cssi/SciSciGPT-SciSciNet huggingface dataset:
Synthesis and Structural Characterization of New Polyphosphorus Ring and Cage Compounds.

The 1:1 and 2:1 reactions of (Me3Si)2PLi·2THF with several amino chlorophosphanes have been surveyed. With iPr2NPCl2, both reactant stoichiometries produce the four-membered ring compound (3) via different reaction schemes. Compound 3 combines with Fe2(CO)9 to produce a monometallic complex (4) in which the Fe(CO)4 fragment is bonded to one of the Me3SiP centers. With the cyclic hydrazino phosphane ClP(MeNNMe)2PCl only the bis-phosphane substitution product, (Me3Si)2PP(MeNNMe)2PP(SiMe3)2, is isolated. With the cyclic diazadiphosphetidine (tBuNPCl)2 a bis-phosphane substitution product [tBuNPP(SiMe3)2]2 (10) is formed along with a cage compound [(tBuNP)2P(SiMe3)]2 (11). The new compounds have been characterized by spectroscopic techniques, and the molecular structure of 4 and 11 have been determined by X-ray crystallography.
Epidermal growth factor-specific protein tyrosine phosphorylation in preimplantation embryo development.

We examined whether epidermal growth factor (EGF)-induced preimplantation mouse embryo development and function are mediated by EGF-speciflc protein tyrosine phosphorylation (PTP). In situ cross-linking and autophosphorylation studies showed that EGF receptor (EGF-R) in Day 4 mouse blastocysts is a protein of approximately 170 kDa that is phosphorylated when exposed to EGF and ATP. Furthermore, EGF induced about a twofold increase in protein tyrosine kinase (PTK) activity in Day 4 blastocysts when incubated in the presence of a peptide substratewith a tyrosine moiety and ATP. RG 50864, a specific inhibitor of EGFdependent PTK, diminished autophosphorylation of the 1 70-kDa protein and completely blocked PTK activity in the blastocyst induced by EGF. However, this inhibitor did not affect EGF binding to the embryonic cell surface. In contrast, an inactive tyrphostin compound, RG 50862, did not alter EGF-induced PTK activity in the blastocyst. These findings led us to examine the effects of these tyrphostin compounds on preimplantation mouse embryo development and blastocyst hatching in vitro. R(; 50864, in a dose.dependent manner, inhibited EGF-dependent development of 2-cell embryos to blastocysts and the number of cells per blastocyst. This inhibitor also antagonized EGF-induced zona-hatching of blastocysts formed from 8.cell embryos in culture. However, the inhibitor was not effective in deterring transforming growth factor-�1-induced blastocyst formation. The inactive compound, RG 50862, had no effects on EGF-dependent blastocyst formation or zona-hatching. The data show that the effects of RG 50864 are specificand mediated by inhibition of EGF-speciflc PTK activity. Taken together, the results suggest that signal transduction by EGF Iigand-receptor-mediated PTP is important for mouse preimplantation embryo development and function.
Multiple terminals under user program control in a time-sharing environment

User-written programs on the Dartmouth Time-Sharing System can communicate with many remote terminals simultaneously and can control the interactions between these terminals. Such programs can be written using standard input and output instructions in any language available on the system. This paper describes how this multiple-terminal facility was implemented without requiring any changes in the system executive or in any of the system's compilers or interpreters.
Glycosylation Is Dispensable for Sorting of Synaptotagmin 1 but Is Critical for Targeting of SV2 and Synaptophysin to Recycling Synaptic Vesicles

Glycosylation is a major form of post-translational modification of synaptic vesicle membrane proteins. For example, the three major synaptic vesicle glycoproteins, synaptotagmin 1, synaptophysin, and SV2, represent ∼30% of the total copy number of vesicle proteins. Previous studies suggested that glycosylation is required for the vesicular targeting of synaptotagmin 1, but the role of glycosylation of synaptophysin and SV2 has not been explored in detail. In this study, we analyzed all glycosylation sites on synaptotagmin 1, synaptophysin, and SV2A via mutagenesis and optical imaging of pHluorin-tagged proteins in cultured neurons from knock-out mice lacking each protein. Surprisingly, these experiments revealed that glycosylation is completely dispensable for the sorting of synaptotagmin 1 to SVs whereas the N-glycans on SV2A are only partially dispensable. In contrast, N-glycan addition is essential for the synaptic localization and function of synaptophysin. Thus, glycosylation plays distinct roles in the trafficking of each of the three major synaptic vesicle glycoproteins.
Stabilized approximation to degenerate transport equations via filtering

Abstract We analyze a stabilization technique for degenerate transport equations. Of particular interest are coupled parabolic/hyperbolic problems, when the diffusion coefficient is zero in part of the domain. The unstabilized, computed approximations of these problems are highly oscillatory, and several techniques have been proposed and analyzed to mitigate the effects of the sub-grid errors that contribute to the oscillatory behavior. In this paper, we modify a time-relaxation algorithm proposed in [1] and further studied in [10] . Our modification introduces the relaxation operator as a post-processing step. The operator is not time-dependent, so the discrete (relaxation) system need only be factored once. We provide convergence analysis for our algorithm along with numerical results for several model problems.
The effect of the treatment of hypothyroidism and hyperthyroidism on plasma lipids and apolipoproteins AI, AII and E

Objective Although lipid abnormalities are well described in hypothyroidism, effects on apolipoproteins are less well understood. The aim of this study was to examine the effects of thyroid dysfunction on plasma lipids and apolipoproteins. Design A prospective study of lipids and apolipoproteins before and after treatment of hypothyroidism and hyperthyroidism. Patients Eighteen patients with hypothyroidism and 5 patients with hyperthyroidism were included. Measurements Plasma cholesterol, triglycerides, HDL cholesterol, apo AI, apo AII, and apo E were measured before and after treatment of the thyroid abnormality. Results Total and HDL cholesterol, apo AI and apo E decreased with treatment of hypothyroidism, while triglycerides and apo AII levels were unchanged. The total/HDL cholesterol and LDL/HDL cholesterol ratios also decreased with treatment of hypothyroidism. In contrast, treatment of hyperthyroidism was associated with an increase in total and HDL cholesterol, and apo AI. Triglycerides, apo AII and Apo E were unchanged by treatment of hyperthyroidism. The total/HDL cholesterol and the LDL/HDL cholesterol ratios increased with treatment of hyperthyroidism. Conclusions Hypothyroidism and hyperthyroidism have opposite effects on plasma lipids and apolipoproteins. In hypothyroidism, total and HDL cholesterol, total/HDL cholesterol ratio, apo AI and apo E are elevated. The increase in apo AI without a concomitant increase in apo AII suggests selective elevation of HDL2. In contrast, hyperthyroidism is associated with decreased total and HDL cholesterol, total/HDL cholesterol ratio, and apo AI levels. These effects are reversible with treatment of the underlying thyroid disorder.
Enhancing the value delivered by the statistician throughout drug discovery and development: putting statistical science into regulated pharmaceutical innovation.

With the dawn of the 21st century, the pharmaceutical industry faces a dramatically different constellation of business and scientific predictors of success than those of just a few years ago. Significant advances in science at the genetic, molecular and cellular levels, combined with progress demonstrated around the globe with drug regulations, have increased business and competitive opportunities. This has occurred in search of better and cheaper medicines that reach patients with unmet medical needs as quickly as possible. Herein lie new opportunities for those who can help business and regulatory leaders make good decisions about drug development and market authorization as quickly and efficiently as possible in the presence of uncertainty. The statistician is uniquely trained and qualified to render such value. We show how the statistician can contribute to the process of drug innovation from the very early stages of drug discovery until patients, payers and regulators are satisfied. Indeed, the very nature of regulated innovation demands that efficient and effective processes are implemented which yield the right information for good decision making. The statistician can take the lead in setting a strategy that directs such processes in the direction of greatest value. This demands skills that enable one to identify important sources of variability and uncertainty and then leverage those skills to make decisions. If such decisions call for more information, then the statistician can render experimental designs which generate the right information needed to make the decision in an efficient, timely manner. To add value to the enterprise, statisticians will have to become more intimately associated with business and regulatory decisions by building on their traditional roles (for example, numerical analyst, tactician) and unique skill sets (for example, analysis, computation, logical thought and work process, precision, accuracy). Business and regulatory savvy, coupled with excellent communication and interpersonal skills, will allow statisticians to help create the knowledge needed to drive success in the future.
Using a Novel Dual Fluorescence Quenching Assay for Measurement of Tryptophan Depth within Lipid Bilayers To Determine Hydrophobic α-Helix Locations within Membranes†

A novel fluorescence method for determining the depth of Trp residues in membrane-inserted polypeptides is introduced. Quenching of Trp by acrylamide and 10-doxylnonadecane (10-DN) was used to measure Trp depth. Transmembrane helices with Trp residues at varying positions (and thus locating at different depths in lipid bilayers) were used to calibrate the method. It was found that acrylamide quenches Trp close to the bilayer surface more strongly than it quenches deeply buried Trp, while 10-DN quenches Trp close to the center of the bilayer more strongly than Trp close to the surface. The ratio of acrylamide quenching to that of 10-DN was found to be nearly linearly dependent on the depth of Trp in a membrane. It was also found that it was possible to detect coexisting shallowly and deeply inserted populations of Trp-containing polypeptides using these quenchers. In the presence of such mixed populations, acrylamide induced large blue shifts in fluorescence emission lambda(max) whereas 10-DN induced large red shifts. In a more homogeneous population quencher-induced shifts were found to be minimal. Dual quencher analysis can be used to distinguish hydrophobic helices with a transmembrane orientation from those located close to the bilayer surface and, when applied to a number of different peptides, revealed novel aspects of hydrophobic helix behavior.
Pneumatic skin flattening reduces pain during laser hair reduction.

*Laser surgery and Cosmetic Dermatology Centers, Inc., Bryn Mawr, PennsylvaniaIntroduction: Laser hair reduction targets melanin pig-ment within hair shafts, causing heating and an inﬂam-matory response that sends hair into a prolonged telogenphase. Pain may be a limiting factor for patients seekinglaser hair reduction.Methods: We investigate the affect of pneumatic skinﬂattening (PSF) as compared to conventional treatmentusingthedynamiccoolingdevice(DCD)onpainduringlaserhairreductiontreatmentandevaluatedimmediatelyfollow-ing treatment, as well as the studying its impact on post-treatment effects of laser hair reduction using an alexan-drite and Nd:YAG laser to treat the hair in the axillae of40volunteersubjects.Thirty-foursubjectsweretreatedwitha 755 nm, 3 millisecond pulse-duration alexandrite laserusing ﬂuences ranging from 16 to 20 J/cm
Bloodless cardiac surgery is associated with decreased morbidity and mortality.

Background: Blood transfusion with cardiac surgery accounts for 20% of transfusions in the United States. The effect of perioperative transfusion on cardiac surgery outcomes is unknown. We hypothesized that cardiac surgery with perioperative blood transfusion was associated with worse outcomes. Methods: A prospectively maintained (Society of Thoracic Surgeons) institutional database was analyzed from 2000 to 2005. All patients undergoing coronary artery bypass and/or valve operations were evaluated for the association of preoperative and intraoperative risk factors with blood transfusion. The association of transfusion with postoperative complications and mortality was evaluated. Results: During the study period, 2691 patients met inclusion criteria. Sixty-four percent received transfusions. Preoperative risk factors associated with transfusion (p < 0.05) were lung disease, elevated creatinine, peripheral vascular disease, and previous cardiac interventions. Patients requiring transfusion were older (mean 65.2 vs. 61.2 years, p < 0.001). Transfusion was associated with longer cross-clamp (median 78 vs. 88 minutes, p < 0.001) and perfusion times (median 114 vs. 128 minutes, p < 0.001). Perioperative blood transfusion was associated with increased postoperative complications (53.5% vs. 30.5%, p < 0.001). Significant transfusion-associated complications were renal failure, prolonged ventilation time, pneumonia, cardiac arrest, gastrointestinal complications, atrial fibrillation, stroke, myocardial infarction, and bleeding requiring reoperation. Blood transfusion was associated with an increased operative mortality (3.4% vs. 1.7%, p = 0.005) and length of stay after surgery (median 6 vs. 5 days p < 0.001). Conclusion: Identification and management of risk factors associated with transfusion may reduce the transfusion requirement, minimize perioperative complications and improve outcomes. Bloodless cardiac surgery is associated with a decreased morbidity and mortality.
Increased urinary phosphate excretion following volume expansion in normal man

After expansion of the extracellular fluid volume by approximately 10 per cent with isotonic saline, the mean rate of phosphate excretion more than doubled in 16 normal subjects, although the inulin clearance and amount of filtered phosphate remained constant. Both the total and ultrafilterable plasma concentrations of calcium and magnesium decreased during volume expansion. Phosphate excretion increased even further when hypertonic saline was infused into previously expanded subjects, despite the lack of any additional change in their plasma calcium or magnesium levels. The phosphaturia of volume-expanded individuals could not be reversed rapidly by calcium infusion, even though ultrafilterable plasma calcium concentrations increased to values greater than control. The excretion of sodium, calcium, and magnesium increased during volume expansion, but the extent of change in fractional excretion values for these cations did not correlate with the magnitude of the phosphaturic response. Thus, if phosphate excretion data are utilized in an attempt to assess parathyroid secretory activity, it is imperative that the degree of extracellular fluid volume expansion also be ascertained.
Acoustic emission patterns from the surfaces of red oak wafers under transverse bending stress

One of the applications of acoustic emission (AE) technology in the forest products field is likely to be in monitoring and/or controlling the drying of wood. This report describes experiments designed to monitor the acoustic emission patterns from the lower surfaces of small red oak test beams which were undergoing failure in tension perpendicular to the grain. Similar patterns are likely to develop in wood which surface checks during drying. When the wood was green, the emission patterns from beams under test were well defined and could be used to predict the onset of cracking before the surfaces under tension were visibly cracked. These patterns were quite similar to the acoustic response of brittle, glassy polymers under stress. Additional experiments on partially dried test beams showed that the clearly predictable emission patterns disappeared and the general level of acoustic emissions increased. This increase in emissions may correspond to shrinkage, at the cell level, of the partially dried beams.
Vibrational spectroscopy, Fourier transforms and analytical chemistry

Apports de la spectrometrie a transformee de Fourier a l'etude de spectres de vibration d'echantillons divers
Local Cytokine Environments Drive Aneurysm Formation in Allografted Aortas

The mechanistic differences between the pathways that induce stenotic vs. aneurysmal manifestations of atherosclerosis remain unknown. In a murine aortic interposition graft model, T helper cell type 1 (Th1)- vs. Th2-slanted cytokine environments differentially affected the vascular pathology; specifically, blockade of interferon- γ signaling and/or Th2-enriched environments induced aneurysm formation associated with elastic tissue fragmentation. A Th2 cytokine milieu was shown to increase selected matrix metalloproteinase (MMP) expression, and interleukin 4 stimulated macrophage production of elastolytic matrix metalloproteinase 12 in vitro. The new findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling, and have important implications for the pathophysiology of abdominal aortic aneurysms as well as atherosclerosis.
Factors affecting student performance in an undergraduate genetics course

The objective of this study was to determine some of the factors that affect student success in a genetics course. Genetics for the Kansas State University College of Agriculture is taught in the Department of Animal Sciences and Industry and covers Mendelian inheritance, molecular genetics, and quantitative/population genetics. Data collected from 1,516 students over 7 yr included year and semester of the course; age; gender; state of residence; population of hometown; Kansas City metro resident or not; instructor of course; American College Testing Program (ACT) scores; number of transfer credits; major; college; preveterinary student or not; freshman, sophomore, junior, and senior grade point average (GPA); semester credits when taking genetics; class standing when enrolled in genetics; cumulative GPA before and after taking genetics; semester GPA in semester taking genetics, number of semesters between the biology prerequisite and genetics; grade in biology; location of biology course; and final percentage in genetics. Final percentage in genetics did not differ due to instructor, gender, state of residence, major, or college (P > 0.16). Transfer students tended to perform better than nontransfer students (P = 0.09), and students from the Kansas City metro outscored students from other areas (P = 0.03). Preveterinary option students scored higher in genetics than non-preveterinary students (P < 0.01). Seniors scored higher than juniors and sophomores, who scored higher than freshmen (P < 0.02). We observed a tendency for students with higher grades in biology to perform better in genetics (P = 0.06). Students who took biology at Kansas State University performed better in genetics than students who transferred the credit (P < 0.01). There was a negative regression of hometown population on score in genetics (P < 0.01), and positive regressions of ACT score, all measures of GPA, course load, and cumulative credits on final percentage in the course (P < 0.02). To maximize chances for success in genetics, students should take biology from Kansas State, perform well in biology, and wait until at least sophomore standing to enroll in genetics.
Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism.

Amyloid plaques composed of the peptide Aβ are an integral part of Alzheimer's disease (AD) pathogenesis. We have modeled the process of amyloid plaque growth by monitoring the deposition of soluble Aβ onto amyloid in AD brain tissue or synthetic amyloid fibrils and show that it is mediated by two distinct kinetic processes. In the first phase, “dock”, Aβ addition to the amyloid template is fully reversible (dissociation t1/2 ≈ 10 min), while in the second phase, “lock”, the deposited peptide becomes irreversibly associated (dissociation t1/2 ≫ 1000 min) with the template in a time-dependent manner. The most recently deposited peptide dissociates first while Aβ previously deposited becomes irreversibly “locked” onto the template. Thus, the transition from monomer to neurotoxic amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the prion diseases. Interestingly, two Aβ peptides bearing primary sequence alterations implicated in heritable Aβ amyloidoses display...
Functional analysis of a conserved amino-terminal region of HSP70 by site-directed mutagenesis.

Hsp70 proteins have been highly conserved throughout evolution. As a first step in a structure–function analysis of hsp70, we constructed and analysed the consequences of mutations in a portion of the SSA1 gene, a member of the Saccharomyces cerevisiae HSP70 multigene family, that encodes a nearly invariant region near the amino terminus. Analysis of strains expressing SSA1 proteins with alterations at positions 8, 11 and 15 showed that these conserved residues within this region are critical for normal functioning of the protein. SSA1 protein containing either of two changes at position 15 was able to slightly complement the inviability of an ssa1ssa2ssa4 strain, but was inactive in other complementation assays. The other mutant proteins tested were unable to complement any tested phenotype. Effective interallelic complementation of several phenotypes was observed when a mutant protein substituted at position 8 was expressed in the same cell with either of two proteins carrying substitutions at position 15, suggesting that hsp70 acts as a multimer. Evidence from previous studies suggests that hsp70 proteins engage in ATP-driven cycles of binding and release from peptides. The ability of the mutant proteins to bind ATP and a peptide was tested. The Ssa 1p carrying a substitution at position 8, which inhibits growth of cells carrying wild-type SSA proteins, showed a defect in release from a peptide relative to wild type. Two mutations, one each at position 8 and 15, resulted in accumulation of phosphorylated isoforms which may be a normal, transient hsp70 intermediate.
Complex coordinate rotation calculation of branching ratios

It is shown how branching ratios can be obtained from complex coordinate rotation calculations. The procedure is applied to a rotational Feshbach resonance in a model atom-diatom van der Waals complex which has two open channels present, and to a simple two-channel model potential problem which has been treated by other workers.
Effects of d-Amphetamine in Grouped Versus Isolated Humans

Abstract de WIT, H., M. CLARK AND L. H. BRAUER. Effects of d-amphetamine in grouped versus isolated humans. PHARMACOL BIOCHEM BEHAV 57(1/2) 333––340, 1997.—This study was designed to determine whether the subjective, behavioral or physiological effects of a stimulant drug in humans depend on whether subjects are tested under isolated or social conditions. Forty-two subjects were randomly assigned to either the Social (SOC) or Isolated (ISO) condition. SOC subjects participated in 4 h laboratory sessions in groups of 3 or 4, whereas ISO subjects participated in the sessions alone. All subjects participated in three sessions, during which they received capsules containing d-amphetamine (10 or 20 mg) or placebo, in mixed order under double blind conditions. Subjective, physiological and behavioral measures were obtained at regular intervals. d-amphetamine produced dose-related, prototypic stimulant effects on many measures, including self-reported mood states, behavioral indices and physiological measures. Most of these effects were unaffected by the setting in which subjects were tested (SOC vs ISO). However, body temperature was overall higher in the SOC group, and there was a trend for d-amphet-amine to produce greater hyperthermic effects in the SOC group. In addition, 10 mg d-amphetamine increased heart rate in the SOC group but not in the ISO group. The results suggest that, like in laboratory animals, some of the effects of stimulants in humans are greater under aggregated conditions. However, unlike in the animal studies, this observed enhancement of the drug's effects under aggregated conditions was limited to physiological measures and did not apply to other subjective or behavioral measures.
Bora-aromatic systems I. Competition between haloboration and phenylboration in the attempted synthesis of triphenylboracyclopropene☆☆☆

A possible tactical approach to the synthesis of triphenylboracyclopropene (triphenylborirene) is described as involving: (a) the addition of phenylboron dibromide to the triple bond of diphenylacetylene; and (b) the interaction of the resulting (cis-2-bromo-1,2-diphenylvinyl)phenylboron bromide with lithium metal in tetrahydrofuran at −77°. Factors determining the competition between BBr bond addition in step “a” and the slower BC6H5 bond addition to the triple bond are analyzed. By treatment of aliquots of the reaction product of steps “a” and “b” with alkyl halides, with carbon dioxide and with O-deuterioacetic acid, it is concluded that a stilbene derivative with vicinal cis-carbon-boron bonds has been formed. The nature of the organoborane precursor of cis-stilbene is discussed in terms of structural alternatives, such as triphenylborirene, hexaphenyl-1,4-diboracyclohexadiene or a polymer.
Synthesis-Dependent Atomic Surface Structures of Oxide Nanoparticles

Using SrTiO3 nanocuboids as a model system, we show with aberration-corrected high resolution electron microscopy at sub-A resolution that surface relaxations or reconstructions are present on the nanocuboids, depending on the synthetic process. Oleic acid synthesis, acetic acid synthesis, and microwave-assisted acetic acid synthesis result in a SrO termination, TiO2-rich reconstruction, and mixed termination, respectively. The experimental atomic positions are in better agreement with density functional theory calculations using an exact-exchange corrected PBEsol functional than the Perdew-Burke-Ernzerhof (PBE) functional.
Effect of Gas Distributor on Gas Holdup in Fiber Suspensions

Two different aeration plates are used to study their effect on gas holdup and flow regime transition in fiber suspensions. Two gas distributors with different open areas (A = 0.57% and 2.14%) and the same orifice diameter (do = 1 mm) are used, and experiments are performed using three different Rayon fiber lengths (L = 3, 6, and 12 mm) over a range of superficial gas velocities (Ug ≤ 18 cm/s) and a range of fiber mass fractions (0 ≤ C ≤ 1.8%) in a 15.24 cm diameter semi-batch bubble column. Experimental results show that the distributor with A = 2.14% tends to produce lower gas holdup than the one with A = 0.57% for both air-water systems and fiber slurries. However, the effect of distributor open area on gas holdup diminishes at high fiber mass fractions (C ≤ 1.2%). Both distributors generate homogeneous, transitional, and heterogeneous flow regimes over the range of superficial gas velocities for air-water and low fiber mass fraction suspensions. However, the distributor with A = 2.14% enhances the flow regime transition, i.e., the superficial gas velocity at which the transitional flow regime appears is lower. Additionally, the fiber mass fraction at which purely heterogeneous flow is observed is lower when A = 2.14%.Copyright © 2004 by ASME
Thyroid hormone regulation of the pulsatile discharges of luteinizing hormone in ovariectomized rats.

The pulsatile discharges of luteinizing hormone (LH) were characterized in ovariectomized rats in the presence or absence of thyroid hormone. LH secretion in ovariectomized rats with intact thyroid glands and rhyroidectomized-ovariectomized rats receiving daily physiological doses of thyroxine (2 µ.g⁄100 g BW⁄day for 8 days) showed equivalent periodic discharges with frequencies between 15 and 45 min. Though the frequency of the plasma LHrhythm in untreated athyroid-ovariectomized rats was normal, the maximum and minimum concentrations were 2- to 3-fold higher than those ofeuthyroid-ovariectomized animals. On the other hand, treatment of athyroid-ovariectomized rats with a daily hyperthyroid dose of thyroxine (20 eg⁄100 g BW) for 8 days, attenuated pulsatile discharges of LH. The LH measured in the sera of these animals each gave dose-response curves by radioimmunoassay which were identical to the authentic rat LH reference preparation. Furthermore, neither the molecular profile nor the metabolic clearanc...
The role of predictive biopharmaceutical modeling and simulation in drug development and regulatory evaluation

Advances in predicting in vivo performance of drug products has the potential to change how drug products are developed and reviewed. Modeling and simulation methods are now more commonly used in drug product development and regulatory drug review. These applications include, but are not limited to: the development of biorelevant specifications, the determination of bioequivalence metrics for modified release products with rapid therapeutic onset, the design of in vitro–in vivo correlations in a mechanistic framework, and prediction of food effect. As new regulatory concepts such as quality by design require better application of biopharmaceutical modeling in drug product development, regulatory challenges in bioequivalence demonstration of complex drug products also present exciting opportunities for creative modeling and simulation approaches. A collaborative effort among academia, government and industry in modeling and simulation will result in improved safe and effective new/generic drugs to the American public.
Inhibition of deoxycholate-induced apoptosis in iron-depleted HCT-116 cells

The bile acid, deoxycholate (DOC), can induce apoptosis in cells containing adequate amounts of all key nutrients, but it is unknown whether DOC-induced apoptosis can occur in cells lacking a single key nutrient. The aim of this study was to determine if DOC is able to induce apoptosis in HCT-116 colon epithelial cells depleted of iron. The cells were made iron-deficient by pre-treating them with the iron chelator, deferoxamine (DFO), before subsequent exposure to DOC. Mitochondrial dysfunction was detected in control cells exposed to DOC, but not in iron-depleted cells exposed to DOC. Moreover, characteristic features of apoptosis, namely, membrane blebbing, formation of apoptotic bodies, cytochrome c release into cytosol, generation of the activated form of caspase-3, chromatin condensation and fragmentation, and also plasma membrane phospholipid translocation, were all induced by DOC in control cells but not in iron-depleted cells. Treating DFO-pretreated cells with ferrous sulfate to replenish cellular iron restored the ability of DOC to induce apoptosis. In relating these findings to oxidative stress, it was found that DOC also induced the formation of reactive oxygen species and caused DNA damage in control cells, but not in iron-depleted cells. Collectively, the results suggest that in order for HCT-116 cells to undergo apoptosis when exposed to DOC, adequate amounts of intracellular iron must be present.
Chronology of primate discoveries in Myanmar: Influences on the anthropoid origins debate

The history of primate paleontology in Asia is long and complex, beginning with the first discoveries of fossil primates on the Indian subcontinent in the early 1830's. The first Eocene mammals from Asia were collected in Myanmar and described in 1916, while the first primates, Pondaungia and Amphipithecus, were described in 1927 and 1937, respectively, both from the Pondaung Formation in Myanmar. For the next 60 years, these two Pondaung taxa remained as the only known Eocene primates from Myanmar and one of the few records of Eocene primates from all of Asia. Taxonomically, Pondaungia and Amphipithecus were linked with a number of different groups, including archaic, hoofed ungulates (condylarths), adapiform primates, omomyid primates, and anthropoids. While no consensus existed, Pondaungia and Amphipithecus were most commonly compared with anthropoids. Beginning in the late 1990s, new primates were discovered in Myanmar, including smaller-bodied forms such as Bahinia and Myanmarpithecus. Also, new and better specimens of the larger-bodied Pondaungia and Amphipithecus began to appear, including the first cranial and postcranial fragments. Evaluations based on these new specimens, especially the postcrania, indicate that the two larger-bodied Myanmar taxa are adapiform primates that show their closest affinities to North American notharctines. The smaller-bodied taxa remain enigmatic, but may share their closest affinities with North American and Asian omomyid primates and Asian Tarsius. None of the known Asian primate taxa appear closely related to African anthropoids, which suggests that true anthropoids did not reach Asia until the latest Oligocene or earliest Miocene. These facts make an Asian origin for Anthropoidea unlikely. Additional and earlier evidence from both Asia and Africa is required before the ultimate origin of anthropoids can be determined. It appears possible that true anthropoids were an ancient radiation that may have been part of a Gondwanan (southern hemisphere) community that is, at present, poorly sampled and little understood.
Urticaria pigmentosa and Nager syndrome

No family members were known to have urticaria pigmentosa or similar anomalies. On physical examination at age 3 years her height was 92.2 em (40th percentile) and her weight was 13.1 kg (25th percentile). There were multiple 1 to 3 rom brown macules scattered on the limbs and torso that were most pronounced on the upper shoulders and buttocks (Fig. 1). Themacules urticated when rubbed (Darier's sign). Her head was microcephalic (45 em) with malformed, low-set ears. She had an imperforate external auditory canal on the right and a stenotic canal on the left. She also had severe micrognathia and slight webbing oftheneck (Fig. 2). Her thumbs were hypoplastic, and she had mild 3-4 syndactyly of the toes. Fig. 1. Multiple brown macules ofurticaria pigrnentosa on the buttocks.
Determinations of Residual Thermal Stresses in a SiC-Al2O3 Composite Using Neutron Diffraction

Residual thermal stresses and strains, developed during cooling of a SiC whisker-Al2O3 composite, were determined by an experimental neutron diffraction technique and the results were compared with analytically determined values. High compressive residual thermal stresses were generated in the whiskers during cooldown after sintering. Analytical estimates of the residual stresses were obtained by using two self-consistent models: (1) a plane strain composite cylinder model and (2) Eshelby's ellipsoidal inclusion theory. The two models gave almost identical estimates of the stresses and strains in the whiskers. The interpretation of the measured strains in the whiskers by neutron diffraction had some uncertainty because of the lack of a clearly defined crystal structure of SiC.
Implementation Details of an Adaptive Flight Controller

The U.S. Naval Research Laboratory has implemented a novel neural-network adaptive flight controller architecture for helicopter-based unmanned aerial vehicles (UAVs) originally presented by Eric Johnson and Suresh Kannan of the Georgia Institute of Technology. Johnson and Kannan utilized on-line adaptation of a neural network to cancel model errors present in an approximate dynamic inversion of the plant. Due to the advantages of risk reduction during controller development and the increased operational flight envelope resulting from the adaptation of the neural-network, this controller was utilized on a number of dierent rotorcraft at the U.S. Naval Research Laboratory. This paper will describe several interesting implementation details of the controller, as well as modifications made to the basic controller architecture during implementation on dierent vehicles. Eects of scale, rotor system design, and sample time will be discussed. Simulation and flight test data will be presented showing the results of these modifications.
Free Standing Silicon as a Compliant Substrate for SiGe

We show that SiGe grown on free-standing silicon is elastically relaxed. The free-standing Si structure consists of a ∼30 nm-thick, 5 μm-square silicon slab supported by a SiO2 pedestal at a single contact point at the center of the square (the cross-section resembles a mushroom). A matrix of free-standing structures was made by patterning a bonded silicon-on-insulator (SOI) wafer and undercutting the SiO2 to form the pedestal. Un-patterned areas of the SOI wafer and the exposed bulk Si substrate were included as reference regions. A UHVCVD Si0.8Ge0.2 film, about 200 nm-thick, was grown epitaxially on both sides of the free-standing silicon and the surrounding exposed bulk Si. The SiGe was also grown on the un-patterned SOI and bulk substrate control areas. The SiGe film grown on both SOI and bulk silicon was found to be fully strained. In contrast, the SiGe layer grown on free-standing silicon is ∼89% strain-relaxed, and the free-standing silicon film was measured to be under tensile strain. Since the same lattice mismatch was found between the SiGe layer and the Si on the free-standing silicon and on the SOI and bulk Si control regions, we conclude that the strain relaxation of the SiGe film on freestanding Si is elastic with the strain accommodated entirely by the free-standing silicon film under tensile strain. This was further confirmed by AFM measurements. The SiGe film on the control regions showed a very smooth SiGe surface with only a few surface steps originating from misfit dislocations at the SiGe/Si interface. No surface steps from misfit dislocations were observed on the surface of the SiGe film on free-standing Si. These results show that freestanding silicon serves as an ideal compliant substrate for SiGe.
Reversal of cancer anorexia by blockade of central melanocortin receptors in rats.

Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options are limited. To investigate the role of central melanocortin receptor signaling in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into the third cerebral ventricle of Lobund-Wistar rats that were anorexic from prostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU9119 (0.35 nmol, intracerebroventricularly) increased food intake from 71 ± 3% to 110 ± 6% of preanorectic baseline and caused significant weight gain (13 ± 5 vs. 5 ± 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 was ineffective at increasing food intake. The specificity of the SHU9119 feeding response was assessed using two other orexigenic peptides, NPY and the novel hormone ghrelin. Treatment of tumor-bearing r...
Achieving Full Frequency and Space Diversity in Wireless Systems via BICM, OFDM, STBC, and Viterbi Decoding

Orthogonal frequency-division multiplexing (OFDM) is known as an efficient technique to combat frequency-selective channels. In this paper, we show that the combination of bit-interleaved coded modulation (BICM) and OFDM achieves the full frequency diversity offered by a frequency-selective channel with any kind of power delay profile (PDP), conditioned on the minimum Hamming distance dfree of the convolutional code. This system has a simple Viterbi decoder with a modified metric. We then show that by combining such a system with space-time block coding (STBC), one can achieve the full space and frequency diversity of a frequency-selective channel with N transmit and M receive antennas. BICM-STBC-OFDM achieves the maximum diversity order of NML over L-tap frequency-selective channels regardless of the PDP of the channel. This latter system also has a simple Viterbi decoder with a properly modified metric. We verify our analytical results via simulations, including channels employed in the IEEE 802.11 standards
High-Affinity Androgen Binding and Androgenic Regulation of α1(I)-Procollagen and Transforming Growth Factor-β Steady State Messenger Ribonucleic Acid Levels in Human Osteoblast-Like Osteosarcoma Cells*

Clinical observations have demonstrated a positive effect of estrogens and androgens on the maintenance of structural bone integrity. This study examines the direct effects of androgenic hormones on the osteoblast-like human osteosarcoma cell line, HOS TE85. Employing radiolabeled dihydrotestosterone (DHT), 2800 saturable, high-affinity (dissociation constant = 0.66 nM) androgen binding sites were detected per HOS TE85 cell. Androgen binding was specific in that DHT and testosterone (T) displayed significantly greater competition than the progestins, progesterone and medroxyprogesterone. The expression of androgen receptors in HOS TE85 cells was further substantiated by Northern analysis. A human androgen receptor complementary DNA probe revealed a 9.5 kilobase transcript which corresponds to the predominant human androgen receptor transcript detected in human male reproductive tissues. Androgens were also found to elicit biological responses in HOS TE85 cells. Physiological concentrations of DHT and T de...
Formaldehyde gas inactivation of Bacillus anthracis, Bacillus subtilis, and Geobacillus stearothermophilus spores on indoor surface materials.

Aims: To evaluate the decontamination of Bacillus anthracis, Bacillus subtilis, and Geobacillus stearothermophilus spores on indoor surface materials using formaldehyde gas. Methods and Results: B. anthracis, B. subtilis, and G. stearothermophilus spores were dried on seven types of indoor surfaces and exposed to approx. 1100 ppm formaldehyde gas for 10 h. Formaldehyde exposure significantly decreased viable B. anthracis, B. subtilis, and G. stearothermophilus spores on all test materials. Significant differences were observed when comparing the reduction in viable spores of B. anthracis with B. subtilis (galvanized metal and painted wallboard paper) and G. stearothermophilus (industrial carpet and painted wallboard paper). Formaldehyde gas inactivated ‡50% of the biological indicators and spore strips (approx. 1 · 10 6 CFU) when analyzed after 1 and 7 days. Conclusions: Formaldehyde gas significantly reduced the number of viable spores on both porous and nonporous materials in which the two surrogates exhibited similar log reductions to that of B. anthracis on most test materials. Significance and Impact of the Study: These results provide new comparative information for the decontamination of B. anthracis spores with surrogates on indoor surfaces using formaldehyde gas.
Multimarket contact and intensity of competition: evidence from an airline merger.

This paper examines the relationship between multimarket contact (MMC) and the intensity of competition. We take advantage of a recent merger, which altered the extent of MMC throughout the US airline industry, to understand the nature of MMC’s impact on the airlines’ frequency of service. Evidence that non-price effects of MMC are a part of the longer-term industry equilibrium is not robust. However, we observe that following the merger the market players started taking the degree of MMC into account in making their frequency decisions in line with the ‘mutual forbearance’ hypothesis; however, the effect showed signs of diminishing over time. Our results have implications for merger evaluation in industries where consolidation may lead to a higher extent of multimarket contact.
Using a spreadsheet programme to teach introductory statistics: reducing anxiety and building conceptual understanding

This paper presents an innovative method using spreadsheets to reduce anxiety and build understanding in introductory statistics courses. Empirical data show that instruction using spreadsheets is currently concentrated in business statistics classes. The authors advocate the use of spreadsheets in statistics education in other fields and present supporting cases.
Early Neglect Is Associated With Alterations in White Matter Integrity and Cognitive Functioning

Cognitive deficits have been reported in children who experienced early neglect, especially children raised in institutionalized settings. Previous research suggests that early neglect may differentially affect the directional organization of white matter in the prefrontal cortex (PFC). This may be one mechanism to explain cognitive deficits associated with neglect. To test this idea, properties of white matter and neurocognitive performance were assessed in children who suffered early neglect and those raised in typical environments (n = 63, Mage = 11.75 years). As predicted, prefrontal white matter microstructure was affected, consistent with more diffuse organization, in children that suffered early neglect and this was related to neurocognitive deficits. Such findings underscore how early adversity may affect the PFC and explain cognitive deficits associated with neglect. A growing body of research investigating the sequelae of early childhood neglect underscores that such adverse experiences can compromise cognitive development (Fox, Levitt, & Nelson, 2010). Yet, little is currently known about the mechanisms through which early experience influences later cognitive functioning in humans. Early postnatal experience plays a key role in aspects of neurobiological development such as changes in synaptic production, axonal pruning, and myelination in the brain, especially the prefrontal cortex (PFC; for a review, see Petrosini et al., 2009). The PFC has been linked to cognitive development (Diamond, 2002), has one of the most protracted developmental timelines in the brain (Lenroot & Giedd, 2006), and therefore may be particularly vulnerable to the effects of early experience. In addition, experimental research in nonhuman animals, where the early social environment has been controlled or manipulated, suggests that the PFC may be especially vulnerable to
Optical particle sizing for in situ measurements Part 1.

A particle sizing counter suitable for in situ measurements in two-phase flows is presented in a two-part sequence. The technique employs near forwardscatter from the focus of a He–Ne laser beam, together with pulse-height analysis of the signals from individual particles. A novel and essential feature of the technique is a numerical inversion scheme to unfold the dependence of the scattered signals on particle trajectory through the measurement volume. This feature allows the capability of truly in situ measurements with a working space of 50 cm between optical elements. The inversion procedure is performed by an on-line computer or microprocessor unit and uses a prior calibration with monodisperse aerosols of known size. As presently configured, the instrument has a demonstrated capability of determining size distributions in the 1–30-μm diam range, at concentrations up to ~105 cm−3 in flows of temperatures up to 1600 K. The measured dependence of response on particle diameter agrees well with calculations from the Mie scattering theory. It is anticipated that the technique can be extended to cover particle diameters in the 0.5–50-μm range with concentrations up to 106 cm−3. Adaptation to measurements of absorbing and irregular particles can be achieved by a straightforward calibration technique. Part 1 describes the trade offs in the optical design and develops the numerical inversion scheme. Part 2 discusses experimental measurements at ambient conditions and combustion temperatures (1600 K). An assessment of the accuracy of the technique is also presented.