cssi/SciSciGPT-SciSciNet huggingface dataset:
Divalent cation requirements for mounting a respiratory burst in response to phorbol diesters by macrophages from SENCAR and C57BL/6 mice.

Abstract Oxygen radicals are thought to play an important role in the promotion phase of carcinogenesis and the action of phorbol esters [1,2]. Inflammatory cells are an abundant source of reactive oxygen intermediates (ROI) in the body and release large quantities of ROI when exposed to phorbol esters. Both protein kinase C (PKC), the receptor for phorbol esters, and the NADPH oxidase which generates ROI are Ca 2+ - and Mg 2+ -dependent. We investigated the requirements for Ca 2+ and Mg 2+ of macrophages from strains of mice sensitive and resistant to the promotion of tumors by phorbol esters. Macrophages from SENCAR mice, which are sensitive to phorbol ester promotion, required much lower levels of Ca 2+ or Mg 2+ to mount a full respiratory burst, as measured by the release of H 2 O 2 in response to phorbol ester stimulation, than macrophages from C57BL/6 mice, which are resistant to promotion by phorbol esters. Conversely, when the particulate stimulus zymosan was used, there was little difference between macrophages from the two strains in requirements for Ca 2+ and Mg 2+ to release H 2 O 2 . Lowering the concentration of either cation in the absence of the other was more inhibitory than in the presence of the other cation. The studies demonstrate that differences in sensitivity to divalent cations by macrophages from these two strains is selective for phorbol ester stimulation and that lower requirements for Ca 2+ and Mg 2+ for ROI release correlates with sensitivity to the promotion of tumors by phorbol esters.
A decision analytic model for chemical control of sooty blotch and flyspeck diseases of apple

Abstract A model is presented for the optimal timing of chemical sprays to control the diseases of apple, sooty blotch and flyspeck. The model accounts, at a simplified level, for dynamics of disease progress, chemical inhibition of disease spread, decay of fungistat, cost of control and market structure for apples. Computed sensitivities and estimated uncertainties for the key parameters are used to compute Bayes optimal control decisions, as well as expected value of improved accuracy. It is concluded that the decision as to chemical treatment is logically divided into two steps: (i) whether or not to treat; (ii) level of treatment. Crop quality is the most important determinant for the first step; fungistat decay rate for the second. Because of asymmetries in the economic loss curves, uncertainties lead to levels of treatment considerably above the deterministic optimum.
The CardioSEAL Device: History, Techniques, Results

The CardioSEAL™ Septal Occlusion Device is the current version of a type of transcatheter closure device developed in the early 1980s. It is a direct modification of the Bard Clamshell Septal Occluder, which was first utilized in humans in 1988. Modifications include the use of a metal alloy, which is far more resistant to fatigue fractures, and the addition of a second stress relieving coil along the length of each arm. Trials with the current version of the CardioSEAL device began in late 1996. Preliminary results from the CardioSEAL study indicate that the CardioSEAL device should be implantable in over 95% of selected patients. Acute transient events have been seen in <3% of procedures, and long-term morbidity or mortality has been <1%. The device is not necessarily immediately occlusive, and approximately two thirds of patients have evidence of a small residual shunt at the time of implantation. Any residual leaks tend to decrease or resolve over time. Longer-term results from the original Clamshell study support the long-term safety and efficacy of this type of device. It is anticipated that 85%–90% of patients treated with the CardioSEAL device will have no further need of intervention and can be spared the need for open heart surgery.
Visceral pleural invasion is not predictive of survival in patients with lung cancer and smaller tumor size.

Background Visceral pleural invasion (VPI) is used as an indicator of adverse prognosis in non-small cell lung cancer (NSCLC). The purpose of this retrospective study was to evaluate the impact of VPI on disease-free survival (DFS) and overall survival (OS) in patients with node-negative NSCLC. Methods Between 1998 and 2009, 1,166 patients with pathologic N0M0 NSCLC underwent surgical resection by lobectomy. Two hundred fourteen patients with VPI were compared with 952 patients without VPI. Results Median follow-up was 59 months. In multivariate analysis, VPI, larger tumor size, older age, female sex, and poor performance status were significantly associated with decreased OS. In contrast, larger tumor size, female sex, and poor performance, but notably not VPI, were associated with decreased DFS. After examining interactive effects of VPI and T stage subgroups, we found that VPI did not significantly affect either OS or DFS in the subgroups of patients with smaller tumor sizes—stage T1a, stage T1b, or stage T2a. In contrast, a deleterious effect of VPI on DFS was seen for tumors larger than 5 cm—stages T2b and T3—with the VPI–stage T3 interaction effect being statistically significant for DFS but not for OS. Conclusions The effect of VPI on survival in NSCLC varies greatly with tumor size, with VPI not strongly associated with OS or DFS in tumors smaller than 5 cm, but showing large negative effects on DFS for stage T2b and stage T3 tumors. Using VPI to upstage T1 tumors to a higher T stage is not warranted because it would misrepresent these VPI–T stage subgroup effects.
Regulation of gene expression: How can molecules make the right ventricle distinct from the left?

Abstract Regulation of gene expression is a complex process that can occur at numerous steps along the route that directs DNA to ultimate production of a functional protein. In this brief review, I have tried to illustrate some of the more common ways by which regulation is orchestrated. Although multiple control mechanisms have been discussed, others, including use of alternative promoters, localization of mRNA transcripts to unique regions of the cytoplasm, mRNA editing, identification of the translational start site, translational recoding and post-translational modification of a protein, can also alter function of a gene's protein. The interested reader is referred to some of the excellent references for more information. An understanding of gene regulation is paramount in helping us develop new strategies for treatment of cardiovascular diseases such as cardiac hypertrophy and heart failure. Currently we are aware that series of genes are induced or suppressed, even prior to the onset of morphologic hypertrophy and likewise before there is any evidence of heart failure or cellular dysfunction. A combination of genetic and physiologic manipulations in transgenic mice has given us a powerful strategy for studying these processes. A more comprehensive understanding of molecular and cellular events, including ones of gene regulation, may ultimately give us the ability to modify myocardial growth. As we get more deeply involved in this era of molecular medicine, we must all must keep abreast of developments in molecular biology.
Magnetic Anisotropy at 0°K

The results of the spin-wave method of Holstein and Primakoff are extended to obtain approximate values for the dependence of the energy of magnetically saturated cubic crystals upon the direction of magnetization. The anisotropy at 0\ifmmode^\circ\else\textdegree\fi{}K is calculated for the cases of dipolar ferromagnetism and exchange ferromagnetism. In a nearest neighbor approximation, the results agree with those obtained by Van Vleck from a treatment of ferromagnetic anisotropy. However, in the case of dipolar interaction, the nearest neighbor approximation is not sufficient and more distant neighbors are included. For dipolar ferromagnetism, the method gives the following results: In a face-centered cubic (fcc) lattice of spins $S$, the anisotropy constant ${K}_{1}$ is a maximum when there is no external field and is then given by ${K}_{1}=\ensuremath{-}0.11$ $\frac{{{M}_{0}}^{2}}{S}$, where ${M}_{0}$ is the saturation magnetization. In a body-centered cubic (bcc) lattice, with no external field, ${K}_{1}=\ensuremath{-}0.15\frac{{{M}_{0}}^{2}}{S}$. An external field must be applied to obtain saturation in a simple cubic (sc) lattice; ${K}_{1}=+0.43\frac{{{M}_{0}}^{2}}{S}$ when the external field $H=0.6{M}_{0}$. More generally, in the presence of an external field $H$, then ${K}_{1}=\ensuremath{\kappa}(\frac{{{M}_{0}}^{2}}{S}){((\frac{4\ensuremath{\pi}}{3})+\frac{H}{{M}_{0}})}^{\ensuremath{-}1}$, where $\ensuremath{\kappa}=\ensuremath{-}0.46$ for an fcc lattice, -0.63 for a bcc lattice, and +2.06 for an sc lattice. All values given are for specimens having zero demagnetizing field.
Characterizing the mechanism of lean blowout for a recirculation-stabilized premixed hydrogen flame

The stability of hydrogen combustion under lean premixed conditions in a back-mixed jet-stirred reactor (JSR), is experimentally and numerically investigated. The goal is to understand the mechanism of flame extinction in this recirculation-stabilized flame environment. Extinction is achieved by holding the air flow rate constant and gradually decreasing the flow rate of the hydrogen fuel until a blowout event occurs. In order to gain insight on the mechanism controlling blowout, two dimensional computational fluid dynamic (CFD) simulations are carried out for the lean premixed combustion (LPM) of hydrogen as the fuel flow rate is reduced. The CFD model illustrates the evolution of the flow-field, temperature profiles, and flame structure within the JSR as blowout is approached. A single element chemical reactor network (CRN) consisting of a plug flow reactor (PFR) with recirculation is constructed based on the results of the CFD simulations, and its prediction of blowout is in good agreement with the experimental results. The chemical mechanism of Li et al. is used in both the CFD and CRN models, and GRI is used in the CRN for comparison. The modeling suggests that lean blowout does not occur with the flame in a spatially homogeneous condition, but rather under a zonal structure. Specifically, the flame is stabilized by the entrainment of combustion products from the re-circulation zone into the base of the reactant jet. The mixture of hot products and incoming premixed reactants proceeds through an ignition induction period followed by an ignition event. As the fuel flow decreases, the induction period increases and the ignition event is pushed further around the recirculation zone. Eventually, the induction period becomes so long that the ignition is incomplete at the point where the recirculating gas is entrained into the jet. This threshold leads to overall flame extinction.Copyright © 2012 by ASME
Making a successful case for a hypertextual doctoral dissertation

In August, 1998 the first hypertextual dissertation at Rensselaer Polytechnic Institute was accepted (http://www.nutball.com), a case study applying methods of rhetorical analysis and cultural critique to the online phenomenon called the “Xenaverse,” the cyberspaces devoted to the cult following of the syndicated television program Xena, Warrior Princess. The hypertextual research site, a vital online culture, seemed to demand a new kind of scholarship to describe and analyze it. Still, there were many hurdles to getting such an unorthodox presentation form accepted by the dissertation committee and the Graduate School. This paper summarizes a few of the justifying arguments that led to the successful acceptance this dissertation, a hypertext that could not be reproduced in any way on paper. In showing how one case for a hypertextual dissertation was successfully argued, I hope to help other scholars make similar cases at other institutions, perhaps leading to further debate on the ways arguments and epistemologies will be defined in the future.
Embryonic exposure to sodium arsenite perturbs vascular development in zebrafish

Exposure to arsenic in its inorganic form, arsenite, causes adverse effects to many different organs and tissues. Here, we have investigated arsenite-induced adverse effects on vascular tissues in the model organism zebrafish, Danio rerio. Zebrafish embryos were exposed to arsenite at different exposure windows and the susceptibility to vascular tissue damage was recorded at 72hours post fertilization (hpf). Intersegmental vessel sprouting and growth was most perturbed by exposure to arsenite during the 24-48hpf window, while disruption in the condensation of the caudal vein plexus was more often observed at the 48-72hpf exposure window, reflecting when these structures develop during normal embryogenesis. The vascular growth rate was decreased by arsenite exposure, and deviated from that of control embryos at around 24-26.5hpf. We further mapped changes in expression of key regulators of angiogenesis and vasculogenesis. Downregulation of vascular endothelial growth factor receptor 1/fms-related tyrosine kinase 1 (vegfr1/flt1) expression was evident already at 24hpf, coinciding with the decreased vascular growth rate. At later time points, matrix metalloproteinase 9 (mmp9) expression was upregulated, suggesting that arsenite affects the composition of the extracellular matrix. In total, the expression of eight key factors involved in different aspects of vascularization was significantly altered by arsenic exposure. In conclusion, our results show that arsenite is a potent vascular disruptor in the developing zebrafish embryo, a finding that calls for an evaluation of arsenite as a developmental vascular toxicant in mammalian model systems.
Comparison of Foliar and Preplant Applied Nitrogen Fertilizer for Sugar Beet

Leaf canopies of sugar beet (Beta vulgaris L.) grown in the Red River Valley of Minnesota and North Dakota sometimes display mid-season (July) symptoms of N deficiency. The influence of in-season foliar N applications on sugar beet grown under non-irrigated conditions on a Wheatville loam (coarse silty over clayey, frigid Aeric Calciaquoll) with low and medium levels of soil N fertility was studied for 3 yr. A combination of eight soil and foliar treatments were investigated. The soil treatments were (i) soil NO 3 − -N in the 0- to 60-cm depth of soil in the previous autumn (45 kg ha −1 in the 1986 and 1987 experiments, and 78 kg ha −1 in the 1988 experiment), and (ii) the above soil NO 3 − -N levels plus sufficient fall-applied urea-N to give the equivalent of 157 kg N ha −1 [...]
Bias and Mean Square Error from Ignoring Genetic Groups in Mixed Model Sire Evaluation

Abstract Criteria based on mean square error were developed to determine whether differences among genetic groups ought to be included in sire evaluation. Simulation was used for a population of 2000 first lactations from daughters of 50 sires with 25 sires per group. Designs were simulated for semen exchanges between groups of 5,10, 25, and 50% both one-directional and reciprocal. Analyses were with and without the inverse of a matrix of numerator relationships among sires. The matrix averaged 10.3 and 5.8% related sire pairs within and between groups, respectively. For unrelated sires, mean square error of sire evaluation ignoring genetic groups was less than including genetic groups when true genetic differences between groups were less than 176.7, 132.4, 103.1, or 93.9kg for one-way exchanges of 5, 10, 25, or 50% and 126.0, 102.8, 84.6, or 79.3kg for reciprocal exchanges. For related sires, corresponding genetic differences were 179.8, 137.1, 109.5, or 100.5 for one-way exchanges and 131.1, 109.1, 92.1, or 87.2 for reciprocal exchanges. For only two groups, ignoring genetic groups leads to smaller mean square error of sire evaluation if the true genetic difference is less than the standard error of estimate of the difference between groups.
From Hypertension to Heart Failure: Role of Nitric Oxide–Mediated Endothelial Dysfunction and Emerging Insights from Myocardial Contrast Echocardiography

There is growing evidence that nitric oxide (NO)-mediated endothelial dysfunction occurs in hypertension and may represent the earliest stage of target organ damage, which ultimately leads to hypertensive heart disease and heart failure (HF). An understanding of how impaired myocardial microvascular function and flow reserve relate to early remodeling during the transition to HF in patients with hypertension may lead to new therapeutic insights. The hypertrophied heart, which is a feature of the adverse structural remodeling in hypertensive heart disease, may be accompanied by impaired coronary flow reserve (CFR). Reduced CFR could potentially cause subendocardial ischemia during conditions of high metabolic demand, such as uncontrolled hypertension and tachycardia. Such vulnerability of the subendocardium to abnormal perfusion or ischemia may accelerate the progression from compensated hypertrophy to HF. In this review, we discuss preliminary evidence that altered NO balance may contribute to cardiac hypertrophy-mediated myocardial ischemia. We also describe early results with myocardial contrast echocardiography in the postulated transition from compensated hypertrophy to cardiac failure. These data support further evaluation of NO mediators as potential targets for novel therapies in hypertensive heart disease.
Prevalence of vertebral artery origin stenosis in a multirace-ethnic posterior circulation stroke cohort: Miami Stroke Registry (MIAMISR).

Background Vertebral artery origin stenosis is an important etiology for stroke in the posterior circulation. Data from the Oxford Vascular Study and New England Registry show a prevalence of vertebral artery origin disease of 26–32%. These populations are largely comprised of Caucasians. The prevalence of vertebral artery origin disease in multirace-ethnic stroke population is unknown. Aim The study aims to assess the prevalence of vertebral artery origin stenosis in a multirace population with posterior circulation stroke. Design/Methods The Miami Stroke Registry is a prospective registry which offers enrollment to consecutive patients admitted with a diagnosis of stroke/transient ischemic attack. Baseline demographics, vascular risk factors, and stroke topography in the posterior circulation were analyzed. All vascular imaging studies were reviewed for the presence of vertebral artery origin stenosis, and stroke etiology was adjudicated by TOAST classification. Results Mean age of the population was 63 ± 13 years; 149 (70%) were men. Among cases, 123 were Hispanic (58%), almost one third 70 (32%) were of African descent, and 15 (7%) were white. The most common stroke etiology was small vessel occlusion (27%), followed by large artery intracranial disease 25% (posterior cerebral arteries, basilar and vertebral arteries), cardioembolic 19%, and cryptogenic 16%. Vertebral artery origin stenosis/occlusion was present in 28 (13·1%) patients, of whom only 2 (0·9%) were bilateral; it was attributed as the direct cause of stroke in 11 (5·2%) patients. Conclusions We found a lower prevalence of vertebral artery origin stenosis in a predominately non-white population with posterior circulation stroke than previously reported. Vertebral artery origin stenosis was a direct cause of posterior circulation stroke in only 5·2% of patients.
An integrative framework for the momentum-accounting based change management

In today's 'hyper-changing and hyper-competitive' business environment, change management has become the 'essence' of all management activities. Management must have a good understanding of the nature of changes, as well as the 'momentum and forces' behind the changes. In this paper, we adopt the momentum accounting concept initially proposed by Ijiri (1982, 1986, 1988) and extend it to the practice of change management. With momentum accounting as the backbone, we also incorporate the flow concept and the change-causation-possibility (CCP) model of change management to facilitate the implementation of momentum accounting. Such an integrative framework not only helps a firm gain a better understanding of the nature, the processes and causal relationships of the past or potential changes in the firm's internal and external environments, but also provides a practical procedure for facilitating and improving change management. This integrative framework also provides a solid foundation for building decision support systems for change management.
Effective dielectric properties of binary dielectric mixtures on checkerboards

Effective dielectric properties of checkerboard structures composed of two media are calculated using the finite element method. Random arrangements of media are considered on 16 × 16, 32 × 32 and 64 × 64 checkerboards with different concentration ratios of the medium. Using three different board sizes allow us to study finite-size scaling effects. Electrical field distributions estimated from the finite element method are used to predict the amount of electrically stressed regions. It is concluded that for the considered systems these structures can plausibly be described with the symmetric Bruggeman effective medium expression.
Total Synthesis of Epicoccin G

An expedient enantioselective total synthesis of epicoccin G and related dithiodiketopiperazines through a strategy featuring direct two-directional sulfenylation, photooxygenation, and Kornblum-DeLaMare rearrangement is described.
Low Skin Temperatures Produced by New Skin Refrigerants

Temperatures produced by Cryosthesia -30 degrees C, Cryosthesia -60 degrees C, and Frigiderm were measured in minipigs. Cryosthesia -60 degrees C and Cryosthesia -30 degrees C were both found to rapidly lower skin temperatures to levels that have been shown to cause cell injury, necrosis, and loss of melanocytes. Use of these agents requires extreme caution in dermabrasion.
IMD Access Control During Emergencies

IMDs are widely used to treat chronic diseases. Many IMDs can communicate wirelessly with an outside programmer (reader). However, wireless access also introduces security concerns. An attacker may obtain an IMD reader and gain unauthorized access to a patient’s device. IMD security is an important issue, since attacks on IMDs may cause physical harm to the patient. A number of research groups have studied IMD security issues when the patient is in a non-emergency situation. However, these security schemes usually require the patient’s participation, and therefore may not work during emergencies (e.g., when the patient is in a coma). In this chapter, we present a light-weight secure access control scheme for IMDs during emergencies. Our scheme utilizes the patient’s biometric information to prevent unauthorized access to the IMD. The scheme consists of two levels: level 1 is a lightweight scheme using some basic biometric information about the patient; level 2 utilizes a patient’s iris for authentication in a very effective manner. We also make one contribution in human iris verification: we show that it is possible to perform iris verification by comparing partial iris data rather than using iris data of an entire eye. This significantly reduces the overhead of iris verification, which is critical for resource-limited IMDs. We evaluate the performance of our schemes by using real iris data sets. Our experimental results show that the secure access control scheme is very effective and has small overhead (hence feasible for IMDs). Specifically, the false acceptance rate (FAR) and false rejection rate (FRR) of our secure access control scheme are close to 0.000 % when suitable thresholds are used, and the memory and computation overheads are very small. Our analysis shows that the secure access control scheme reduces computation overhead by an average of 58 %.
The Diffusion Equation

The first chapter of this monograph deals with diffusion. Diffusion processes play an important role in hydrogeological modeling. In subsurface porous structures there are really two processes that are lumped together into a diffusion term. One is ordinary molecular diffusion caused by the random collisions between molecules, and the other is dispersion, a velocity-driven process where molecules disperse by tracking through the tortuous pathways of the medium. Both processes cause molecules, say, a contaminant dissolved in water, to spread out in the medium. In this chapter we focus on one part of the diffusion-dispersion process, namely molecular diffusion.
On the formation of anisole from phenoxyacetamides

A major fragmentation route of N-t-butyl-N-isopropyl-and N-ethylphenoxyacetamide is the formation of [C7H8O]+. Deuterium labeling implicates hydrogen transfer from nitrogen in all three species and from the t-butyl groups of the t-butylamide. The anisole structure is assigned to the [C7H8O]+· ion on the basis of its secondary fragmentation.
Factors associated with female provider preference among African American women, and implications for Breast cancer screening

Globally, breast cancer incidence is increasing. Early detection remains important for addressing disparities, including among U.S. minorities. Seeing a female physician increases screening, but the effects of unmet provider gender preference among underserved populations remain unexplored. Among 576 urban African American women age 45-93, we examined predictors of gender preference and how met and unmet preference influenced screening. We conclude that provider gender is a "double-edged sword." We saw a female provider screening benefit, but also that gender preference was associated with past disadvantage and attitudes inconsistent with health maintenance. Provider gender preference merits further consideration in women's health research.
The Histone Acetyltransferase Domains of CREB-binding Protein (CBP) and p300/CBP-associated Factor Are Not Necessary for Cooperativity with the Class II Transactivator*

The class II transactivator (CIITA) is a transcriptional co-activator regulating the constitutive and interferon-γ-inducible expression of class II major histocompatibility complex (MHC) and related genes. Promoter remodeling occurs following CIITA induction, suggesting the involvement of chromatin remodeling factors. Transcription of numerous genes requires the histone acetyltransferase (HAT) activities of CREB-binding protein (CBP), p300, and/or p300/CBP-associated factor (pCAF). These co-activators cooperate with CIITA and are hypothesized to promote class II major histocompatibility complex transcription through their HAT activity. To directly test this, we used HAT-defective CBP and pCAF. We demonstrate that cooperation between CIITA and CBP is independent of CBP HAT activity. Further, although pCAF enhances CIITA-mediated transcription, pCAF HAT domain dependence appears contingent upon the concentration of available CIITA. When HAT-defective CBP and pCAF are both present, cooperativity with CIITA is maintained. Consistent with a recent report, we show that nuclear localization of CIITA is enhanced by lysine 144, an in vitro target of pCAF-mediated HAT. Yet we find that neither mutation of lysine 144 nor deletion of residues 132–209 affects transcriptional cooperation with CBP or pCAF. Thus, acetylation of this residue may not be the primary mechanism for pCAF/CBP cooperation with CIITA. In conclusion, the HAT activities of the co-activators are not necessary for cooperation with CIITA.
Two-dimensional simulation of controls of fracture parameters on fracture connectivity

Two-dimensional fracture simulation is conducted to analyze the controls of different fracture parameters (variations in fracture orientation, density, and length) on fracture network connectivity. Three different scenarios, which are commonly encountered in natural fracture systems, are analyzed: (1) a single fracture set; (2) two fracture sets, with one primary through going set; and (3) two fracture sets with approximately equal parameters. The modeling reveals that certain parameters are more dominant in controlling the connectivity for each of the settings. For a single set of fractures, increases in length and dispersion and a decrease in spacing all result in higher fracture-parallel connectivity, but the decrease in spacing is the most important in increasing fracture-normal connectivity, especially where the dispersion in fracture strike is very low. Simulations of two sets of fractures reveal that the density, length, and angle between the two sets are important factors in producing complete connectivity. In cases where one set of fractures is a systematic throughgoing set, a critical combination of length of the second set and the angle between the two sets results in complete connectivity. Where both sets of fractures have varying length and density, the influence of increasing density of one set has a great effect on connectivity when the other set is short and a more subtle to insignificant change when the other set is long. The network also shows higher connectivity with increasing angles (up to 90°) between the two sets.
Documenting the value of care for rheumatoid arthritis, analogous to hypertension, diabetes, and hyperlipidemia: is control of individual patient self-report measures of global estimate and physical function more valuable than laboratory tests, radiographs, indices, or remission criteria?

Recent recommendations for treatment of rheumatoid arthritis (RA) include “treat-to-target” with a “primary target…a state of clinical remission”1. Remission is now a realistic target in RA, because patient status is substantially better than in previous decades in most developed countries2. Capacity to induce remission may be an effective rationale for support of aggressive treatment with expensive therapies to insurance company and government payers. The concept of “treat-to-target” was developed over the years in other chronic diseases, notably hypertension3,4, diabetes5, and hyperlipidemia6. The basis of treat-to-target was not “remission,” a state that may often be possible, but as in RA, usually requires continued lifelong medication. The target, in other diseases, involves “tight control” of a “gold standard” biomarker of dysregulation — elevated blood pressure, serum glucose, or serum cholesterol — to a lower level that results in improved quality of life and reduction of premature mortality rates. Such a target – not a state of remission – provides a strong rationale for aggressive treatment. RA differs substantially from hypertension, diabetes, or hyperlipidemia in that there is no single, gold standard biomarker (or any other measure) for diagnosis, management, or prognosis in all individual patients. Biomarkers are of unquestioned importance in RA to understand pathogenesis and develop new therapies: Biological agents would not be available without them. However, biomarkers are limited in clinical application to diagnosis, management, and prognosis of RA: Forty percent of new patients have normal erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)7,8, and > 30% test negative for rheumatoid factor or anti-citrullinated protein antibodies (ACPA)9. Clinical decisions in RA are based more on a patient history and physical examination than on biomarkers; in contrast, biomarkers dominate clinical decisions in many … Address correspondence to Dr. Pincus; E-mail: tedpincus{at}gmail.com
Loss of Normal G1 Checkpoint Control Is an Early Step in Carcinogenesis, Independent of p53 Status

Recent studies have described a diminished radiation-induced G1 arrest in some wild-type (wt) p53 human tumor cell lines compared to normal human fibroblasts. However, the significance of this finding was unclear, particularly because tumor cell lines may have accumulated additional genetic changes after long periods in culture. Because malignant transformation of individual cells is thought to be an early step in carcinogenesis, we have used a model system of normal and transformed mouse fibroblast 10T1/2 cell clones to examine whether loss of G1 checkpoint control may be an early event in tumor development and to study the relationships between G1 arrest, radiosensitivity, and genetic alterations. Twelve transformed clones were established from type III foci induced by irradiation of normal 10T1/2 cells and were compared with six clones derived from wt 10T1/2 cells. Three of the transformed clones expressed mutant p53; two of these had the same point mutation at codon 132 (exon 5), and one had a point mutation at codon 135. The remaining transformed and normal clones had wt p53 status. The radiosensitivity of transformed clones, as measured by a clonogenic assay, was similar to that of normal clones; the three clones with mutant p53 did not differ from the others. There was no relationship between G1 arrest and radiosensitivity. Normal 10T1/2 cell clones showed a transient G1 arrest lasting ∼9 h after 6 Gy of irradiation. This G1 arrest was either absent or markedly reduced in all of the transformed clones, regardless of p53 status. These results suggest that diminished G1 checkpoint control is an early event in the process of carcinogenesis that is associated with the malignant transformation of individual cells and is independent of p53 status.
Altered splenic B cell subset development in mice lacking phosphoinositide 3-kinase p85α

The signaling enzyme phosphoinositide 3-kinase (PI3K) is activated following B cell receptor (BCR) engagement and by many other receptors on B lymphocytes. Mice lacking p85alpha, the predominant PI3K regulatory isoform, exhibit defects in B cell development and activation that are grossly similar to those found in mice lacking Bruton's tyrosine kinase (Btk) and other critical signaling molecules. However, a detailed analysis of splenic B cell subsets in p85alpha-deficient mice has not been reported. Here we show that these mice are deficient in four major B cell subsets: transitional-1, transitional-2, follicular and marginal zone. These defects are distinct from those observed in Xid mice that express a mutant Btk unable to interact with PI3K lipid products. Moreover, mice with both genetic lesions exhibit even greater impairment in B cell development. Finally, we show that transgenic expression of the anti-apoptotic protein Bcl-2 in p85alpha-deficient mice restores the transitional B cell subsets but not the marginal zone subset, and produces a follicular population with an aberrant phenotype. These findings establish a role for PI3K-p85alpha in differentiation of both follicular and marginal zone B cells, and suggest that these functions are required not solely for the propagation of anti-apoptotic signals.
A Primer on Functional Magnetic Resonance Imaging

In this manuscript, basic principles of functional magnetic resonance imaging (fMRI) are reviewed. In the first section, two intrinsic mechanisms of magnetic resonance image contrast related to the longitudinal and transverse components of relaxing spins and their relaxation rates, T1 and T2, are described. In the second section, the biophysical mechanisms that alter the apparent transverse relaxation time, $$T_2^*$$ , in blood oxygenation level dependent (BOLD) studies and the creation of BOLD activation maps are discussed. The physiological complexity of the BOLD signal is emphasized. In the third section, arterial spin labeling (ASL) measures of cerebral blood flow are presented. Arterial spin labeling inverts or saturates the magnetization of flowing spins to measure the rate of delivery of blood to capillaries. In the fourth section, calibrated fMRI, which uses BOLD and ASL to infer alterations of oxygen utilization during behavioral activation, is reviewed. The discussion concludes with challenges confronting studies of individual cases.
Vernalization, photoperiod and GA3 interact to affect flowering of Japanese radish (Raphanus sativus Chinese Radish Jumbo Scarlet)

Raphanus sativus L. Chinese Radish Jumbo Scarlet has characteristics that make it an excellent plant model for vernalization studies. This study further characterizes flower induction of R. sativus Chinese Radish Jumbo Scarlet. Seed were imbibed in distilled water containing 0, 10 -5 M or 10 -3 M GA 3 for 24 h and were then exposed to 6 ± 0.5°C (vernalized) for 0, 2, 4, 6, or 8 days. Seedlings were then grown under a short- (8 h) or long-day photoperiod (8 h with or without a 4-h night interruption; 2200-0200 h). Of unvernalized plants grown under long- and short-day conditions, 45 and 3% flowered, respectively. Saturation of the vernalization response occurred after a 4- or 8-day vernalization treatment when plants were placed under long- or short-days, respectively. Basal leaf number and days to anthesis decreased when seeds were cooled for 2 or 4 days and were imbibed with 10 -3 M GA 3 compared to distilled water only. These data indicate that R. sativus Chinese Jumbo Scarlet has principally an obligate vernalization requirement when grown under short-days. GA 3 application only facilitated flowering when the length of the vernalization treatment was marginal. Taken together, these data support the use of this plant as a model plant for identifying vernalization responses under short-day conditions.
Studies on the metabolism of testosterone in normal women in different phases of the menstrual cycle.

THAT the size and function of the adrenal cortex can be influenced by ovarian activity has been demonstrated in rats (1–4). It is not known whether adrenal cortical activity in man similarly varies with ovarian activity in any consistent manner. Although the urinary 17-ketosteroids reflect at least certain aspects of adrenal function, certainly no regular alterations in the rate of their excretion have been noted in normal women during different phases of the menstrual cycle (5–9). However, Koets (10) has made the interesting observation that in women suffering from simple hirsutism there does exist a cyclic variation in the 17-ketosteroid excretion correlated with the menstrual cycle. Why the output of 17-ketosteroids should vary in this manner in these women and not in normal women requires explanation. As an approach to an understanding of the relation between ovarian and adrenal cortical function it seemed important to investigate the manner in which a precursor of the 17-ketosteroids is metabolized d...
A comparative morphological study of head shape and olfactory cavities of sharks inhabiting benthic and coastal/pelagic environments

Abstract There is great diversity in head shape and olfactory morphology among shark species, which is predicted to be related to habitat. As sharks swim forward water flows into the incurrent nostril placing dissolved chemicals into direct contact with the olfactory epithelium, before exiting the excurrent nostril. The nostrils exhibit diversity in form, size, and position on the rostrum among species. Variation in the nasal morphology and the position and size of the nostrils may influence how water flows through the cavity, and therefore how the animal receives the chemical stimuli. Morphometric data were collected on twenty-three shark species from benthic and coastal/pelagic environments. External morphological characteristics of the head and the internal anatomy of the olfactory cavities were examined. Computed tomography scans of olfactory cavities were performed on thirteen of the twenty-three shark species to examine the internal nasal morphology (e.g., cavity volume, nasal cavity width and length). Results showed significant differences in head and nasal morphology among benthic and coastal/pelagic species. There was a strong positive correlation between narial length (maximum distance between perimeters of incurrent nostril to excurrent nostril) and nose to mouth distance. Olfactory cavities of coastal/pelagic species were far separated from the mouth. Benthic species had external or internal connections between the olfactory and oral cavities. Coastal/pelagic species possessed greater narial lengths and mouth lengths than Sphyrna spp. (hammerhead sharks) and benthic species. Benthic and Sphyrna spp. possessed smaller nostril angles than coastal/pelagic species. It is predicted that coastal/pelagic species rely heavily on external flow for hydrodynamic flow through the olfactory cavities, whereas benthic species rely more on active respiration to pull water through the olfactory cavities.
The JOBS Act

Signed into law on April 5, 2012, the Jumpstart Our Business Startups (JOBS) Act remains a revolutionary development in the world of startup and small business financing. The revolutionary potential of the JOBS Act has been gradually activated by phased regulatory implementation of its various parts, called titles. Only since May 16, 2016, for example, have startups and small businesses been enabled to tap the promise of certain provisions in the JOBS Act to use the power of the Internet to raise equity capital from investors across the country and around the globe. These provisions allow small companies, including startups, to raise via crowdfunding (described in full later in this chapter) up to $1 million per year, subject to a five-year and $700 million market-value limit. For such companies, the JOBS Act has also created exemptions to accounting and auditing rules, as well as to rules that require public companies to report details concerning executive compensation and other financial data.
100-mJ, Q-switched, diode-end-pumped Nd 3+ :YLF laser oscillator

Because of the problems associated with delivering the output from large area diode arrays to the ends of small laser rods, diode-pumped, rod-laser oscillators capable of delivering output energies of 100 ml or more in a Q-switched pulse have generally used a transverse-diode-pump geometry. This transverse pump geometry puts very stringent requirements on the diode wavelength tolerance because of the short absorption lengths available. Beam quality can also be negatively impacted because of axially asymmetric gain profiles that can be imprinted on the output beams. We have developed and demonstrated a scalable end-pumping technology applicable to solid- state lasers that addresses these drawbacks of the transverse-pump geometry.
Self‐protection from weather risk using improved maize varieties or off‐farm income and the propensity for insurance

We investigate how self-protection from the adoption of Improved Maize Varieties (IMV) and off-farm income affects risk premiums for smallholder maize producers in Uganda. To unbundle these effects, we specify the cost of risk to explicitly capture four risk components—mean, variance, skewness, and kurtosis. Using unique plot-level panel data for Uganda, we estimate and test moments of a flexible production function based on an expanded form of the Johnson SU family distribution and proceed to simulate the degree of responsiveness of risk premiums and welfare estimates to marginal changes in the share of land under IMV and off-farm income. Scenarios of joint adoption of IMV accompanied with low and high application of inorganic fertilizer, and the effect of off-farm income when there is high and low supply of farm labor are examined. Results show that the use of IMV and off-farm income substantially reduces risk premiums and the individual effect is much higher under low fertilizer application and high supply of farm labor, respectively. Thus implying that self-protection is likely to reduce the propensity for index insurance especially if its design fails to consider the reduction in downside risk.
Natural Gas Engine Performance Ignited by a Passively Q-Switched Microlaser

A robust end pumped, passively Q-switched, air-cooled, microlaser was designed and prototyped, and tested in a natural gas fueled single-cylinder engine, and in one cylinder of a turbocharged 6-cylinder engine.
Is human trafficking the dark side of economic freedom

Economic freedom has increased living standards worldwide. Concurrent with such gains are rising concerns about potential human costs associated with free markets. This paper uses data on human trafficking and anti-trafficking policies, in conjunction with a measure of economic freedom, to examine whether free markets exacerbate or attenuate the incidence of human trafficking and policies designed to combat it. We do not find evidence suggesting that economic freedom is associated with human trafficking. In addition, our results suggest that economically free countries are more likely to enact and enforce policies to fight human trafficking.
Introduction of Cyclically Constrained γ-Residues Stabilizes an α-Peptide Hairpin in Aqueous Solution

The synthesis and structural characterization of hybrid α/γ-peptides resulting from a 1:1 α→γ residue substitution at cross-strand positions in a hairpin-forming α-peptide sequence are described. Cyclically constrained γ-residues based on 1,3-substituted cyclohexane or benzene scaffolds support a native-like hairpin fold in aqueous solution, and the unnatural residues stabilize the folded state by ∼0.2 kcal/mol per α→γ substitution.
Attenuation of isoproterenol-mediated vasodilatation in blacks.

Background The mechanism of enhanced vascular reactivity in young blacks, which may play a part in the development of hypertension, has not been defined. To determine the contribution of blunted vasodilatation mediated by β2-adrenergic receptors to this phenomenon, we compared forearm blood-flow responses to isoproterenol in young black and white normotensive men. Methods We used venous-occlusion plethysmography to measure the responses of blood flow in the forearm to the intraarterial administration of isoproterenol (10 to 400 ng per minute) in 9 normotensive black men (mean [±SD] age, 31.3±8.0 years) and 13 normotensive white men (mean age, 32.9±5.6 years). Sympathetic activity in the forearm was measured simultaneously by isotope-dilution techniques. Results Base-line blood flow in the forearm was similar in blacks and whites, but the degree of vasodilatation in response to isoproterenol was markedly lower in blacks. Isoproterenol at an infusion rate of 400 ng per minute produced a 9-fold increase in b...
Prognostic value of NT-proBNP and big ET-1 in severe heart failure:significance of NT-proBNP and big ET-1 in cardiovascular diseases combining with severe heart failure

Objective To investigate the prognostic ability of NT-proBNP(N-terminal B-type natriuretic peptide)and big ET-1(big endothelin-1)in patients with severe heart failure(HF),and the correlation of NT-proBNP and big ET-1 with atrial fibrillation(Af)and pulmonary artery hypertension (PAH)in severe HF patients.Methods Plasma concentrations of NT-proBNP and big ET-1 in 132 consecutive patients with severe HF were measured on admission.The left ventricular ejection fractions (LYEF)of the patients were also measured.Results The 132 patients consisted of 83 males and 49 females aged 24-80 years.All the patients showed severe HF(NYHA class Ⅲ to Ⅳ,LVEF 13%-66%).The LgNT-proBNP were positively correlated with big ET-1(r = 0.414,P 0.001)in the patients.Significant differences were observed in plasma big ET-1 concentrations between HF patient groups with and without Af and between groups with and without PAH(P0.05 and P0.001,respectively).Plasma big ET-1 was moderately accurate in discriminating HF patients with or without PAH.The area under ROC curve was 0.74 (95 % CI:0.65-0.83,P0.001)with 71.4 % sensitivity and 67.8 % specificity at a cutoff of d.09 fmol/ ml.during a follow-up of 6 months,there were 20 deaths and 25 readmissions in 132 HF patients.On a Cox proportional hazards analysis,NT-proBNP was an independent predictor of cardiac events,with a RR of 5.30(95% CI 2.07-13.55,P =0.001),and the only independent predictor of death with an OR of 13.67 (95% CI 2.59-72.25,P =0.002).Big ET-I,LVEF and NYHA were not independent predictors of cardiac events.Conclusions There is a possible interaction between NT-proBNP and big ET-1.Endothelia damage may exist in HF patient with Af.The plasma big ET-1 level may be useful as an aid in the diagnosis of HF patients with PAH.NT-proBNP,but not big ET-1 is independently predictive of cardiac events in severe HF.Measurement of NT-proBNP in severe HF patients is beneficial to identify patients at higher short-term risk of cardiac events.