cssi/SciSciGPT-SciSciNet huggingface dataset:
A bivariate confidence interval approach to calculate drug interaction and bioequivalence study power

Sample size for drug-drug interaction (DDI) and bioequivalence (BE) studies is usually calculated based on AUC and Cmax as independent parameters. The default acceptance regions using the confidence interval (CI) approach are typically predefined dependent on variability of each parameter. Clinical DDI experience shows that changes in AUC and Cmax are highly correlated regardless of effect size. This may impact the power to establish no-effect (equivalence) for both parameters. Purpose. To evaluate the probability (P) of declaring no-effect for select variability, effect and sample size scenarios, assuming a correlation (r) range from 0.3 to 0.9. Methods. P of different scenarios to declare no-effect was calculated using univariate and bivariate CI approaches for simulated datasets using SAS®. Both approaches were applied to actual clinical data for comparison. Results. P appears to decrease with increasing r regardless of sample size. When no-effect was present, the P of meeting the 0.8–1.25 limits for declaring no-effect for both parameters was lower for the bivariate approach. When an effect was present, P for declaring no-effect was higher for the univariate approach. Conclusions. The bivariate CI approach with a consistent 0.75–1.33 acceptance region is recommended for evaluating DDI and BE studies for both high and low variability drugs, especially when equivalence is expected. The relationship between P and r is dependent on relative variance between Cmax and AUC. Clinical Pharmacology & Therapeutics (2004) 75, P91–P91; doi: 10.1016/j.clpt.2003.11.349
Where Have All of the Pro‐Choice Lawyers Gone? An Analysis of Post‐Roe Reproductive Rights Lawyering

A body of scholarship attests to the importance of experienced litigators before the U.S. Supreme Court. In this article, we specifically consider the role of experienced litigators in the thirty years of reproductive rights litigation that followed Roe v Wade. To that end, we divide the lawyers by their pro-choice or pro-life affiliations and ask (1) how often individual lawyers appear before the Court in reproductive rights cases, (2) who the lawyers arguing these case before the Supreme Court are, and (3) how their participation has changed over time. We find changes in the pro-choice and pro-life bars that mirror the reproductive rights movement at large. Pro-choice groups, which once employed a stable of elite lawyers with significant expertise, have been decimated by the retirements of pro-choice counsel with no lawyers emerging to replace them. At the same time, the pro-life bar and pro-life groups appear to be developing a strong litigation campaign complete with experienced litigators.
Shrinkage of Print Butter

One of the most annoying considerations in handling butter is shrinl~ge, which makes it difficult to maintain legal weights. This is particularly true when it is held in cold storage for several months and when there has been sufficient time for evaporation of moisture: Shrinkage of butter is largely loss of water, and the decrease in moisture content is due mostly to evaporation. This phenomenon is accelerated when the moisture is not thoroughly mixed with the fat. I t is decreased when these two components of butter are so thoroughly worked together that the moisture droplets are small and thoroughly encased in fat. I t is, therefore, apparent that the evaporation of moisture from butter, which may result in a shrinkage in weight below the legal limit, can be one of the butter dealer's most perplexing problems. The amount of working that butter receives probably has more to do with this loss of moisture than has any other factor. In 1921 the author made a study of the effect of different types of tin-foil wrappers for one-pound butter prints on the keeping quality and the shrinkage of butter. It was easy a t that time to obtain ~lditional data on the loss in weight by evaporation when the butter was worked only sufficiently to prevent mottles and on additional working to better incorporate the moisture. The butter was the regular make of sweet-cream goods in the Cornell University creamery. The Victor churn with one set of rolls was used. At the usual time of 50 revolutions of the churn in the working process, all of the butter was removed from the churn with the exception of one 90-pound Friday boxful. This butter was worked 18 additional revolutions. Seventy-five prints of the butter worked 50 revolutions and seventysix prints of the butter worked 68 revolutions were put in the experiment.
Changes in the Human Electroretinogram during Early Dark Adaptation

Psychophysical measurements using visual thresholds have revealed a course of dark adaptation in which the threshold rises before cessation of the adapting light, then falls during dark adaptation. In the present research, measurements were made of the ERG to brief stimulus flashes before and during very early dark adaptation, using a contact-lens electrode and a precisely timed light stimulator to investigate this peculiar effect. No significant decrease of the b-wave potential could be detected prior to the onset of darkness, but the b wave showed a rapid increase in response after the cessation of the adapting light. Although the latency of the b wave to a weak test light is prolonged, it is not long enough to be correlated with the early threshold rise, which occurs as much as 0.2 sec before darkness. The discrepancy also seems to preclude any suggestion that the threshold rise can be due to inhibition by the negative potential of the off effect.Relationships between x and b waves during dark adaptation were also studied, particularly with a red test light. The data emphasize that the human ERG is a dual manifestation of both scotopic and photopic functions of the retina.
Possible role of cardloaortic reflexes in postcoronary bypass hypertension

A study of hemodynamic and humoral characteristics of postcoronary bypass hypertension has been pursued in 85 patients in the immediate postoperative period. Paroxysmal hypertension developed in 69 of these patients. None of the 85 patients had a history of hypertension before operation. Hemodynamic evaluation demonstrated that the increase in blood pressure was associated with an elevation in systemic vascular resistance and a rapid heart rate. The increase in mean arterial pressure correlated significantly with the change in plasma catecholamine levels (r = 0.50, P < 0.05). There was no significant change in cardiac output. Changes in plasma renin activity showed no correlation with the increase in blood pressure. Average values of plasma renin activity on sequential determinations were not significantly different either in those who remained normotensive or in those who became hypertensive. Similarly, blood volume did not seem to play an important role. Baroreceptor sensitivity appeared blunted in both normotensive and hypertensive patients. The increase in systemic catecholamines associated with the increase in blood pressure suggested a sympathetic overdrive. This was further supported by the control of hypertension in 81 percent of patients by unilateral stellate block. The reduction in pressure consequent to the block was associated with a reduction in systemic vascular resistance (P < 0.025). Heart rate slowed slightly but significantly (P < 0.01) after stellate block irrespective of the effect on blood pressure whereas cardiac output did not change significantly. The results suggest that postcoronary bypass hypertension could be due to an afferent sympathetic reflex originating from the heart, great vessels or coronary arteries.
Inertial and interference effects in optical spectroscopy

Interference between free-space and material components of the displacement current plays a key role in determining optical properties. This is illustrated by an analogy between the Lorentz optical model and a-c circuits. Phase shifts in material-polarization currents, which are inertial, relative to the non-inertial vacuum-polarization current cause interference in the total displacement current and, hence, variation in E-M wave propagation. If the displacement-current is reversed, forward propagation is inhibited yielding the semimetallic reflectivity exhibited by intrinsic silicon. Complete cancellation involves material currents offsetting free-space currents to form current-loops that correspond to plasmons.
Potential renal protective benefits of intra-operative BNP infusion during cardiac transplantation.

Abstract Background Recombinant BNP (nesiritide) is known to reduce endothelin levels, cause afferent arteriole vasodilation, and increase natriuresis and diuresis. We hypothesized that intraoperative infusion of BNP may benefit renal function in cardiac transplant patients. Methods From June 2003 to September 2005, 22 consecutive heart transplant patients received BNP at a dose of 0.01 μg/kg/min before initiation of cardiopulmonary bypass (group A). BNP infusion was continued for a mean of 3.3 ± 1.9 days. Hemodynamics, urine output, and serum creatinine levels were prospectively collected and compared with 22 consecutive patients who underwent heart transplantation between May 2002 and June 2003 following the identical transplant protocol, but without BNP infusion (group B). Results At 24 hours postoperatively, mean blood pressure was comparable between groups (87 ± 11 mm Hg vs 89 ± 17 mm Hg, P = .7), but pulmonary artery pressure (18 ± 5 mm Hg vs 24 ± 5 mm Hg, P = .001) and central venous pressure (12 ± 5 mm Hg vs 16 ± 4 mm Hg, P = .01) were lower with BNP infusion, whereas cardiac index was augmented (2.8 ± 0.5 vs 2.4 ± 0.6, P = .03). Requirement of low-dose inotropic and vasopressor support was equally distributed between groups ( P ≥ .72). Postoperative urine output for the initial 24 hours was higher in group A (84 ± 15 vs 55 ± 36 mL/h, P = .01). None of the patients with BNP infusion required additional diuretics or renal replacement therapy during the first week after transplantation. Mean postoperative serum creatinine levels as compared with preoperative values remained unchanged within group A ( P = .12), but increased significantly in group B ( P Conclusions Intraoperative BNP infusion in heart transplant recipients was associated with favorable postoperative hemodynamics, significantly improved urine output, and stable serum creatinine levels. A prospective, randomized, multicenter trial is warranted to evaluate the potential renal protective benefits of intraoperative BNP infusion in this patient population.
Site-Directed Mutagenesis and Biochemical Analysis of the Endogenous Ligands in the Ferrous Active Site of Clavaminate Synthase. The His-3 Variant of the 2-His-1-Carboxylate Model†

The facial 2-His-1-carboxylate (Asp/Glu) motif has emerged as the structural paradigm for metal binding in the alpha-ketoglutarate (alpha-KG)-dependent nonheme iron oxygenases. Clavaminate synthase (CS2) is an unusual member of this enzyme family that mediates three different, nonsequential reactions during the biosynthesis of the beta-lactamase inhibitor clavulanic acid. In this study, covalent modification of CS2 by the affinity label N-bromoacetyl-L-arginine near His297, which is within the HRV signature of a His-2 motif, suggested this histidine could play a role in metal coordination. However, site-specific mutagenesis of eight His residues to Gln identified His145 and His280, but not His297, as involved in iron binding. Weak homology of His145 and its flanking sequence and the presence of Glu147 fitting the canonical acidic residue of the His-Xaa-Asp/Glu signature are consistent with His145 being a coordinating ligand (His-1). His280 and its flanking sequence, which give poor alignments to most other members of this enzyme family, are similar among a subset of these enzymes and notably to CarC, an apparent oxygenase involved in carbapenem biosynthesis. The separation of His145 and His280 is more than twice that seen in the current 2-His-1-carboxylate model and may define an alternative iron binding motif, which we propose as His-3. These ligand assignments, based on kinetic measurements of both oxidative cyclization/desaturation and hydroxylation assays, establish that no histidine ligand switching occurs during the catalytic cycle. These results are confirmed in a recent X-ray crystal structure of CS1, a highly similar isozyme of CS2 (81% identical). Tyr299, Tyr300 in CS2 modified by N-bromoacetyl-L-arginine, is hydrogen bonded to Glu146 (Glu147 in CS2) in this structure and well-positioned for reaction with the affinity label.
Orienting otolith-ocular reflexes in the rabbit during static and dynamic tilts and off-vertical axis rotation

Orienting otolith-ocular reflexes were assessed in rabbits using static tilt, off-vertical axis rotation (OVAR) and sinusoidal oscillation about earth-horizontal axes. In all paradigms, head pitch produced ocular counter-pitch and vergence, and head roll produced ocular counter-roll and conjugate yaw version. Thus, vergence and version are essential components of orienting reflexes along the naso-occipital and bitemporal axes. Vergence and version caused misalignment between the axes of eye and head movement during pitch and roll head movements. Semicircular canal input broadened the band-pass of these orienting reflexes, which would make them more appropriate when compensating for head movement during active motion.
Simultaneous confidence bands for ratios of survival functions via empirical likelihood

We derive a simultaneous confidence band for the ratio of two survival functions based on independent right-censored data. Earlier authors have studied such bands for the difference of two survival functions, but the ratio provides a more appropriate comparison in some applications, e.g., in comparing two treatments in biomedical settings. Our approach is formulated in terms of empirical likelihood and allows us to avoid the use of simulation techniques that are often needed for Wald-type confidence bands. By the transformation-preserving property we also obtain confidence bands for the difference in the cumulative hazard functions. The approach is illustrated with a real data example.
Library of Synthetic 5′ Secondary Structures To Manipulate mRNA Stability in Escherichia coli

A DNA cassette system has been developed to allow for the convenient introduction of synthetic DNA oligonucleotides between the transcription and translation start sites of a gene in order to examine the effect of 5' hairpin structure and strength on mRNA stabilization. Rationally designed synthetic DNA cassettes were introduced into the 5' untranslated region of a modified lacZ gene to form hairpins at the 5' end of the mRNA. These DNA inserts influenced mRNA half-lives over an order-of-magnitude range, with some groups of predicted structures having half-lives that showed a strong correlation with hairpin strength while half-lives for another group of predicted structures exhibited little or no dependence on this property. These results indicate the importance of 5' hairpin structure and strength in determining stabilization of Escherichia coli mRNA. This synthetic library, as well others generated using the DNA cassette system described here, should prove useful in understanding the mechanisms of mRNA stabilization and in designing structures for recombinant gene expression control.
Use of internal control T-cell populations in the flow cytometric evaluation for T-cell neoplasms.

OBJECTIVES Flow cytometry is an important tool for identification of neoplastic T-cells, but immunophenotypic abnormalities are often subtle and must be distinguished from nonneoplastic subsets. Use of internal control (IC) T-cells in the evaluation for T-cell neoplasms was explored, both as a quality measure and as a reference for evaluating abnormal antigen expression. METHODS All peripheral blood specimens (3-month period), or those containing abnormal T-cells (29-month period), stained with CD45 V500, CD2 V450, CD3 PE-Cy7, CD7 PE, CD4 Per-CP-Cy5.5, CD8 APC-H7, CD56 APC, CD16&57 FITC, were evaluated. IC T-cells were identified (DIVA, BD Biosciences) and median fluorescence intensity (MFI) recorded. Selected files were merged and reference templates generated (Infinicyt, Cytognos). RESULTS IC T-cells were present in all specimens, including those with abnormal T-cells, but subsets were less well-represented. IC T-cell CD3 MFI differed between instruments (p = 0.0007) and subsets (p < 0.001), but not specimen categories, and served as a longitudinal process control. Merged files highlighted small unusual IC-T subsets: CD2+(dim) (0.25% total), CD2- (0.03% total). An IC reference template highlighted neoplastic T-cells, but was limited by staining variability (IC CD3 MFI reference samples different from test (p = 0.003)). CONCLUSIONS IC T-cells present in the majority of specimens can serve as positive and longitudinal process controls. Use of IC T-cells as an internal reference is limited by variable representation of subsets. Analysis of merged IC T-cells from previously analyzed patient samples can alert the interpreter to less-well-recognized non-neoplastic subsets. However, application of a merged file IC reference template was limited by staining variability. © 2016 Clinical Cytometry Society.
The Incident Command System: a literature review

Given the foundational and the fundamental role that the Incident Command System (ICS) is intended to play in on-scene response efforts across the United States, it is important to determine what is known about the system and how this is known. Accordingly, this study addresses the following research question: 'How has research explored the ICS?'. To probe this question, a methodological review of the scant, but widening, pool of research literature directly related to the ICS was conducted. This paper reports on the findings of the analysis related to the focus, theoretical frameworks, population and sampling, methods, results, and conclusions of the existing research literature. While undertaken using different methodological approaches, the ICS research suggests that the system may be limited in its usefulness. In addition, the paper discusses the implications of the research for the state of knowledge of the system and for the direction of future research.
Vitamin D status and antibody levels to common viruses in pediatric-onset multiple sclerosis

Background: The relative contribution and interaction of risk factors for multiple sclerosis (MS) have not been evaluated.Objectives: To determine whether vitamin D status is associated with antibody levels to common viruses in pediatric-onset MS or clinically isolated syndrome (CIS) patients and controls.Methods: We assessed whether vitamin D status was associated with viral antibody levels to Epstein–Barr virus, cytomegalovirus (CMV), and herpes simplex virus (HSV)-1 or -2 in subjects who demonstrated evidence of remote infection with these viruses and whether these associations differed depending on disease status.Results: In 140 subjects, vitamin D status was weakly associated with antibody levels to CMV but not to the other viruses. However, there were some interactions between vitamin D status and disease state. Among those with vitamin D sufficiency (≥30 ng/ml), MS/CIS patients had higher antibody levels to Epstein–Barr nuclear antigen-1 than controls. Vitamin D sufficiency was associated with high...
STRUCTURE ELUCIDATION WITH BOREHOLE GRAVIMETRY

The observed densities, assuming infinite homogeneous‐horizontal beds, computed from borehole gravimetry were as much as 15 percent greater than those derived from gamma‐gamma density logs in the lower portion of several clustered boreholes at the U.S. Energy Research & Development Administration (USERDA) Nevada Test Site. A model having a single high‐density buried scarp to the west of the holes was constructed, the gravimetric density calculated, and the model varied in an attempt to improve agreement between measurement and calculation. Only slight improvement was obtained. Newly acquired geologic information made it possible to construct a more complex multiscarp model, providing much better agreement between measurement and calculation. In turn, this more complete model was refined with the help of the calculations. This method permits one to choose between qualitatively different models and, given a qualitatively correct model, to improve it quantitatively.
Two Drug Interaction Studies of Sirolimus in Combination with Sorafenib or Sunitinib in Patients with Advanced Malignancies

Purpose: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination. Experimental Design: Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in C max for each drug alone compared with its C max during combination therapy. Results: The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in C max for any of the drugs alone compared with the C max during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib. Conclusions: Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug–drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling. Clin Cancer Res; 17(7); 1956–63. ©2011 AACR .
Early repolarization masquerading as STEMI.

A 46-year-old man presented to the Emergency Department for chest pain and perianal pain. His blood pressure was 125/79 mm Hg; heart rate was 86 beats per minute. An electrocardiogram (ECG) revealed ST-segment elevation in the inferior and lateral leads (Figure, panel A). Repeat ECG 5 minutes later was identical. Troponin T was elevated at 0.13 ng/mL. ST-elevation myocardial infarction (STEMI) was diagnosed and the patient went immediately to the cardiac catheterization laboratory for revascularization. At angiography, coronary arteries were entirely normal, without any evidence of coronary artery disease. Left ventricular ejection fraction was 0.56; wall motion was completely normal. Left ventricular volumes were 88 mL at end-diastole and 39 mL at end-systole. After STEMI was ruled out, he had an incision and drainage of a perirectal abscess. ECG the next day showed classic changes of early repolarization (Figure, panel B). The patient had no family history of atherosclerotic vascular disease and had never smoked. Glycosylated hemoglobin (commonly called hemoglobin A1c) was 5.8%, total cholesterol was 107 mg/dL, low-density lipoprotein 66 mg/dL, triglycerides 69 mg/dL, and high-density lipoprotein 27 mg/dL. The patient made a rapid, complete recovery without incident. At time of discharge, the ECG was normal, without any changes of repolarization. Intermittent presence of ECG changes of early repolarization has been described.
Modeling the switching dynamics of programmable-metallization-cell (PMC) memory and its application as synapse device for a neuromorphic computation system

A physical model is developed to investigate the switching dynamics of programmable-metallization-cell (PMC) memory. Both “quasi-DC” and time-dependent transient characteristics of PMC are captured by this model in good agreement with the experimental data from Cu/SiO 2 and Ag/Ge 0.3 Se 0.7 cells. For the first time, the time-dependent switching process of PMC is quantified, thus paving the way for a compact SPICE model for circuit simulation. This model reveals that experimentally measured switching parameters such as threshold voltage and cell resistance are dynamic quantities that depend on the programming pulse shape and not the pulse amplitude alone. Using this model, we show that the PMC has the potential to emulate the function of a biological synapse and exhibit the spike-timing-dependent plasticity (STDP) behavior for emerging neuromorphic computation system designs.
Improving energy efficiency of embedded DRAM caches for high-end computing systems

The number of cores in a single chip in the nodes of high-end computing systems is on rise, due, in part, to a number of constraints, such as power consumption. With this, the size of the last level cache (LLC) has also increased significantly. Since LLCs built with SRAM consume high leakage power, power consumption of LLCs is becoming a significant fraction of processor power consumption. To address this issue, researchers have used embedded DRAM (eDRAM) LLCs which consume low leakage power. However, eDRAM caches consume a significant amount of energy in the form of refresh energy. In this paper, we propose ESTEEM, an energy saving technique for embedded DRAM caches. ESTEEM uses dynamic cache reconfiguration to turn off a portion of the cache to save both leakage and refresh energy. It logically divides the cache sets into multiple modules and turns off possibly different number of ways in each module. Microarchitectural simulations confirm that ESTEEM is effective in improving performance and energy efficiency and provides better results compared to a recently-proposed eDRAM cache energy saving technique, namely Refrint. For single and dual-core simulations, the average energy saving in memory subsystem (LLC+main memory) with ESTEEM is 25.8% and 32.6% respectively, and the average weighted speedup is 1.09x and 1.22x respectively. Additional experiments confirm that ESTEEM works well for a wide-range of system and algorithm parameters.
A minimum profile uniform current density electrode

An electrode that produces an injected charge density that is uniform over the surface of the electrode and thus permits maximum utilization of the surface is described. Charge density is the time integral of current density, and the alteration of the current density is obtained by adding curvature to the electrode and recessing it within a cylindrical insulating well. A novel numerical method is used to determine the recession and curvature. The benefit of this technique is that it permits a reduction in the electrode size while maintaining the maximum safe injected charge level of a disk-type electrode. A minimum profile uniform current density electrode and the algorithms used in its design are presented. Finally, a flat electrode that is recessed by as little as 1/10 of its diameter is shown to have an injected current density on the electrode surface that is superior to that of a flat surface mounted electrode. >
Photovoltaic differential power converter trade-offs as a consequence of panel variation

Photovoltaic (PV) elements have inherent variation between cells and panels due to manufacturing tolerance, degradation, and situational differences. This variation increases over system lifetime and creates maximum power point current mismatch that reduces output power when PV elements are strung in series. Traditionally, mismatch loss is addressed using cascaded converters. However, this research examines a differential converter architecture that achieves higher efficiency by processing a fraction of the total power. The effect of PV maximum power point (MPP) current variance on output power is modeled and examined using Monte Carlo simulation for the series string architecture with and without bypass diodes, and the PV-to-Bus and PV-to-PV differential power processing (DPP) architectures at various power ratings. Hot spotting can be a problem that significantly reduces output power. PV elements at fault can be bypassed, passively or actively, to reduce power loss. Simulation results show that both DPP architectures employing active bypass are able to compensate mismatch over the 25-year lifetime of a PV system with converters sized at approximately 10–20% of the panel ratings.
Etching of Partially Cured Polyimide

The fabrication of patterns in partially cured polyimide films may be accomplished by wet etching with potassium hydroxide. In practice, problems encountered in obtaining uniform etching result from thickness variations in coatings and temperature variations in typical process ovens. The relationship between coating thickness, thermal exposure, degree of cyclization, and etchability was studied. The degree of cyclization was determined by Fourier Transform Infrared Spectroscopy and etch rates were measured by monitoring coating thickness. It was found that the level of imidization was directly influenced by coating thickness as well as thermal exposure. For films exposed to the same thermal conditions, the etch rate decreased as the thickness increased beyond 15 pm. However, when films of various thicknesses were brought to the same level of imidization, a constant etch rate was obtained. A significant improvement in the etch rate can be achieved by reducing the level of imidization, increasing the etchant temperature, or enhancing the solubility of the carboxylate salt of the polyamic acid produced during etching.
ATP is Required for Receptor-Mediated Endocytosis Both in Vivo and in Vitro

The process of receptor-mediated endocytosis via clathrin-coated pits has been well-defined at the ultrastructural level. Receptors are concentrated in specialized “coated pit” regions of the cell surface which invaginate and pinch-off to form coated vesicles carrying receptors and bound ligands into the cell. At the molecular level, most of the constituents of the protein coat are known (although new coat constituents are still being identified, Ahle and Ungewickell, 1990) and a growing number of these have been cloned allowing primary sequence determination (for reviews see Pearse and Crowther, 1987; Brodsky, 1988; Morris et al., 1989). The major coat proteins are clathrin triskelions which consist of three 180kD clathrin heavy chains each with a tightly associated ∼30kD light chain. Assembly protein (AP) complexes or ‘adaptins’ appear to mediate the binding of the clathrin coat to the plasma membrane perhaps through direct interaction with the cytoplasmic domains of receptors (Keen, 1987; Virshup and Bennett, 1988; Glickman et al. 1989). These complexes consist of two ∼110kD, two ∼50 kD and two ∼20 kD subunits and are present at a 3:2 molar ratio to triskelions in the coat (reviewed by Morris et al., 1989). Two distinct protein kinases have also been identified as constituents of the coat structure, the 50kD kinase subunit of the assembly protein complex API and a casein kinase II-activity. An additional light chain B kinase activity has also been identified. No function has yet been ascribed to either of these kinase activities.
Calcineurin Inhibitor-Free GVHD Prophylaxis with Post-Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT)

Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. Although advances in immunosuppressive regimens have had a significant impact on the incidence and severity of acute GVHD, it is noteworthy that CNIs have had little impact on chronic GVHD. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. Twenty-seven patients with high risk hematologic malignancies were enrolled in the study: median age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD. Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). Transplant-related toxicity included BK virus-associated cystitis in 33% of patients and a non-fatal hepatotoxicity syndrome in three patients consisting of transaminase elevation and ascites, with resolution following discontinuation of sirolimus. CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT. ![Graphic][1] Disclosures: Off Label Use: fludarabine, cyclophosphamide, and sirolimus are not FDA-labeled for stem cell transplantation. [1]: /embed/inline-graphic-1.gif
Simulation modeling of customer checkout configurations

A simulation model based on a case study of a retail customer check out area and two extended models is presented. The first extended model examines the customer's criteria when picking a checkout lane. The second extension examines the checkout layout, in which the payment is separated from the checkout station. The results show no significant difference in checkout time based on the lane choice criteria. However, the average waiting time drops significantly when payment is separated from the checkout area.
Leucine kinetics at graded intakes in young men: quantitative fate of dietary leucine

To explore leucine metabolism in relation to leucine intake, five young adult men received an L-amino acid diet that supplied 40, 30, 20, and 10 mg leucine.kg-1.d-1 for 6 d. A stable-isotope-tracer infusion study was then conducted for 5 h while subjects received an intragastric infusion of the test diet. Primed, constant infusions of L-[1-13C]leucine (intragastric) and L-[2H3]leucine (intravenous) were given simultaneously. A final infusion study was conducted in subjects in the postabsorptive state after an additional 2 d with the 10-mg diet. Estimates were made of leucine flux and oxidation, rates of uptake and release of absorbed leucine by the splanchnic region, and leucine balance. The rate of appearance of dietary leucine in the systemic circulation (Leud) decreased (p less than 0.01) between the 40- and 10-mg diets. At the latter intake, splanchnic uptake was approximately 37% of absorbed leucine. The correlation between Leud and plasma leucine concentration was highly positive. A leucine intake of approximately 40 mg. kg-1.d-1 was close to that required to maintain leucine balance under these conditions.
Embryogenesis Recapitulates Oogenesis in Swine

Events during oogenesis can affect embryogenesis so dramatically that oocytes can be identified that are progenitors of embryos which would probably die if they remained in the host pig, but would live if appropriately transferred to another female. This review goes backward from embryonic to oocyte development, first discussing how subtle differences between littermate embryos can result in the death of some embryos and then relating the causes of those differences to events during follicular maturation. Embryonic development is not uniform in swine. The larger blastocysts within a litter synthesize estradiol sooner than their less developed contemporaries. Estradiol advances uterine secretions to the benefit of the more developed blastocysts, but results in an asynchronous and hostile environment for the less developed blastocysts. Through a series of experiments, the pattern of oocyte and follicular development was found to be one of the sources of subsequent disparity among blastocysts. In pigs mated before ovulation, the first oocytes released at ovulation were the first fertilized and became the more developed blastocysts 12 days later. Inversely, the later ovulated oocytes were the last to be fertilized and became the smaller blastocysts. These smaller blastocysts can develop normally, but because of estrogenic advancement of uterine secretions, they will preferentially die.
A New Test of Self-Paced Work Sensitive to the Effects of Prolonged Work and Sleep Deprivation

This study evaluated a new test of physical persistence, a wall building task. Volunteers (n=14) built as many 10 × 10 walls as possible using brick-size wooden blocks in 25 min on six different days. Four of the six days were without treatment effects to measure test reliability. Assessment was also done twice during a simulated military sustained operation scenario (SUSOPS) at 48 and 72 hours after SUSOPS initiation. Volunteers were kept busy with military tasks 21–22 hours per day when not being tested. There was a 26% decrement (p≤0.001) in walls built after 48 hrs of SUSOPS, with intraclass reliability of R = 0.84. The wall building test was demonstrated to be reproducible, easily administered, and is sensitive to the effects of prolonged work and sleep deprivation that occur during SUSOPS. This test would be a useful tool to measure potential interventions used to combat the effects of SUSOPS.
Identification of Pupae of Six Species of Tribolium (Coleoptera: Tenebrionidae)

The confused flour beetle, T. confusnm Jacquelin duVal; the red flour beetle, T. castaneum (Herbst); T.destructor Uyttenboogaart; T. madens Charpentier; and T. brevicornis (LeConte) are stored-grain pests in the United States. The 6th species, T. anaphe Hinton, is amember of a species-group which is not yet establishedin this country. The pupae are distinguishable by the use of setal maps of the pronotum and of the abdominalprojections, and by the arrangement of the facets betweenthe 2 optical lobes of the compound eyes. A generaldescription of these pupae, with a taxonomic keyfor identifying them, is presented, and the systematicrelationships between them are discussed. Classificationof the species on the basis of pupal characteristics is compared with that derived by use of larval and adult characters.
Endotoxin-induced uveitis in rodents

Uveitis can affect individuals of all ages, genders, and races and accounts for 10-15% of all cases of blindness. Uveitis represents a diverse array of intraocular inflammatory conditions that can be associated with complications from autoimmune diseases, bacterial infections, viral infections, chemical injuries, and metabolic issues. In rodents, endotoxin-induced uveitis (EIU) is an efficient experimental model to study pathological mechanisms associated with the disease and evaluate the pharmacological efficacy of potential new drug agents. In the EIU model, uveitis is characterized by clinically relevant inflammation, including inflammatory exudates and cells infiltrated into the anterior and vitreous eye chambers. EIU in small animal models, including rats, mice, and rabbits, is characterized by a short-lived uveal inflammation. This inflammation can be facilitated using bacterial endotoxins, such as lipopolysaccharide (LPS). In this chapter, we present a reliable, reproducible, and simplified protocol to induce EIU in mice. This method is flexible and can be applied for EIU induction in other small animals and rodents.
Probing electrocolored Fe-doped SrTiO3 bulks using optical second harmonic generation

We have investigated the spatial distribution of non-centrosymmetric defects in the electrocolored bulks of oxidized and reduced Fe-doped SrTiO3 (Fe:STO) single crystals by optical second harmonic generation (SHG) spectroscopy in the transmission geometry. Transmitted SHG intensities were examined across the anodic, mixed, and cathodic bulk regions of both Fe:STO crystals. The obtained nonlinear susceptibility ratios show that the structural distortions in the anodic and cathodic bulks of the electrocolored crystals are dominated by Fe:TiO bond bending around Fe4+ defect centers and Fe:TiO bond stretching around Fe3+ defect centers, respectively. Moreover, we identified a stronger local strain field at the color front of the oxidized crystal over the reduced one. This is attributed to more efficient strain relaxation during oxygen vacancy demixing in the reduced crystal.
Using an Angle-Based, Sampled-Data Approach to Modeling a Diesel Engine

Abstract This paper presents a technique for using state space sampled-data analysis in the modeling of systems containing samplers operating at regular intervals of some variable other than time. A state space sampled-data approach to modeling of systems with natural samplers is a precursor to using sampled-data or discrete state space control design techniques. The technique is applied to the problem of modeling a diesel engine which has natural samplers that operate at regular intervals of the engine's angle of rotation.
Minimizing opioid use after acute major trauma

Purpose Results of an initiative at an academic medical center to reduce prescription opioid use in patients with acute traumatic injuries are reported. Methods In 2014, the University of Kentucky Hospital trauma service implemented a pain management strategy consisting of patient and provider education emphasizing the use of nonopioid analgesics to minimize opioid use without compromising analgesia effectiveness. To assess the impact of the initiative, a retrospective analysis of data on cohorts of patients admitted with acute trauma before ( n = 489) and after ( n = 424) project implementation was conducted. The primary endpoint was opioid use (prescribed daily milligram morphine equivalents [MME]) at discharge. Secondary endpoints included inpatient opioid and alternative analgesic use, pain control, ileus development, length of stay, and discharge disposition. Results Compared with the preintervention cohort, the postintervention cohort had a lower median daily discharge MME overall (45 MME versus 90 MME, p Conclusion Targeted provider and patient education on minimizing opioid use was associated with a reduction in MME on discharge from the hospital after traumatic injury.
Effect of prenatal EPA and DHA on maternal and umbilical cord blood cytokines

Investigators have hypothesized that omega-3 fatty acid supplementation may modulate the immune response. However, available evidence is conflicting. We performed this study to investigate the effect of prenatal eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-rich fish oil supplementation on maternal and fetal cytokine production. This study is a secondary analysis of a randomized controlled trial designed to assess whether prenatal EPA- or DHA-rich fish oil supplementation would prevent perinatal depressive symptoms among women at risk. Enrolled participants received EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA) or soy oil placebo. Maternal venous blood was collected at enrollment (12–20 weeks gestation) and after supplementation (34–36 weeks gestation). Umbilical cord blood was collected at delivery. We analyzed stored plasma specimens for 16 human cytokines using multiplex immunoassays. Maternal and cord blood cytokine levels were compared among the treatment groups. Associations of serum DHA and EPA with maternal and cord blood cytokines were explored via regression analysis. We enrolled 126 women, of whom 118 completed the trial. Prenatal supplementation with EPA-rich fish oil significantly lowered maternal IL6, IL15, and TNFα concentrations. However, supplementation with DHA-rich fish oil had no significant effect on maternal cytokine profiles. Maternal serum DHA fraction was significantly associated with IL1α, and maternal serum DHA and EPA fractions were significantly associated with IL 10 concentrations after supplementation. Compared with placebo, supplementation with EPA- or DHA-rich fish oils had no significant effect on cord blood cytokine concentrations. Prenatal supplementation with EPA-rich fish oil significantly reduced levels of several inflammatory cytokines in maternal plasma, while prenatal DHA-rich fish oil had no significant effect on cytokine concentrations. Supplementation with EPA- and DHA- rich fish oil had no significant effect on umbilical cord blood cytokine concentrations. Clinical Trial Registration: registration number NCT00711971 7/7/2008.
Markers of central nervous system glia and neurons in vivo during normal and pathological conditions.

Cell markers are valuable tools for examining the function of cells in normal conditions as well as during disease and repair processes. In fact, our understanding of the cell types that make up the central nervous system (CNS) is very much shaped by the markers available to identify them. CNS cell types were originally identified by morphology. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells in situ. An ideal marker is specific to a given cell type in normal conditions and/or during conditions involving injury or disease. As simple as these criteria sound, they are not easy to fulfill. Markers can be expressed on more that one cell type. Astrocytes and olfactory-tract-ensheathing glia both express glial fibrillary acidic protein (GFAP), even though they have clear phe-notypic, anatomical, and functional differences (Ramon-Cueto and Valverde 1995). Also, a marker that is specific for a given cell type in normal conditions can be induced or up-regulated on other cell types during conditions such as inflammation, disease, or injury. Therefore cell type markers alone do not always conclusively identify a cell type.
Dominant negative GPR161 rare variants are risk factors of human spina bifida

Spina bifida (SB) is a complex disorder of failed neural tube closure during the first month of human gestation, with a suspected etiology involving multiple gene and environmental interactions. GPR161 is a ciliary G-protein coupled receptor that regulates Sonic Hedgehog (Shh) signaling. Gpr161 null and hypomorphic mutations cause neural tube defects (NTDs) in mouse models. Herein we show that several genes involved in Shh and Wnt signaling were differentially expressed in the Gpr161 null embryos using RNA-seq analysis. To determine whether there exists an association between GPR161 and SB in humans, we performed direct Sanger sequencing on the GPR161 gene in a cohort of 384 SB patients and 190 healthy controls. We identified six rare variants of GPR161 in six SB cases, of which two of the variants were novel and did not exist in any databases. Both of these variants were predicted to be damaging by SIFT and/or PolyPhen analysis. The novel GPR161 rare variants mislocalized to the primary cilia, dysregulated Shh and Wnt signaling and inhibited cell proliferation in vitro. Our results demonstrate that GPR161 mutations cause NTDs via dysregulation of Shh and Wnt signaling in mice, and novel rare variants of GPR161 can be risk factors for SB in humans.