Using Auxiliary Data to Guide the Recruitment of Sites for Randomized Controlled Trials

Sampling methods such as Stratified Random Sampling can be used to select representative samples of schools for randomized controlled trials of educational interventions. However, these methods may still yield external validity bias when participation by schools is voluntary and participation decisions are associated with unobserved variables. This paper offers a new sampling method called Stratified Random Sampling with Quotas. Under this method, quotas are set to avoid including too many schools of a particular type, as defined by auxiliary variables that are unobserved in the sampling frame, but whose population distribution can be estimated from external data. Our simulations find that when the auxiliary variables affect whether or not a school participates in the study, quotas set based on those variables reduce external validity bias. These results suggest that when auxiliary data are available on strong impact moderators for the target population, these data can be used to address non-ignorable self-selection by schools into randomized controlled trials

Super-stoichiometric Ratios between Ion Movements and Electron Transport in Rat Liver Mitochondria

Abstract The number of Ca++ ions accumulated per pair of electrons passing through each energy-conserving site of the respiratory chain during Ca++-induced respiratory jumps in isolated rat liver mitochondria (i.e. the Ca++: ∼ ratio) is normally approximately 2.0 when the suspending medium contains 80 mm KCl or NaCl at pH 7.4, but no permeant anion. However, when the concentration of impermeant salts is raised to as high as 240 mm, or when the pH is raised to above 8.0, the Ca++ ∼ ratio increases to values exceeding 4.0 to 5.0, primarily because of a decrease in the amount of extra oxygen uptake evoked by addition of Ca++. The ratio H+ ejected: ∼ also increases in proportion to the Ca++: ∼ ratio. Increase in sodium chloride concentration does not influence the adenosine diphosphate to oxygen ratio of oxidative phosphorylation. Such super-stoichiometric ratios of Ca++ uptake are almost completely dependent on electron transport, and occur in the presence of high concentration of impermeant anions such as chloride, bromide, iodide, and thiocyanate, but not when such salts are replaced with sucrose. In the presence of permeant anions, such as phosphate, the Ca++: ∼ ratio remains constant at about 2.0. The possible causes of the apparently "flexible" stoichiometry of Ca++ uptake and H+ ejection with electron transport in the absence of phosphate are discussed

Observations on the Kinetics of the Reaction of Hemoglobin with Oxygen

Abstract The kinetics of the reaction of human deoxyhemoglobin with oxygen at high concentrations of ligand (∼10-4 m) has been studied with the use of a fast stopped flow apparatus with a dead time of approximately 300 µsec. The shape of the progress curve reveals that the apparent second order rate constant for the reaction with oxygen (k') increases with the extent of the reaction, similar to what was reported for other ligands (i.e. carbon monoxide). Within the oxygen concentration range studied, the rate of the reaction at any stage is proportional to the ligand concentration, notwithstanding the change in rate as the reaction proceeds. These results are interpreted to indicate that the ligand-linked intramolecular change in hemoglobin is a fast process which occurs in a fraction of a millisecond

Significance of the dissociation of Dna2 by flap endonuclease 1 to Okazaki fragment processing in Saccharomyces cerevisiae

Okazaki fragments are initiated by short RNA/DNA primers, which are displaced into flap intermediates for processing. Flap endonuclease 1 (FEN1) and Dna2 are responsible for flap cleavage. Replication protein A (RPA)-bound flaps inhibit cleavage by FEN1 but stimulate Dna2, requiring that Dna2 cleaves prior to FEN1. Upon cleavage, Dna2 leaves a short flap, which is then cut by FEN1 forming a nick for ligation. Both enzymes require a flap with a free 5'-end for tracking to the cleavage sites. Previously, we demonstrated that FEN1 disengages the tracking mechanism of Dna2 to remove it from the flap. To determine why the disengagement mechanism evolved, we measured FEN1 dissociation of Dna2 on short RNA and DNA flaps, which occur during flap processing. Dna2 tracked onto these flaps but could not cleave, presenting a block to FEN1 entry. However, FEN1 disengaged these nonproductively bound Dna2 molecules, proceeding on to conduct proper cleavage. These results clarify the importance of disengagement. Additional results showed that flap substrate recognition and tracking by FEN1, as occur during fragment processing, are required for effective displacement of the flap-bound Dna2. Dna2 was recently shown to dissociate flap-bound RPA, independent of cleavage. Using a nuclease-defective Dna2 mutant, we reconstituted the sequential dissociation reactions in the proposed RPA/Dna2/FEN1 pathway showing that, even without cutting, Dna2 enables FEN1 to cleave RPA-coated flaps. In summary, RPA, Dna2, and FEN1 have evolved highly coordinated binding properties enabling one protein to succeed the next for proper and efficient Okazaki flap processing

Effects of mu- and kappa-2 opioid receptor agonists on pain and rearing behaviors

<p>Abstract</p> <p>Background</p> <p>Management of pain involves a balance between inhibition of pain and minimization of side effects; therefore, in developing new analgesic compounds, one must consider the effects of treatment on both pain processing and behavior. The purpose of this study was to evaluate the effects of the mu and kappa-2 opioid receptor agonists on general and pain behavioral outcomes.</p> <p>Methods</p> <p>As a general behavioral assessment, we modified the cylinder rearing assay and recorded the number and duration of rearing events. Thermal sensitivity was evaluated using either a reflexive measure of hindpaw withdrawal latency to a radiant heat source or using an orofacial operant thermal assay. Acetic acid-induced visceral pain and capsaicin-induced neurogenic inflammatory pain were used as painful stimuli. The mu-opioid receptor agonist, morphine or the kappa-2 receptor agonist GR89696 was administered 30 min prior to testing. A general linear model repeated measures analysis was completed for baseline session comparisons and an analysis of variance was used to evaluate the effects of treatment on each outcome measure (SPSS Inc). When significant differences were found, post-hoc comparisons were made using the Tukey honestly significant difference test. *P < 0.05 was considered significant in all instances.</p> <p>Results</p> <p>We found that morphine and GR89,696 dose-dependently decreased the number of reaching events and rearing duration. Rearing behavior was not affected at 0.5 mg/kg for morphine, 1.25 × 10^-4mg/kg for GR89,696. Hindpaw thermal sensitivity was significantly increased only at the highest doses for each drug. At the highest dose that did not significantly influence rearing behavior, we found that visceral and neurogenic inflammatory pain was not affected following GR89,696 administration and morphine was only partially effective for blocking visceral pain.</p> <p>Conclusion</p> <p>This study demonstrated that high levels of the opioids produced significant untoward effects and made distinguishing an analgesic versus a more general effect more difficult. Quantification of rearing behavior in conjunction with standard analgesic assays can help in gaining a better appreciation of true analgesic efficacy of experimental drugs.</p

Shade and Drought Stress-Induced Changes in Phenolic Content of Wild Oat (Avena fatua L.) Seeds

Plants develop under a wide range of maternal environments, depending on the time of emergence, prevailing competition from other plants, and presence or absence of other biotic or abiotic stress factors. Stress factors, such as light limitation and drought, during plant development typically reduces the reproductive allocation to seeds, resulting in fewer and often smaller seeds. Such stress factors may also influence seed quality traits associated with persistence in the soil, such as seed dormancy and chemical defense. For this research, we hypothesized that light limitation and drought during wild oat (Avena fatua L.) seed development would result in reduced allocation to seed phenolics and other aliphatic organic acids previously identified in the seeds of this species. Wild oat isolines (M73 and SH430) were grown in the greenhouse under cyclic drought conditions (2005 only) or two levels of shade (50 and 70%; 2005 and 2006) achieved with standard black shade cloth. The soluble and cellular bound chemical constituents were identified and quantified using gas chromatography - mass spectrometry. The shade and drought stress treatments often significantly affected the mass of the caryopsis and hull seed fractions, as well as the phenolic content of these seed fractions, depending upon isoline, seed fraction, phenolic fraction, and specific phenolics analyzed. Phenolic content of the hull was reduced by the stress environments by up to 48%, whereas there was some evidence of an increase in the soluble phenolic content of the caryopsis in response to the stress environments. Ferulic and p-coumaric acids were the most abundant phenolic acids in both soluble and bound fractions, and bound phenolics comprised generally 95% or more of total phenolics. There was no discernable evidence that the aliphatic organic content was affected by the stress environments. Our results indicate that plant stress during seed development can reduce both the physical and chemical defense in seeds, which may result in seeds that are less persistent in the soil seed bank and potentially less of a weed management concern

Characterization of mouse orofacial pain and the effects of lesioning TRPV1-expressing neurons on operant behavior

<p>Abstract</p> <p>Background</p> <p>Rodent models of orofacial pain typically use methods adapted from manipulations to hind paw; however, limitations of these models include animal restraint and subjective assessments of behavior by the experimenter. In contrast to these methods, assessment of operant responses to painful stimuli has been shown to overcome these limitations and expand the breadth of interpretation of the behavioral responses. In the current study, we used an operant model based on a reward-conflict paradigm to assess nociceptive responses in three strains of mice (SKH1-Hr^hr, C57BL/6J, TRPV1 knockout). We previously validated this operant model in rats and hypothesized in this study that wild-type mice would demonstrate a similar thermal stimulus-dependent response and similar operant pain behaviors. Additionally, we evaluated the effects on operant behaviors of mice manipulated genetically (e.g., TRPV1 k.o.) or pharmacologically with resiniferatoxin (RTX), a lesioning agent for TRPV1-expressing neurons. During the reward-conflict task, mice accessed a sweetened milk reward solution by voluntarily position their face against a neutral or heated thermode (37–55°C).</p> <p>Results</p> <p>As the temperature of the thermal stimulus became noxiously hot, reward licking events in SKH1-Hr^hrand C57BL/6J mice declined while licking events in TRPV1 k.o. mice were insensitive to noxious heat within the activation range of TRPV1 (37–52°C). All three strains displayed nocifensive behaviors at 55°C, as indicated by a significant decrease in reward licking events. Induction of neurogenic inflammation by topical application of capsaicin reduced licking events in SKH1-Hr^hrmice, and morphine rescued this response. Again, these results parallel what we previously documented using rats in this operant system. Following intracisternal treatment with RTX, C57BL/6J mice demonstrated a block of noxious heat at both 48 and 55°C. RTX-treated TRPV1 k.o. mice and all vehicle-treated mice displayed similar reward licking events as compared to the pre-treatment baseline levels. Both TRPV1 k.o. and RTX-treated C57BL/6J had complete abolishment of eye-wipe responses following corneal application of capsaicin.</p> <p>Conclusion</p> <p>Taken together, these results indicate the benefits of using the operant test system to investigate pain sensitivity in mice. This ability provides an essential step in the development of new treatments for patients suffering from orofacial pain disorders.</p

The Messenger Sector of SUSY Flavour Models and Radiative Breaking of Flavour Universality

The flavour messenger sectors and their impact on the soft SUSY breaking terms are investigated in SUSY flavour models. In the case when the flavour scale M is below the SUSY breaking mediation scale M_S, the universality of soft terms, even if assumed at M_S, is radiatively broken. We estimate this effect in a broad class of models. In the CKM basis that effect gives flavour off-diagonal soft masses comparable to the tree-level estimate based on the flavour symmetry.Comment: 24 pages, 3 figures. v3: minor changes in the text, typos corrected, version accepted for publication in JHE

mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell-derived hematopoietic progenitors

Generation of functional hematopoietic stem and progenitor cells (HSPCs) from human pluripotent stem cells (PSCs) has been a long-sought-after goal for use in hematopoietic cell production, disease modeling, and eventually transplantation medicine. Homing of HSPCs from bloodstream to bone marrow (BM) is an important aspect of HSPC biology that has remained unaddressed in efforts to derive functional HSPCs from human PSCs. We have therefore examined the BM homing properties of human induced pluripotent stem cell-derived HSPCs (hiPS-HSPCs). We found that they express molecular effectors of BM extravasation, such as the chemokine receptor CXCR4 and the integrin dimer VLA-4, but lack expression of E-selectin ligands that program HSPC trafficking to BM. To overcome this deficiency, we expressed human fucosyltransferase 6 using modified mRNA. Expression of fucosyltransferase 6 resulted in marked increases in levels of cell surface E-selectin ligands. The glycoengineered cells exhibited enhanced tethering and rolling interactions on E-selectin-bearing endothelium under flow conditions in vitro as well as increased BM trafficking and extravasation when transplanted into mice. However, glycoengineered hiPS-HSPCs did not engraft long-term, indicating that additional functional deficiencies exist in these cells. Our results suggest that strategies toward increasing E-selectin ligand expression could be applicable as part of a multifaceted approach to optimize the production of HSPCs from human PSCs

A Generalized Q-operator for U_q(\hat(sl_2)) Vertex Models

In this paper, we construct a Q-operator as a trace of a representation of the universal R-matrix of $U_q(\hat{sl}_2)$ over an infinite-dimensional auxiliary space. This auxiliary space is a four-parameter generalization of the q-oscillator representations used previously. We derive generalized T-Q relations in which 3 of these parameters shift. After a suitable restriction of parameters, we give an explicit expression for the Q-operator of the 6-vertex model and show the connection with Baxter's expression for the central block of his corresponding operator.Comment: 22 pages, Latex2e. This replacement is a revised version that includes a simple explicit expression for the Q matrix for the 6-vertex mode