cssi/SciSciGPT-SciSciNet huggingface dataset:
Educating the future mental health executive: a public health approach.

The mental health program we are developing at the Yale School of Public Health has as its basic element a broad introduction to the concepts and principles of public health and mental health administration and is rooted in concern for community well-being. It is our belief that this combination of public health — mental health training will produce administrators for mental health, psychiatric and human resource agencies who will be able to design, implement, manage, and evaluate programs that improve mental health and help communities evaluate and structure the human services they need.
Immunologic mechanisms in hypersensitivity pneumonitis. I. Evidence for cell-mediated immunity and complement fixation in pigeon breeders' disease.

Abstract Immunologic studies were performed on 5 patients with pigeon breeders' disease. Intradermal injection of pigeon serum produced an immediate wheal-and-flare reaction within 15 minutes and a secondary Arthus-type reaction within 4 to 8 hours. Immunofluorescent studies of the secondary reaction site showed IgG, C3, and C4 in 2 patients. Patients' sera produced multiple precipitin bands with pigeon serum when reacted by double diffusion in gel. IgG antibody isolated from each of the patients' serum formed precipitating immune complexes that fixed large amounts of complement (C4) when added to fresh human serum. Peripheral blood lymphocytes from 4 of the 5 patients produced macrophage migration inhibitory factor (MIF) when challenged with dilute pigeon serum. These studies are the first to show complement fixing antibodies and macrophage MIF production by lymphocytes from patients with hypersensitivity lung disease and suggest that both humoral and cellular immunity may be important in the pathogenesis of these disorders.
Current state of the art photoselective vaporization prostatectomy: laser therapy for benign prostatic hyperplasia

Current state of the art photoselective vaporization prostatectomy: laser therapy for benign prostatic hyperplasia
The role of fluorodeoxyglucose and positron emission tomography in the evaluation of pancreatic disease

Abstract Background: The difficulties involved in the timely and accurate diagnosis of pancreatic disease are well known. The usual imaging modalities usually identify abnormalities but may not always differentiate malignancy from other condition such as scar tissue or chronic inflammation. The purpose of our study was to determine if fluorodeoxyglucose positron emission tomography (FDG PET) can accurately diagnose pancreatic disease. Methods: The records of 15 patients presenting with pancreatic disease were retrospectively reviewed. The diagnosis suspected by imaging modalities was compared with the final tissue diagnosis. Two patients were excluded because no tissue was obtained. Results: Adenocarcinoma was diagnosed in 9 patients. A mass consistent with this diagnosis was seen in 8 of 9, 6 of 9, 6 of 8, and 5 of 5 patients by PET, computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound (EUS), respectively. Chronic pancreatitis (CP) was diagnosed in 2 patients. The unique appearance on FDG PET made the diagnosis in both these patients. Both patients with CP were thought to have a malignancy by CT and EUS and 1 of 2 by ERCP. Neuroendocrine tumors were diagnosed in 2 other patients. One of 2 was seen by FDG PET and both by CT. Conclusions: FDG PET can accurately differentiate a pancreatic adenocarcinoma from chronic pancreatitis in a patient with a suspicious pancreatic mass. Thus, FDG PET may help in establishing a diagnosis and subsequently managing a patient with pancreatic disease. (Surgery 1998;124:793-8.)
Electrical resistance of epitaxially-grown films of (SN)x

Abstract The d.c. electrical resistance of three epitaxially-grown thin films of (SN) x was measured from 0.030 to 8.9 K in a low ambient magnetic field. Above 0.25 K the data for all samples are best fit by an equation representing transport of electrons by tunneling between metallic particles of (SN) x . A change in the temperature dependence of resistance below 0.25 K is interpreted as suggestive, but not conclusive evidence, of superconductivity.
Spin delocalization in the Copper(I) Complexes of Bis(verdazyl) Diradicals

1,1‘,5,5‘-tetramethyl-6,6‘-dioxobis(verdazyl) (BVD) reacts with copper(I) halides in acetonitrile and copper(II) halides in methanol to give copper(I) coordination polymers of composition [Cu2X2(BVD)]x. When X = Cl and X = Br, these polymers crystallize in orthorhombic unit cells with dimensions a = 6.684(1) A, b = 12.524(3) A, and c = 8.717(2) A (X = Cl) and a = 12.680(2) A, b = 6.744(1) A, and c = 8.822(2) A (X = Br). With X = I, powder diffraction indicates a monoclinic unit cell with dimensions a = 12.669 A, b = 8.461 A, c = 7.679 A, and β = 91.88°, although poor crystal quality prevented a full structure determination. Magnetic susceptibility measurements taken on the three polymers indicate that the spins couple in one-dimensional chains with alternating exchange parameters: J1 = −190 cm-1, J2 = −116 cm-1 (X = Cl); J1 = −200 cm-1, J2 = −110 cm-1 (X = Br); and J1 = −271 cm-1, J2 = −200 cm-1 (X = I). Variable temperature ESR measurements on the unstable monomeric complex resulting from reaction of BV...
Global approaches to the promotion of women's health

After decades of work at international and national levels and by the activities of organization such as the World Health Organization to improve the status of womens health the promotion of womens health and health care research are receiving high priority on the international health agenda. The World Health Organization goal of Health for All by the year 2000 has been acknowledged as instrumental in focusing the worlds attention upon womens lack of access to and equity in health care. The issue is one of twelve critical areas of concern in the draft Platform of Action the basic document which will be negotiated by governments at the Fourth World Conference on Women to be held in Beijing during September 4-15 1995. The author considers the Platform of Action womens health issues and strategies for health promotion.
The direct determination of cadmium in hair using carbon bed atomic absorption spectroscopy. Daily rate of loss of cadmium in hair, urine and sweat

(1980). The direct determination of cadmium in hair using carbon bed atomic absorption spectroscopy. Daily rate of loss of cadmium in hair, urine and sweat. Journal of Environmental Science and Health . Part A: Environmental Science and Engineering: Vol. 15, No. 6, pp. 663-697.
Developmental abnormalities of the corpus callosum in schizophrenia

• Magnetic resonance imaging was used to evaluate neuroanatomical and neuropathologic abnormalities in a consecutive series of 140 patients with schizophrenia for comparison with normal controls. Partial agenesis of the corpus callosum, a rare neurodevelopmental abnormality, was found in two patients, one of whom also had a callosal lipoma. Evidence is presented suggesting that this finding represents an increased prevalence of partial agenesis in schizophrenia. The corpus callosum develops embryologically in intimate relationship to the hippocampal formation, fornix, septum pellucidum, and cingulate gyrus. In individuals with callosal agenesis, abnormalities also occur in the development of these limbic structures. Recent neuropathologic studies have suggested the occurrence of abnormal neurogenesis in the hippocampal formation and in the cingulate gyrus in schizophrenic patients. An increased prevalence of callosal agenesis and its related limbic abnormalities would further support investigation into neurodevelopmental abnormalities of these anatomical regions in schizophrenia.
Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation.

Src homology 3 domain (SH3)-containing proline-rich protein kinase (SPRK)/mixed-lineage kinase (MLK)-3 is a serine/threonine kinase that upon overexpression in mammalian cells activates the c-Jun NH2-terminal kinase pathway. The mechanisms by which SPRK activity is regulated are not well understood. The small Rho family GTPases, Rac and Cdc42, have been shown to bind and modulate the activities of signaling proteins, including SPRK, which contain Cdc42/Rac interactive binding motifs. Coexpression of SPRK and activated Cdc42 increases SPRKs activity. SPRKs Cdc42/Rac interactive binding-like motif contains six of the eight consensus residues. Using a site-directed mutagenesis approach, we show that SPRK contains a functional Cdc42/Rac interactive binding motif that is required for SPRKs association with and activation by Cdc42. However, experiments using a SPRK variant that lacks the COOH-terminal zipper region/basic stretch suggest that this region may also contribute to Cdc42 binding. Unlike the PAK family of protein kinases, we find that the activation of SPRK by Cdc42 cannot be recapitulated in an in vitro system using purified, recombinant proteins. Comparative phosphopeptide mapping demonstrates that coexpression of activated Cdc42 with SPRK alters the in vivo serine/threonine phosphorylation pattern of SPRK suggesting that the mechanism by which Cdc42 increases SPRKs catalytic activity involves a change in thein vivo phosphorylation of SPRK. This is, to the best of our knowledge, the first demonstrated example of a Cdc42-mediated change in the in vivo phosphorylation of a protein kinase. These studies suggest an additional component or cellular environment is required for SPRK activation by Cdc42.
Autoantibody prevalence and lupus characteristics in a unique African American population.

Objective The Gullah population of the Sea Islands of South Carolina is a unique group of African Americans who, due to geographic and cultural factors, remained isolated with minimal genetic admixture until the 1950s. Because of the unique homogeneous nature of the Gullah, we sought to define the genetic and environmental factors contributing to systemic lupus erythematosus (SLE) in this population. Methods Using data from our ongoing cohort study of lupus in the Gullah population, which we established in 2003, disease characteristics and serologic profiles were summarized for 184 patients with SLE, 144 unaffected first-degree relatives, and 144 matched unrelated, unaffected control subjects. These findings were compared with those in 2 other large cohorts of African Americans with SLE. Results In the Gullah cohort, we observed a high prevalence of SLE multiplex families (26.6%), malar rash (56.0%), discoid rash (34.2%), photosensitivity (60.9%), and oral/nasal ulcerations (43.5%), but a lower prevalence of hematologic and pleuropericardial disease than has been reported in other African American cohorts. Overall renal and central nervous system involvement, number of American College of Rheumatology disease criteria met, and SLE Damage Index scores were similar to those reported in other cohorts. Of interest, male and female first-degree relatives and male and female control subjects in this cohort had similar rates of antinuclear antibody positivity, whereas lupus-specific antibodies were more prevalent in the women than in the men. Conclusion These data indicate that the severity of lupus in the Gullah population is similar to that in other African American populations, whereas skin disease and familial disease prevalence are increased in the Gullah. These findings suggest that there is an increased genetic influence on overall disease in this cohort compared with that in other African American cohorts, which confirms the unique nature of this cohort.
The role of the EP receptors for prostaglandin E2 in skin and skin cancer.

One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE2. In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE2 and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE2 synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.
Extrinsic and intrinsic regulation of early natural killer cell development

Natural killer (NK) cells are lymphocytes that play a critical role in both adaptive and innate immune responses. These cells develop from multipotent progenitors in the embryonic thymus and neonatal or adult bone marrow and recent evidence suggests that a subset of these cells may develop in the thymus. Thymus- and bone marrow-derived NK cells have unique phenotypes and functional abilities supporting the hypothesis that the microenvironment dictates the outcome of NK cell development. A detailed understanding of the mechanisms controlling this developmental program will be required to determine how alterations in NK cell development lead to disease and to determine how to harness this developmental program for therapeutic purposes. In this review, we discuss some of the known extrinsic stromal-cell derived factors and cell intrinsic transcription factors that function in guiding NK cell development.
UNDECIDABILITY OF MACROSCOPICALLY DISTINGUISHABLE STATES IN QUANTUM FIELD THEORY

A heuristic discussion is presented regarding quantum field theory as a synthesis of the complementary theories of classical mechanics and quantum mechanics. If the states of quantum field theory are partitioned in equivalence classes accordingly as their occupation numbers differ in a finite or an infinite number of places, it is suggested that we define states to be macroscopically distinguishable if they belong to different equivalence classes. It is then proven that there is, in general, no effective procedure for determining whether or not two arbitrarily given states of a quantum system having an infinite number of degrees of freedom are macroscopically distinguishable.
Decision-Analytic Modeling to Evaluate Benefits and Harms of Medical Tests: Uses and Limitations

The clinical utility of medical tests is measured by whether the information they provide affects patient-relevant outcomes. To a large extent, effects of medical tests are indirect in nature. In principle, a test result affects patient outcomes mainly by influencing treatment choices. This indirectness in the link between testing and its downstream effects poses practical challenges to comparing alternate test-and-treat strategies in clinical trials. Keeping in mind the broader audience of researchers who perform comparative effectiveness reviews and technology assessments, the authors summarize the rationale for and pitfalls of decision modeling in the comparative evaluation of medical tests by virtue of specific examples. Modeling facilitates the interpretation of test performance measures by connecting the link between testing and patient outcomes, accounting for uncertainties and explicating assumptions, and allowing the systematic study of tradeoffs and uncertainty. The authors discuss challenges en...
Foam mechanics: the linear elastic response of two-dimensional spatially periodic cellular materials

Abstract A theoretical model for the linear elastic response of two-dimensional, spatially periodic cellular materials in simple shear and pure strain is developed. Hexogonally symmetric network morphology, with three identical films intersecting at each junction, is assumed. Film thickness is permitted to vary with distance from the joint. Such hexagonal networks are transversely isotropic; the effective stress does not depend upon the principal directions of strain. The effective in-plane elastic constants are explicitly related to the film compliances for bending and stretching. Film bending is the primary deformation mechanism for low-density, two-dimensional foams, as observed by other investigators. The hexagonal symmetry that is responsible for mechanical isotropy is favored by a foam synthesis route that includes a liquid state. It is shown that a ‘square’ cellular network is neither elastically isotropic nor energetically preferred during formation.
THE SOCIAL PRODUCTION OF SPACE IN TOURISM ENCLAVES: MAYAN CHILDREN’S PERCEPTIONS OF TOURISM BOUNDARIES

Abstract This paper adopts an interpretive approach to investigate children’s perceptions of their socio-spatial surroundings. It focuses on two tourism service towns, Akumal Pueblo and Chemuyil, and two major tourism centers, Akumal Playa and Bahia Principe, all located in the Mexican Yucatan Peninsula. Drawing on scholarship related to tourism’s role in demarcating and segregating space and Lefebvre’s trialectics of space production, this inquiry focuses on ways in which Mayan children residing in Akumal Pueblo and Chemuyil render their surrounding spaces intelligible, while reproducing or challenging the boundaries, symmetries and inclusions/exclusions created by the tourism industry. Tourism scholarship has tended to ignore children. By contrast this study engages the geographies of childhood to understand the lived socio-spatial experiences of this demographic group.
Motivations for the inmigration component of population turnaround in nonmetropolitan areas.

Data from a 1977 survey of metropolitan and nonmetropolitan origin households migrating to 75 high net inmigration counties of the Midwest are examined to consider the motivational basis for the inmigration component of post-1970 non metropolitan migration trends. Findings suggest that the major stated motivations for leaving places of origin, especially among those from metropolitan areas, are “quality of life” considerations. About a fourth of the metropolitan origin migrants’ and half of the non metropolitan origin migrants’ reasons are job-related. Anti-urban push and pro-rural pull responses are prevalent among migrants from metropolitan areas. Subsequent analysis of reasons for leaving metropolitan residences suggests consistency with other objective variables. Among households with a working-age head, those leaving for “quality of life” reasons came disproportionately from the largest metropolitan centers and went to the smallest towns. Those moving for non-employment reasons are not more likely to have taken an initial income loss, though they are less likely to experience immediate income gains.
Fuzzy Power Flow Based on Fuzzilized Matpower

In the last several decades, a couple of fuzzy power flow algorithms were presented to deal with the uncertainties in power grid. But there is no a functional simulation tool introduced to simplify the calculation. This paper presents a simulation tool, Matpower, under one of the algorithms to do the fuzzy power flow calculation. The algorithm gives the user the possibility to specify fuzzy numbers to represent the possible behavior of loads and generations and outputs fuzzy membership functions for voltage magnitudes and phases, active and reactive power flows and generations. Matpower, as a simulation tool, was modified to handle fuzzy numbers and show fuzzy results. In a final section, we present results obtained with a case study based on a real power system to illustrate and highlight details of the proposed algorithm. Suggestions for future implementation of the fuzzy Matpower are also summarized.
Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer

Recent studies have identified a role for insulin receptor substrate-2 (IRS-2) in promoting motility and metastasis in breast cancer. However, no published studies to date have examined IRS-2 expression in human breast tumors. We examined IRS-2 expression by immunohistochemistry (IHC) in normal breast tissue, benign breast lesions, and malignant breast tumors from the institutional pathology archives and a tumor microarray from a separate institution. Three distinct IRS-2 staining patterns were noted: diffusely cytoplasmic, punctate cytoplasmic, and localized to the cell membrane. The individual and pooled datasets were analyzed for associations of IRS-2 staining pattern with core clinical parameters and clinical outcomes. Univariate analysis revealed a trend toward decreased overall survival (OS) with IRS-2 membrane staining, and this association became significant upon multivariate analysis (P = 0.01). In progesterone receptor negative (PR−) tumors, in particular, IRS-2 staining at the membrane correlated with significantly worse OS than other IRS-2 staining patterns (P < 0.001). When PR status and IRS-2 staining pattern were evaluated in combination, PR− tumors with IRS-2 at the membrane were associated with a significantly decreased OS when compared with all other combinations (P = 0.002). Evaluation of IRS-2 staining patterns could potentially be used to identify patients with PR− tumors who would most benefit from aggressive treatment.
Mathematical Knowledge for Teaching Fraction Multiplication

The present study contrasts mathematical knowledge that two sixth-grade teachers apparently used when teaching fraction multiplication with the Connected Mathematics Project materials. The analysis concentrated on those tasks from the materials that use drawings to represent fractions as length or area quantities. Examining the two teachers' explanations and responses to their students' reasoning over extended sequences of lessons led to a theoretical frame that emphasizes relationships between teachers' unit structures and pedagogical purposes for using drawings. In particular, the present study builds on the distinction made in past research between reasoning with two and with three levels of quantitative units and demonstrates that reasoning with three levels of units is necessary but insufficient if teachers are to use students' reasoning with units as the basis for constructing generalized numeric methods for fraction arithmetic. Teachers need also to assemble three-level unit structures with flexibi...
In vivo and in vitro activity of truncated osmotin that is secreted into the extracellular matrix

Osmotin is a basic pathogenesis-related protein of group 5 (PR-5) that displays antifungal activity in vitro and in vivo. Basic, vacuolar forms of PR-5 proteins have a C-terminal extension compared to the acidic forms which are secreted extracellularly. To demonstrate that the C-terminal 20-amino acids extension of osmotin is responsible for intracellular targeting, we made transgenic tobacco and potato plants overexpressing osmotin with or without the 20 C-terminal amino acids. Plants overexpressing an osmotin gene with a complete open reading frame accumulated osmotin mostly in an intracellular compartment, probably the vacuole. In contrast, in plants overexpressing a C-terminal 20 amino acid truncated osmotin gene, osmotin was totally secreted into the extracellular matrix. Truncated osmotin purified from transgenic tobacco plants retained antifungal activity. Potato plants that overexpressed the truncated osmotin protein exhibited resistance to Phytophthora infestans.
Synthesis of novel isoxazolinyl substituted imidazo[1,2-a]pyridine C-nucleoside analogs

Abstract Isoxazoline rings have been successfully connected to imidazo[1,2-a]pyridine derivatives via carboncarbon bonds for the synthesis of new C -nucleoside analogs 7 and 8 . These two isomers, possessing altered positions of nitrogen and oxygen atoms, can be formed through dipolar cycloaddition reactions of the appropriate olefins and nitrile oxides.
Genetic differentiation in theAedes atropalpus complex. I. Isozyme variability and genetic distances betweenAe. atropalpus andAe. epactius

During the course of their evolution,Ae. atropalpus andAe. epactius have undergone considerable genetic differentiation. The average genetic distance between the two species was 0.458 ±0.05. The average genetic distance between populations ofAe. atropalpus was 0.019 ± 0.01 while the average distance between populations ofAe. epactius was 0.075 ±0.02. The GREEN population, representing the new “form” ofatropalpus found breeding in discarded tires, exhibited electromorph frequencies characteristic of the “typical”atropalpus populations. Of the enzymatic loci examined, ADK2 was species diagnostic, and PGi was species discriminating. The electrophoretic results from the populations examined have provided additional support for the present taxonomic status of the two species.
Zebrafish Nkd1 promotes Dvl degradation and is required for left–right patterning

The establishment of the left-right (LR) axis in zebrafish embryos relies on signals from the dorsal forerunner cells (DFC) and the Kupffer's vesicle (KV). While the Wnt signaling network influences many aspects of embryonic development, its precise role in LR patterning is still unclear. One branch of the Wnt network leads to stabilization of β-catenin and activation of downstream target genes. Other Wnt ligands appear to act independently of β-catenin to modulate calcium release and influence cell polarity. Central to regulation of β-catenin and coordination of convergent extension (CE) movements is Dishevelled (Dvl). Naked Cuticle (Nkd) binds Dvl and modulates β-catenin-dependent and independent Wnt signaling. Here, we analyze the expression patterns of three zebrafish Nkd homologs and find enriched expression of nkd1 in DFCs and KV. Dvl is degraded upon Nkd1 overexpression in zebrafish. Knockdown of Nkd1 specifically in the DFC results in β-catenin nuclear localization and transcriptional activation as well as alterations to DFC migration, KV formation, ciliogenesis and LR patterning. Furthermore, we identify asymmetric expression of the Nodal antagonist charon around the KV and show that Nkd1 knockdown impacts asymmetric charon expression. Our findings show that Nkd1 acts as a β-catenin antagonist in the DFCs necessary for LR patterning.
Similar survival for patients undergoing reduced-intensity total body irradiation (TBI) versus myeloablative TBI as conditioning for allogeneic transplant in acute leukemia.

Purpose Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment for adults with acute leukemia. Total body irradiation (TBI) remains an important part of the conditioning regimen for HCST. For those patients unable to tolerate myeloablative TBI (mTBI), reduced intensity TBI (riTBI) is commonly used. In this study we compared outcomes of patients undergoing mTBI with those of patients undergoing riTBI in our institution. Methods and Materials We performed a retrospective review of all patients with acute leukemia who underwent TBI-based conditioning, using a prospectively acquired database of HSCT patients treated at our institution. Patient data including details of the transplantation procedure, disease status, Karnofsky performance status (KPS), response rates, toxicity, survival time, and time to progression were extracted. Patient outcomes for various radiation therapy regimens were examined. Descriptive statistical analysis was performed. Results Between June 1985 and July 2012, 226 patients with acute leukemia underwent TBI as conditioning for HSCT. Of those patients, 180 had full radiation therapy data available; 83 had acute lymphoblastic leukemia and 94 had acute myelogenous leukemia; 45 patients received riTBI, and 135 received mTBI. Median overall survival (OS) was 13.7 months. Median relapse-free survival (RFS) for all patients was 10.2 months. Controlling for age, sex, KPS, disease status, and diagnosis, there were no significant differences in OS or RFS between patients who underwent riTBI and those who underwent mTBI ( P =.402, P =.499, respectively). Median length of hospital stay was shorter for patients who received riTBI than for those who received mTBI (16 days vs 23 days, respectively; P P =.043). Nonrelapse survival rates were also similar ( P =.186). Conclusions No differences in OS or RFS were seen between all patients undergoing riTBI and those undergoing mTBI, despite older age and potential increased comorbidity of riTBI patients. riTBI regimens were associated with shorter length of hospital stay, fewer intensive care unit admissions, and similar rates of nonrelapse survival, which may reflect reduced toxicity. Prospective trials comparing riTBI and mTBI are warranted.
Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl–Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443–mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.
Optical sciences and engineering programs at the Optical Sciences Center

The B.S., M.S., Ph.D., and distance learning programs at the University of Arizona's Optical Sciences Center have all undergone significant changes during the last two years. The rationale behind these program and curriculum changes are discussed, particularly for the undergraduate program, which recently received ABET accreditation.
Accessible sets of linear free nilpotent control systems

Abstract Our goal is to describe the accessible sets of some relatively simple affine control systems which we call free nilpotent. These are systems whose vector fields generate a nilpotent Lie algebra and are maximally free, i. e., all the nonzero Lie brackets are linearly independent. We give a complete characterization of the accessible sets for such systems when all brackets quadratic and higher in the controllable vector field are zero. We show how systems with quadratic brackets can lead to chattering, i.e., an infinite number of control discontinuities in a finite time interval, and offer some conjectures about chattering.
Grasping the Nettle and Femoral Artery Stenting

When brushed against, needles on the leaves of nettles inject a noxious toxin into the skin. However, grasping the nettle firmly bends the needles away from the skin, rendering it is less painful. The expression “to grasp the nettle” is to boldly confront an issue in order to seek its resolution. The advice warns us against half measures and is timely as we gather scientific evidence to assess the value of percutanous (and surgical approaches) to treating peripheral artery disease (PAD). Article see p 495 Claudication and critical limb ischemia are the 2 symptomatic manifestations of PAD. Although they share a common pathology (atherosclerosis) and a high risk of death from cardiovascular causes, their natural histories differ. Claudication impairs patient quality of life by causing painful cramps and dysfunction (eg, limping) while walking. Patients learn to avoid walking or to stop and rest when they claudicate until the discomfort eases. Over several years, symptoms may improve with collateral flow or metabolic adaption in muscle.1 However, many patients experience a progressive decline in walking and subsequent quality of life and independence. Fortunately, claudication rarely progresses to critical limb ischemia and limb loss (<2% per year).2 On the other hand, critical limb ischemia is characterized by rest pain, nonhealing or poorly healing ulcers, or gangrene and more extensive tissue loss. Although this is a smaller group of symptomatic PAD, the immediate risks are to the limb, with subsequent loss of function and independence related to the level of amputation.3 Vascular bypass surgery offers a viable treatment for patients with critical limb ischemia, but traditional surgical practice limits bypass surgery to all but the most severe cases of claudication. This hesitancy is based on small, but definite perioperative risks of death and cardiovascular events,4 the long-term risks of graft …
Impacts of birdwatching on human and avian communities.

Ecotourism can be a vehicle for community-based conservation if it is conducted with an emphasis on the well-being of local ecosystems and human communities. Birdwatchers form the largest group of ecotourists, and are, on average, well-educated, wealthy and committed. This makes them ideal ecotourists for community-based conservation. Therefore, there is a need for a comprehensive review of birdwatching from a conservation biology perspective. Specific objectives here are: (1) to review the economic potential of non-residential birdwatching for community-based conservation; (2) to outline the potential benefits and problems associated with this activity; and (3) to provide suggestions for improving the conservation value of birdwatching. Birdwatching tourism has a high potential to improve the financial and environmental well-being of local communities, educate locals about the value of biodiversity and create local and national incentives for successful protection and preservation of natural areas. However, there needs to be more research on the economical and environmental impacts of this hobby, birdwatching-related disturbance needs to be reduced, and much has to be done to increase the financial contribution of birdwatching to local communities.
Influence of natural and synthetic estrogens on the course of autoimmune disease in the nzb/nzw mouse

Antinuclear antibodies were found in 64% of serum samples obtained from male NZB/NZW mice after 6 weeks of treatment with mestranol. Both female and male mice responded to this synthetic female hormone with marked elevations of serum “2’ and p-globulins; 7-globulins were not increased. There was no evidence that mestranol accelerated the develop ment of autoimmune renal disease in these animals. Treatment of hybrid New Zealand mice with mestranol, 17-pestradiol and oophorectomy exerts divergent effects on serum proteins and the development of serologic abnormalities.
Synthesis of Sequence-Selective C8-Linked Pyrrolo[2,1-c][1,4]benzodiazepine DNA Interstrand Cross-Linking Agents.

An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The “amino thioacetal” cyclization procedure was used to produce the electrophilic DNA-interactive N10−C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a−d), a versatile convergent approach has been developed to join two units of vanillic acid with α,ω-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.
Predictive Performance of a Vancomycin–Aminoglycoside Population Model

OBJECTIVE:To evaluate the Wragge–Cooper method of predicting vancomycin serum concentrations utilizing knowledge of aminoglycoside pharmacokinetic parameters in general medicine and intensive care unit populations, and to develop a revised model if necessary.DESIGN:This study consists of two phases evaluating 50 adults receiving concurrent vancomycin and aminoglycoside therapy. Patients were identified by a retrospective review of medical records. Bayesian analysis of measured serum aminoglycoside and vancomycin concentrations was performed to determine the individualized pharmacokinetic parameters. Phase I of the study tested the predictive performance of a published model incorporating aminoglycoside elimination (Wragge–Cooper) in 25 patients (group 1), and a revised model was developed. Phase II determined the predictive performance of the revised model (revised) and its performance relative to the Wragge–Cooper model and a traditional model incorporating estimated creatinine clearance (traditional) in...
Validity of the MCMI Drug Abuse Scale Varies as a Function of Drug Choice, Race, and Axis II Subtypes

The validity of the Drug Abuse Scale (T) from the Millon Clinical Multiaxial Inventory (MCMI) was studied by administering the MCMI to 110 male veterans seeking treatment for opioid or cocaine dependence. Only 26 and 23 % of the sample obtained base rate (BR) scores above the clinical relevant cutoffs of 84 and 74, respectively. Covariables associated with elevated scores on the T Scale were Black race, presence of narcissistic/antisocial personality features, and more severe psychopathology in general. The authors urge caution in using the Drug Abuse Scale for the purpose of identifying drug abusers.
Effect of the Heating Rate on the Relative Rates of Sintering and Crystallization in Glass

The sintering of glass can sometimes be impeded by crystallization. In the optimum process the glass should sinter to full density before the onset of crystallization. In an earlier paper we showed how sinter-forging experiments can be used to investigate the coupling between densification and crystallization. Here we demonstrate that increasing the heating rate can delay crystallization so that a certain glass can sinter to full density.
Buffer Management for Sequential Decoding

Sequential decoding has been found to be an efficient means of communicating at low undetected error rates from deep space probes, but another failure mechanism known as erasure or computational overflow remains a significant problem. The erasure of a block occurs when the decoder has not finished decoding that block at the time that it must be output. The erasure rate can be unacceptably high even when the decoder is spending over half of its time idly awaiting incoming data. By drawing upon analogies in computer time sharing, this concise paper develops a buffer-management strategy which reduces the decoder idle time to a negligible level, and therefore improves the erasure probability of a sequential decoder. For a decoder with a speed advantage of ten and a buffer size of ten blocks, operating at an erasure rate of 10-2, use of this buffer-management strategy reduces the erasure rate to less than 10-4.
mRNAs have greater negative folding free energies than shuffled or codon choice randomized sequences

An examination of 51 mRNA sequences in GenBank has revealed that calculated mRNA folding is more stable than expected by chance. Free energy minimization calculations of native mRNA sequences are more negative than randomized mRNA sequences with the same base composition and length. Randomization of the coding region of genes yields folding free energies of less negative magnitude than the original native mRNA sequence. Randomization of codon choice, while still preserving original base composition, also results in less stable mRNAs. This suggests that a bias in the selection of codons favors the potential formation of mRNA structures which contribute to folding stability.
Modularity in the Design of Complex Engineering Systems

Modularity accommodates uncertainty because the particular elements of a modular design may be changed after the fact and in unforeseen ways as long as the design rules are obeyed. Thus, within a modular architecture, new module designs may be substituted for older ones easily and at low cost. This chapter will make three basic points. First, we will show that modularity is a financial force that can change the structure of an industry. Then, we will explore the value and costs that are associated with constructing and exploiting a modular design. Finally we will examine the ways in which modularity shapes organizations and the risks that it poses for particular firms.
Abstract at the Least (Reviews of Data‐Based Studies of a Whimsical Nature)

I don't know anyone for whom time isn't a problem—either there is not enough of it or there is too much. We're never satisfied with our punctuality, rate of performance, meeting of deadlines, et cetera. And so it makes sense that time is also a part of performance problems. In the recent article, “Development of Time Concepts: Differentiating Clock and Calendar from Apparent Durations,” Alida Spaans Westman looks at how we acquire time concepts, theorizes about how they are related to perception, and tests how resistant they are to influence from stress. If you have time it might be worthwhile reading.
Bridging strategies for VR-based learning

A distributed immersive virtual environment was deployed as a component of a pedagogical strategy for teaching third grade children that the Earth is round. The displacement strategy is based on the theory that fundamental conceptual change requires an alternative cognitive starting point which doesnt invoke the features of pre-existing models. While the VR apparatus helped to establish that alternative framework, conceptual change was strongly influenced by the bridging activities which related that experience to the target domain. Simple declarations of relevance proved ineffective. A more articulated bridging process involving physical models was effective for some children, but the multiple representations employed required too much model-matching for others.
Scalable microbeam flowsensors with electronic readout

In this paper, we present a scalable microchannel-embedded cantilever flowsensor with electronic readout. The scalable nature of the sensor addresses the need to realize arrays of flowsensors to characterize localized flow patterns. The electronic readout addresses the need to integrate flowsensors in microfluidic channels for closed-loop flow control. The in-channel nature of the flowsensor provides a wide choice for the cap material (e.g., PDMS, glass, silicon, etc.) enabling division of labor between integrated circuit (IC) and microfluidic foundries. This also holds promise for large-scale integrated microfluidic systems. The cantilever beam is placed inside a microfluidic channel in such a way that it utilizes drag forces to cause a flow-induced stress underneath the beam anchor. A Wheatstone bridge of piezoresistors placed directly under the anchor converts the flow-induced stress into a differential output voltage. We present an analytical model and 3-D simulations for the proposed flowsensor. Flowsensors fabricated by standard photolithography were tested to experimentally verify the validity of the model and simulation results. A flow sensitivity (unamplified) of 0.5 ppm/(/spl mu/L/s) was measured with first generation devices with water flow from 10 /spl mu/L/min to 100 /spl mu/L/min. Through experimental results, it is also shown that scaling down the size of the flowsensor results in higher sensitivity. We present a prediction on the noise-floor of flow measurement based on the results obtained using these prototype flowsensors.
Eliminating the Low-Frequency Breakdown Problem in 3-D Full-Wave Finite-Element-Based Analysis of Integrated Circuits

An effective method is developed in this work to extend the validity of a full-wave finite-element-based solution down to dc for general 3-D problems. In this method, we accurately decompose the Maxwell's system at low frequencies into two subsystems in the framework of a full-wave-based solution. One has an analytical frequency dependence, whereas the other can be solved at frequencies as low as dc. Thus, we bypass the numerical difficulty of solving a highly ill-conditioned and even singular system at low frequencies. In addition, we provide a theoretical analysis on the conditioning of the matrices of the original coupled Maxwell's system and the decomposed system. We show that the decomposed system is well conditioned, and also positive definite at dc. The validity and accuracy of the proposed method have been demonstrated by extraction of state-of-the-art on-chip integrated circuits at frequencies as low as dc.
Stimulated Raman scattering: diffractive coupling in transient and steady-state regimes

A numerical study is presented of the steady-state and transient regimes in stimulated Raman scattering, including diffractive coupling of the fields and detuning of the Stokes field from resonance. In the steady-state regime, ring formation in the laser output intensity is observed as well as a ring in the Stokes output intensity when it is detuned from resonance. In the transient regime a solitonlike pulse is initiated by modulation of the phase of the input Stokes field. For Fresnel numbers between 5 and 50, we observe a simultaneous maximum of the on-axis laser and Stokes intensities after a π phase shift is introduced on the Stokes seed. At the same time the transverse profiles of the fields are narrowed and the laser intensity displays a satellite ring. It is found that the soliton remains relatively stable, although diffraction eventually leads to its decay.
Phosphorylation of Protein Inhibitor of Activated STAT1 (PIAS1) by MAPK-Activated Protein Kinase-2 Inhibits Endothelial Inflammation via Increasing Both PIAS1 Transrepression and SUMO E3 Ligase Activity

Objective— Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is known to function as small ubiquitin-like modifier (SUMO) E3 ligase as well as transrepressor. The aim of the study is to elucidate the regulatory mechanisms for these 2 different functions, especially with respect to endothelial inflammation. Methods and Results— The mitogen-activated protein kinase (MAPK)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates PIAS1 at the Ser522 residue. Activation of MAPK-activated protein kinase-2 enhances p53-SUMOylation, but a PIAS1 phosphorylation mutant, PIAS1-S522A, abolished this p53-SUMOylation, suggesting a critical role for PIAS1-S522 phosphorylation in its SUMO ligase activity. Because nuclear p53 can inhibit Kruppel-like factor 2 promoter activity, we investigated the roles for PIAS1 phosphorylation and p53-SUMOylation in the Kruppel-like factor 2 and endothelial NO synthase expression. Both MAPK-activated protein kinase-2 and PIAS1 overexpression increased Kruppel-like factor 2 promoter activity and endothelial NO synthase expression, which were inhibited by expressing a p53-SUMOylation defective mutant, p53-K386R, and PIAS1-S522A. PIAS1-S522A also abolished the anti-inflammatory effect of wild-type PIAS1 in vitro and also in vivo, which was examined by leukocyte rolling in microvessels of skin grafts transduced by adenovirus encoding PIAS1-WT or - S522A mutant. Conclusion— Our study has identified a novel negative feedback regulatory pathway through which MAPK-activated protein kinase-2 limits endothelial inflammation via the PIAS1 S522 phosphorylation-mediated increase in PIAS1 transrepression and SUMO ligase activity.