable and may take arbitrary (possibly adversarial) actions. Such a partially-controllable model is of increasing importance in real-world networked systems such as overlay-underlay networks and uncooperative wireless networks. In this paper, we study two fundamental network optimization problems in a network with adversarial uncontrollable nodes. First, we investigate the network stability problem where the objective is to stabilize the network whenever possible. We develop a lower bound on the total queue length that can be achieved by any causal policy, and propose a throughput-optimal algorithm, called Tracking-MaxWeight (TMW), which enhances the original MaxWeight algorithm with an explicit learning of the behavior of uncontrollable nodes. Second, we study the network utility maximization problem where the objective is to maximize cumulative utility subject to stability constraints. We provide a lower bound on the utility-delay tradeoff, and develop the Tracking Drift-plus-Penalty (TDP) algorithm that achieves tunable utility-delay tradeoffs.
Synthesis of Quinuclidine-Benzyl(ethylcarbamoyl)borane: The First Boron Analogue of a Phenylalanine Derivative.

The nitrile (VI), prepared in 3 steps from the borane (I), reacts with triethyloxonium tetrafluoroborate (VII) to give the nitrilium salt (VIII).
Sensory acceptability and willingness to buy foods presented as having benefits achieved through the use of nanotechnology

Abstract Nanotechnology is the manipulation of matter on a small scale (1-billionth of a meter). Nanomaterials have been used extensively in food production and packaging to improve food safety and eating quality. However, consumer knowledge of nanotechnology is low and the public’s perceptions about its use in foods is poorly understood. This study assessed consumers’ knowledge and attitudes towards food nanotechnology, and measured degree of liking and purchase intent for tasted foods presented as having specific nanotechnology benefits. Participants were 161 young, mostly college-educated adults. They evaluated samples of fresh cherry tomatoes and chocolate ice cream for overall liking and liking of key attributes using 15-cm line scales. They were informed that the first sample of each food had no nanotechnology (control), but the subsequent samples were produced with nanotechnology materials. For the tomatoes, nanoparticles were added to the packaging as an anti-microbial or to extend freshness; for the ice cream, nanoparticles were incorporated into the food matrix to deliver probiotics or reduce icing. In reality, no foods were produced with nanotechnology. Participants also completed surveys on their food attitudes and knowledge of nanotechnology. Results showed that all the samples were highly liked, regardless of whether they claimed to deliver nanotechnology benefits. In addition, most (75–86%) participants were willing to buy the nanotechnology foods; the primary reasons being “sensory appeal” and “nanotechnology benefit” (p
Shape based reconstruction using ultrasound segmentation as prior in ultrasound-guided diffuse optical tomography

We proposed a shape-based diffuse optical tomography (DOT) algorithm which incorporates a target shape obtained from co-registered ultrasound image into a regularization matrix for DOT reconstruction. Simulations, phantom experiments and clinical data have shown significantly improvement of reconstructed large lesion optical absorption maps.
Emerging Themes in Integrating Mathematics into Agricultural Education: A Qualitative Study of Star Teachers in Virginia

Formal agricultural education started in the United States in 1917 when congress passed the Smith-Hughes Act. This piece of legislation put agriculture in the classroom to prepare students for the workforce. From that point agricultural education has had its role in the formal education system. Agricultural education in the public school system has grown tremendously since its inception at the turn of the last century. Agricultural education courses teach way beyond the boundaries of production agriculture. Agricultural educators are now preparing their students for future careers as biologists, business and industry leaders, political officials, and many other advanced careers. These careers and other vocational occupations require post-secondary degrees. Thus, it is more important than ever to examine academic integration in career and technical education (CTE).
On stochastic Itô processes with drift in Ld

Abstract For Ito stochastic processes in R d with drift in L d Aleksandrov’s type estimates are established in the elliptic and parabolic settings. They are applied to estimating the resolvent operators of the corresponding elliptic and parabolic operators in L p and L p + 1 , respectively, where p ≥ d .
Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism

BACKGROUNDBeige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages.METHODSWe measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs.RESULTSTreatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density.CONCLUSIONThe addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants.TRIAL REGISTRATIONClinicalTrials.gov NCT02919176.FUNDINGNIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.
HPV-Positive and HPV-Negative Vulvar Squamous Cell Carcinoma Are Biologically, but Not Clinically, Distinct.

ABSTRACT Vulvar squamous cell carcinoma (VSCC) pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remains ambiguous across studies. Here, we present a retrospective cohort analysis of 36 patients with invasive VSCC where HPV status was determined using RNA in situ hybridization (ISH) and polymerase chain reaction (PCR). Clinical annotation, p16 immunohistochemistry (IHC), programmed death ligand-1 (PD-L1) IHC, HPV16 circular E7 RNA (circE7) detection, and RNA-sequencing (RNA-seq) of the cases was performed. A combination of ISH and PCR identified 20 cases (55.6%) as HPV-positive. HPV-status did not impact overall survival (HR: 1.36, 95% CI: 0.307 to 6.037, p=0.6857) or progression-free survival (HR: 1.12, 95% CI: 0.388 to 3.22, p=0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n=23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs (circRNAs), including several circRNAs that have previously been implicated in the pathogenesis of other cancers.
NASA: Past, Present, and Future

A brief timeline of spaceflight milestones from the launch of Sputnik in 1957 to the International Space Station is presented in this viewgraph presentation, together with historical photographs.
Algebraic Theory of the Marussi Tensor

The Marussi tensor, or the tensor of gravity gradients, or simply the gravity tensor, has long been regarded as the centerpiece of differential geodesy. It was introduced in Marussi (1949) primarily by using the homographic calculus and in Marussi (1951a) he called it the Eotvos tensor since, as he noted, “… it was this geodesist who gave the first systematic consideration to the application of the second derivatives of the potential to geodetic and geophysical problems.” In his formulation the theory of the tensor is essentially that of the Eotvos and generalized Burali-Forti homographies. As he noted, up to second order this tensor systematically synthesizes all of the dynamical and geometric properties of the Earth’s gravity field.
Abstract T P304: A Retrospective Cohort Study: Effect of Ambulation on Urinary Tract Infections in Acute Stroke Patients

Introduction: Urinary tract infection (UTI) is reported in 4-20% ischemic stroke patients. Age, sex, indwelling urinary catheter, and atrial fibrillation have been reported as independent predictors of UTI in stroke patients. There is limited data about the relationship of ambulatory status and the rate of urinary tract infection (UTI) following a stroke admission. Hypothesis: The goal of our retrospective cohort study was to understand the relationship between UTI and a patient’s ambulatory status, adjusting for age, gender, stroke type (ischemic, intracerebral hemorrhage, or subarachnoid hemorrhage), atrial fibrillation, and use of indwelling urinary catheter use. We assessed the hypothesis that the stroke patients who are able to ambulate during hospitalization would have lower rates of UTI. Methods: We retrospectively analyzed 1670 acute stroke patients who were admitted to an academic comprehensive stroke center between Feb 2006 and May 2014. “Get with the guideline” dataset was used to identify acute stroke patients and their ambulatory status (yes/no). UTI was identified using discharge diagnosis. Chi square test and logistic regression methods were used for statistical analysis. Results: Mean age was 64.9 ± 14.6 years with 51% men. 1138 (68%) patients were classified as having ischemic stroke; 291 (17.5%) patients had intracerebral hemorrhage; and 241 (14.5%) patients had subarachnoid hemorrhage. During hospitalization, 444 (27%) were ambulatory. Patients able to ambulate during hospitalization had less rate of UTI (1.4% vs 9.8%; p Conclusion: In conclusion, our findings suggest that the stroke patients who are able to ambulate during their index hospitalization have lower rate of UTI. Early ambulation may result in earlier removal of indwelling urinary catheter which may explain the protective effect of ambulation against UTI.
Hamiltonian dynamical systems for convex problems of optimal control: implications for the value function

For fully convex problems of optimal control, the Hamiltonian dynamical system provides a global description of evolution of the subdifferentials of the value function from those of the initial cost. We employ this description and the convex structure of the problem to investigate the differentiability properties of the value function. Motivation is provided by questions of regularity of optimal feedback, the key ingredients of which the the value function, and by the fact that the Hamiltonian may lead to a reasonable dynamical system, even if the underlying control problem involves various constraints and penalties.
Human design: wearable computers for human networking

Computer technology has mostly focused either on the isolated individual, or has treated the person as a clueless extra wandering in a computer-controlled environment. Researchers seem to have forgotten that people are social animals, and that the quality of their lives is defined by their roles in human organizations. Instead of inventing technology for the individual as an isolated entity, why not invent systems that support people's organizational roles? Or even invent new types of organizations? My colleagues and I are inventing technology that can potentially produce organizations that are more creative and efficient, and that better support the individual. Using wearable computers that actively analyze face-to-face interactions within the workplace we can extract conversational features, identify participants, define context, and determine content. By aggregating this information, high-potential collaborations and expertise within the organization can be identified, information movement and decisionmaking can be augmented, and social networks reinforced. Examples using this technology to initiate productive connections are shown, and privacy concerns are addressed.
Credentials management for high-value transactions

Partner key management (PKM) is an interoperable credential management protocol for online commercial transactions of high value. PKM reinterprets traditional public key infrastructure (PKI) for use in high-value commercial transactions, which require additional controls on the use of credentials for authentication and authorization. The need for additional controls is met by the use of partner key practice statements (PKPS), which are machine-readable policy statements precisely specifying a bank's policy for accepting and processing payment requests. As assurance is crucial for high-value transactions, we use an access-control logic to: (1) describe the protocol, (2) assure the logical consistency of the operations, and (3) to make the trust assumptions explicit.
Caught in the Act

Membranes play a crucial role in living cells by dividing the cell into separate compartments where different chemical processes can take place. But membranes must also be able to fuse and exchange their contents in living cells. In his Perspective, Gruner highlights the report by Yanget al., whose model system allows an unprecedented, detailed look at the intermediate structures during the fusion process.
Crystal structure of the human prion protein reveals a mechanism for oligomerization

The pathogenesis of transmissible encephalopathies is associated with the conversion of the cellular prion protein, PrP(C), into a conformationally altered oligomeric form, PrP(Sc). Here we report the crystal structure of the human prion protein in dimer form at 2 A resolution. The dimer results from the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulfide bond. An interchain two-stranded antiparallel beta-sheet is formed at the dimer interface by residues that are located in helix 2 in the monomeric NMR structures. Familial prion disease mutations map to the regions directly involved in helix swapping. This crystal structure suggests that oligomerization through 3D domain-swapping may constitute an important step on the pathway of the PrP(C) --> PrP(Sc) conversion.
Reconceptualizing the Elementary Science Methods Course Using a Reflection Orientation

(1997). Reconceptualizing the Elementary Science Methods Course Using a Reflection Orientation. Journal of Science Teacher Education: Vol. 8, No. 3, pp. 153-166.
Informed Consent in Clinical and Research Settings: What Do Patients and Families Need to Make Informed Decisions?

Informed consent requires that patients in clinical settings and participants in research voluntarily agree to a proposed plan based on their understanding of a clear and thorough explanation of pu...
Tandem Affinity Purification of Protein Complexes in Mouse Embryonic Stem Cells Using In Vivo Biotinylation

In dissecting the pluripotent state in mouse embryonic stem (ES) cells, we have employed in vivo biotinylation of critical transcription factors for streptavidin affinity purification of protein complexes and constructed a protein-protein interaction network. This has facilitated discovery of novel pluripotency factors and a better understanding of stem cell pluripotency. Here we describe detailed procedures for in vivo biotinylation system setup in mouse ES cells, and affinity purification of multi-protein complexes using in vivo biotinylation. In addition, we present a protocol employing SDS-PAGE fractionation to reduce sample complexity prior to submission for mass spectrometry (MS) protein identification.
Shuttling happens: soluble flavin mediators of extracellular electron transfer in Shewanella.

The genus Shewanella contains Gram negative γ-proteobacteria capable of reducing a wide range of substrates, including insoluble metals and carbon electrodes. The utilization of insoluble respiratory substrates by bacteria requires a strategy that is quite different from a traditional respiratory strategy because the cell cannot take up the substrate. Electrons generated by cellular metabolism instead must be transported outside the cell, and perhaps beyond, in order to reduce an insoluble substrate. The primary focus of research in model organisms such as Shewanella has been the mechanisms underlying respiration of insoluble substrates. Electrons travel from the menaquinone pool in the cytoplasmic membrane to the surface of the bacterial cell through a series of proteins collectively described as the Mtr pathway. This review will focus on respiratory electron transfer from the surface of the bacterial cell to extracellular substrates. Shewanella sp. secrete redox-active flavin compounds able to transfer electrons between the cell surface and substrate in a cyclic fashion—a process termed electron shuttling. The production and secretion of flavins as well as the mechanisms of cell-mediated reduction will be discussed with emphasis on the experimental evidence for a shuttle-based mechanism. The ability to reduce extracellular substrates has sparked interest in using Shewanella sp. for applications in bioremediation, bioenergy, and synthetic biology.
Rate and concentration-dependent effects of UK-68,798, a potent new class III antiarrhythmic, on canine Purkinje fibre action potential duration and Vmax.

1. The frequency-dependent electrophysiological effects of UK-68,798 in concentrations of 1, 3, 10 and 30 nM were examined in isolated cardiac Purkinje fibres of the dog at both a number of constant rates of stimulation and following abrupt changes in pacing cycle length. 2. In all concentrations evaluated, UK-68,798 lengthened action potential duration in a concentration- and rate-dependent manner (e.g., at a cycle length = 500 ms, control APD90 = 234.0 +/- 3.3 ms, while after 10 nM UK-68,798, APD90 = 315.0 +/- 5.9 ms). 3. The duration of action potentials evoked following abrupt changes in pacing rate were also increased in a concentration-dependent manner at all diastolic intervals tested. 4. The fast and slow time constants for restitution of APD were not altered by UK-68,798. However, the amplitude terms for this relation were increased. 5. In addition, the maximum upstroke velocity (Vmax) was not significantly affected by exposure to UK-68,798 at any concentration or diastolic interval. The kinetics for recovery of Vmax were thus unaffected. 6. These findings are similar to those previously reported for recognized class III antiarrhythmic agents (e.g., bretylium, clofilium, and sotalol); however, UK-68,798 was 1,000 to 10,000 times more potent. 7. The combined potency and selectivity of this agent seem to make it an ideal tool for the investigation of cardiac potassium channels believed responsible for controlling the duration of the action potential. 8. This potent and highly selective compound may prove extremely useful in the control of cardiac arrhythmias.
Experimental Evaluation of the Preview Servo Scheme for a Two-Axis Positioning System

A preview servo scheme for position and velocity control is implemented on a two-axis welding table. The Kalman filtering theory is used to estimate the velocity from position measurements, and a cornering scheme is proposed to attain smaller path errors at sharp corners. The experimental results show that the preview-servo scheme with the Kalman filter and corner preview features is suitable for on-line control of the welding system.
Estradiol-sensitive afferents modulate long-term episodic firing patterns of GnRH neurons.

GnRH neurons comprise the final common pathway of an estrogen-sensitive pattern generator controlling fertility. To determine estradiol effects on GnRH neuron firing patterns, adult transgenic mice were ovariectomized (OVX), and half were treated with estradiol (OVX+E). One week later targeted single-unit extracellular recordings were made from GnRH neurons identified by green fluorescent protein expression. Estradiol markedly affected GnRH neuron firing patterns, increasing the percentage and duration of time these cells were quiescent (≤1 action current/min). Estradiol increased the interval between episodes of increased firing rate determined by Cluster analysis of recordings more than 45 min (OVX+E 38.8 ± 7.2 min, OVX 16.7 ± 2.1 min, n = 6 each). Possible mechanisms of estradiol modulation were examined by simultaneously blocking ionotropic secretion of γ-aminobutyric acid and glutamatergic receptors. This treatment had no effect on cells from OVX mice (n = 10), indicating episodic firing of GnRH neur...
Equilibrium gel permeation: a single-photon counting spectrophotometer for studies of protein interaction.

Abstract When a small column or flow cell packed with gel particles is completely saturated with a solution containing molecular species of interest, the average cross-sectional area occupied by the solute (partition cross section) is conveniently and precisely determined by direct optical scanning. For a mixture of interacting solutes this equilibrium gel permeation measurement yields the weight average of the species partition cross sections and the variation of this quantity with solute concentration permits determination of the solute interaction parameters (stoichiometry, equilibrium constants). We have developed a computer-controlled single-photon counting spectrophotometer for these measurements. The instrument exhibits high precision over a wide range of optical density. With counting times in the ranee of 10–1000 s the standard deviations on optical densities of protein solutions measured at 220 nm are typically 0.0006 at 1 OD, 0.002 at 2 OD, 0.005 at 4 OD. Beer's law tests show that deviations from linearity are less than these precision limits. Partition cross-section measurements for proteins can be made with an accuracy of better than 0.001 and information can be obtained with protein solutions at least as low as 1 μg/ml.