cssi/SciSciGPT-SciSciNet huggingface dataset:
Degradation of a Cytosolic Protein Requires Endoplasmic Reticulum-associated Degradation Machinery

Protein misfolding is monitored by a variety of cellular “quality control” systems. Endoplasmic reticulum (ER) quality control handles misfolded secretory and membrane proteins and is well characterized. However, less is known about the quality control of misfolded cytosolic proteins (CytoQC). To study CytoQC, we have employed a genetic system in Saccharomyces cerevisiae using a transplantable degron, CL1 (1). Attachment of CL1 to the cytosolic protein Ura3p destabilizes Ura3p, targeting it for rapid proteasomal degradation. We have performed a comprehensive analysis of Ura3p-CL1 degradation requirements. As shown previously, we observe that the ER-localized ubiquitin E2 (Ubc6p, Ubc7p, and Cue1p) and E3 (Doa10p) machinery involved in ER-associated degradation (ERAD) are also responsible for the degradation of the cytosolic substrate Ura3p-CL1. Importantly, we find that the cytosol/ER membrane-localized chaperones Ydj1p and Ssa1p, known to be necessary for the ERAD of membrane proteins with misfolded cytosolic domains, are also required for the ubiquitination and degradation of Ura3p-CL1. In addition, we show a role for the Cdc48p-Npl4p-Ufd1p complex in the degradation of Ura3p-CL1. When ubiquitination is blocked, a portion of Ura3p-CL1 is ER membrane-localized. Furthermore, access to the cytosolic face of the ER is required for the degradation of CL1 degron-containing proteins. The ER is distributed throughout the cytosol, and our data, together with previous studies, suggest that the cytosolic face of the ER membrane serves as a “platform” for the degradation of Ura3p-CL1, which may also be the case for other CytoQC substrates.
New Ion Sources for Mass Spectroscopy

FOR use in connexion with a new mass-spectrograph, I have recently developed a new type of ion source in which positively charged atoms are formed by sparks between solid electrodes in a high vacuum. Spectroscopic studies in recent years have shown that these vacuum sparks are efficient sources of multiply charged ions. Several forms of sparks were tried; the trembleur a vide the hot-sparks from a large condenser discharge, and finally a spark coupled inductively to a high-frequency oscillating spark circuit. This latter has proved very successful, and an abundance of ions has been obtained, thus far from the following elements: platinum, gold, tungsten, tin, copper, nickel, iron, aluminium, carbon, beryllium and lithium.
Laboratory experiments on electrostatic ion cyclotron waves in a dusty plasma

Abstract Current driven electrostatic ion cyclotron (EIC) waves have been observed in a dusty plasma laboratory experiment. The theoretical prediction that a substantial amount of negatively charged dust makes the plasma more unstable to the EIC instability appears to be borne out by the experimental results.
Eurycormus - - Eurypoma, two Jurassic actinopterygian genera with mixed identity

Abstract. Three Late Jurassic actinopterygian species are commonly placed in the genus Eurycormus: E. egertoni, E. grandis and E. speciosus. A detailed comparison supports an earlier assignment to two different genera, Eurycormus Wagner, 1863 (speciosus) and Eurypoma Huxley, 1866 (E. egertoni and E. grande). Systematically, the two genera are only distantly related; Eurycormus belongs to the Teleosteomorpha, whereas Eurypoma is a halecomorph closely related to or a member of the Caturoidea within the Amiiformes. Drei oberjurassische Actinopterygier-Arten, egertoni, grandis und speciosus, werden gewohnlich zur Gattung Eurycormus gestellt. Ein detaillierter Vergleich der drei Arten bestatigt eine fruhere Zuordnung zu zwei verschiedenen Gattungen, Eurycormus Wagner, 1863 (speciosus) und Eurypoma Huxley, 1866 (E. egertoni und E. grande), die zwei hoheren Taxa innerhalb der Neopterygii zugeordnet werden: Eurycormus zu den Teleosteomorpha und Eurypoma zu den Amiiformes innerhalb der Halecomorphi, moglicherweise nahe oder innerhalb der Caturoidea. doi: 10.1002/mmng.200600016
Ibogaine and the inhibition of acetylcholinesterase.

Abstract Ethnopharmacological relevance Ibogaine is a psychoactive monoterpine indole alkaloid extracted from the root bark of Tabernanthe iboga Baill. that is used globally in medical and nonmedical settings to treat drug and alcohol addiction, and is of interest as an ethnopharmacological prototype for experimental investigation and pharmaceutical development. The question of whether ibogaine inhibits acetylcholinesterase (AChE) is of pharmacological and toxicological significance. Materials and methods AChE activity was evaluated utilizing reaction with Ellman's reagent with physostigmine as a control. Results Ibogaine inhibited AChE with an IC50 of 520 ± 40 μM. Conclusions Ibogaine's inhibition of AChE is physiologically negligible, and does not appear to account for observations of functional effects in animals and humans that might otherwise suggest the possible involvement of pathways linked to muscarinic acetylcholine transmission.
A precise type analysis of logic programs

This paper presents a new type analysis for logic programs. The type information in a set of substitutions is described by a disjunction of variable typings each of which maps a variable to a non-deterministic regular type. The use of non-deterministic regular types, set union and intersection operators, and disjunctions of variable typings makes the new type analysis more precise than those found in the literature. Experimental results on the performance of the new analysis are given together with comparable results from an existing type analysis. The fundamental problem of checking the emptiness of non-deterministic regular types is more complex in the new analysis. The experimental results, however, show that careful use of tabling reduces the effect to an average of 15% of execution time on a set of benchmarks.
The Dynamics of T-Cell Receptor Repertoire Diversity Following Thymus Transplantation for DiGeorge Anomaly

T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRβ V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.
Entropy evolution as a guide for replacing the Liouville equation.

A replacement is proposed for the usual Liouville equation for the evolution of the distribution function of a statistical ensemble of classical, homogeneously thermostatted systems. The correct description of the entropy evolution is an essential criterian for such a replacement to satisfy, since we show from numerical realizations of a physically realistic model system that the Liouville equation is not satisfactory in general. On the other hand, both the Liouville equation and the proposed replacement correctly describe the evolution of ordinary mechanical observables, such as the energy. The particular form of the proposed replacement is shown to describe correctly a variety of experimental conditions.
Brazing of ceramic-matrix composites to Ti and Hastealloy using Ni-base metallic glass interlayers

Abstract Carbon–carbon, carbon–silicon carbide, and silicon carbide–silicon carbide composites were vacuum brazed to Ti and Hastealloy X using Ni-base metallic glass braze foils (MBF-20 and MBF-30). Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) of the joints showed that compositional changes due to substrate dissolution led to secondary-phase precipitation which aided interfacial bonding although inter-laminar shear failure occurred within some composites. Residual thermal stresses in the joint led to hardness gradients; however, stress accommodation by the brazes prevented interfacial cracking. The peak Knoop microhardness in the joints was as high as 1165–1294 KHN.
A graphical technique for describing recursion

One concept in computer science that is very difficult for the beginner to grasp, and equally difficult for the instructor to present in a straight-forward understandable manner, is the concept of recursion. Since this is a fundamental concept through which the amount of computer code required for some algorithms can be drastically reduced, an instructor must discuss this area early in a student's career, even though he runs the risk of confusing a few students for a lecture or two. This paper presents a method of describing recursive procedure calls that utilizes a form of self-generating state diagram. This approach enables the student to visually keep track of where program control is located at each moment during execution.
The interaction of Escherichia coli ribosomes with p-chloromercuribenzoate.

Abstract 1. When ribosomes from early log-phase cultures of Escherichia coli were incubated with 0.5 mM p -chloromercuribenzoate (PCMB) (in 10 mM Tris buffer (pH 7.6) containing 10 mM Mg 2+ ), the 100-S dimers were completely dissociated into 70-S monomers. 2. The dissociation was not reversed by increased concentrations of Mg 2+ and/or spermine. It was reversed, however, by 2-mercaptoethanol. 3. Mild I 2 oxidation also resulted in 100-S dissociation. Other sulfhydryl reagents, N -ethylmaleimide, 5,5′-dithio-bis-(2-nitrobenzoic acid) and iodacetate, showed no effect. 4. Approximately 10 moles of PCMB were bound per ribosome prior to the onset of dissociation of the 100-S particles. When 20–25 PCMB molecules were bound per ribosome dissociation was almost complete. 5. Dissociation of 100-S ribosomes stems from the reaction of PCMB with sulfhydryl groups presumably in the ribosomal protein. 6. Incubation of untreated ribosomes with 2-mercaptoethanol resulted in an association of 70-S particles into the 100-S dimer, suggesting the relative concentration of the 100- and 70-S particles in vivo may be governed by sulfhydryl interactions.
The “other IQ”: Historiometric assessments of intelligence and related constructs.

Running parallel to mainstream research on the psychometric assessment of intelligence is another tradition of research on the historiometric assessment of intelligence and closely affiliated varia...
Brachial artery reactivity: clinical tool or research toy?

Atherosclerosis is a ubiquitous, complex disease process, which is dynamic and multifactorial. Genetic and environmental factors and their interactions lead to the initiation and progression of atherosclerosis over decades. The vascular endothelium, as the largest paracrine organ, maintains vascular health and initiates the atherosclerotic process when injured. Strategically located between the vessel lumen and smooth muscle layer, the endothelium modulates vascular tone, cell growth, platelet and leukocyte interactions, thrombogenicity, and inflammation. Physical and chemical stimuli in the vascular milieu initiate diverse physiologic processes through complex signal transduction mechanisms that are not yet fully understood, by the elaboration and secretion of various substances. The magnitude and duration of exposure to cardiovascular risk factors lead to vascular injury through oxidative stress mechanisms, which ultimately lead to a procoagulant, proinflammatory, and vasoconstrictive state. Moreover, this promotes oxidation of low-density lipoprotein and proliferation of cell growth.
A Summary of Trends in American Time Allocation: 1965–2005

This article summarizes the findings from Aguiar and Hurst (2007, 2008) with respect to changes in time allocation?particularly leisure?within the United States during the last four decades. Included in our measure of leisure is all time people spend watching tele vision, playing sports, socializing with friends and family, reading, engaging in hobbies, and relaxing. The results from Aguiar and Hurst indicate that leisure has increased for both men and women, since 1965, by roughly 5 and 3.5 h per week, respectively. However, most of these gains occurred prior to 1985 and the trends for women have some been somewhat reversed over the last decade.
Rheologische eigenschaften für isotrope linear-viskoelastische kompositmaterialien

Abstract The article describes a method of determining the rheological properties which are associated with an uniaxial state of stress on an isotropic two phase material. It is assumed that the composite is composed of particles in a continuous matrix. Both phases are linear viscoelastic and the contact between them is supposed to be perfect. The method is demonstrated in examples concerning cement and asphalt concrete. Among other things, the influence of aggregate on the creep function and the complex Young's modulus is examined.
Gender and Citizen Participation in Wildlife Management Decision Making

We compared the motivations and preferences of men and women toward citizen participation in wildlife-related decisions. Data were collected via a mail survey of past participants in New York State Department of Environmental Conservation citizen participation processes completed between 1992 and 1999. We explored gender differences in motivations for participation, preferred process characteristics, and criteria used to evaluate process success. Men's participation was more often motivated by a request from a wildlife-related entity. Women placed more importance on processes having unbiased facilitation and the opportunity for open exchange of ideas and information with the agency. Men placed more importance on the use of scientific information in decision making. Attained education level played an important role in observed gender differences. Different strategies are needed to fully engage both women and men in wildlife-related decision making processes.
On the reasoning patterns of agents in games

What reasoning patterns do agents use to choose their actions in games? This paper studies this question in the context of Multi-Agent Influence Diagrams (MAIDs). It defines several kinds of reasoning patterns, and associates each with a pattern of paths in a MAID. We asks the question, what reasoning patterns have to hold in order for an agent to care about its decision? The answer depends on what strategies are considered for other agents' decisions. We introduce a new solution concept, called well-distinguishing (WD) strategies, that captures strategies in which all the distinctions an agent makes really make a difference. We show that when agents are playing WD strategies, all situations in which an agent cares about its decision can be captured by four reasoning patterns. We furthermore show that when one of these four patterns holds, there are some MAID parameter values such that the agent actually does care about its decision.
Postural Orientation and Equilibrium: What Do We Need to Know About Neural Control of Balance to Prevent Falls?

Postural control is no longer considered simply a summation of static reflexes but, rather, a complex skill based on the interaction of dynamic sensorimotor processes. The two main functional goals of postural behaviour are postural orientation and postural equilibrium. Postural orientation involves the active alignment of the trunk and head with respect to gravity, support surfaces, the visual surround and internal references. Sensory information from somatosensory, vestibular and visual systems is integrated, and the relative weights placed on each of these inputs are dependent on the goals of the movement task and the environmental context. Postural equilibrium involves the coordination of movement strategies to stabilise the centre of body mass during both self-initiated and externally triggered disturbances of stability. The specific response strategy selected depends not only on the characteristics of the external postural displacement but also on the individual’s expectations, goals and prior experience. Anticipatory postural adjustments, prior to voluntary limb movement, serve to maintain postural stability by compensating for destabilising forces associated with moving a limb. The amount of cognitive processing required for postural control depends both on the complexity of the postural task and on the capability of the subject’s postural control system. The control of posture involves many different underlying physiological systems that can be affected by pathology or sub-clinical constraints. Damage to any of the underlying systems will result in different, context-specific instabilities. The effective rehabilitation of balance to improve mobility and to prevent falls requires a better understanding of the multiple mechanisms underlying postural control.
Mammography quality assurance. Current issues

Some of the issues being addressed in mammography quality assurance are 1) that image quality is the most important technical aspect of mammography; 2) that image quality has improved steadily over the past two decades and will continue to improve at most mammography sites in the United States; 3) that the American college of Radiology's Mammography Accreditation Program is the best way to ensure high quality mammogram; 4) that access to high quality mammography is not geographically restricted, with over half the mammography sites in the United States now ACR accredited and another 30% participating in the accreditation process
Mechanisms of the Proinflammatory Response of Endothelial Cells to Candida albicans Infection

Endothelial cells can influence significantly the host inflammatory response against blood-borne microbial pathogens. Previously, we found that endothelial cells respond to in vitro infection with Candida albicans by secreting interleukin 8 (IL-8) and expressing E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). We have now examined the mechanisms mediating this endothelial cell response. We determined that C. albicans stimulated endothelial cells to synthesize tumor necrosis factor alpha (TNF-α), which in turn induced these infected cells to secrete IL-8 and express E-selectin by an autocrine mechanism. Expression of VCAM-1 was mediated not only by TNF-α but also by IL-1α and IL-1β, all of which were synthesized by endothelial cells in response to C. albicans. These three cytokines remained primarily cell associated rather than being secreted. Candidal induction of ICAM-1 expression was independent of TNF-α, IL-1α, and IL-1β. These observations demonstrate that different proinflammatory endothelial cell responses to C. albicans are induced by distinct mechanisms. A clear understanding of these mechanisms is important for therapeutically modulating the endothelial cell response to C. albicans and perhaps other opportunistic pathogens that disseminate hematogenously.
Cracking Analysis of Plain Concrete under Coupled Heat Transfer and Moisture Transport Processes

A smeared cracking approach is developed in this paper to simulate the crack propagation in plain concrete caused by coupled heat transfer and moisture transport processes. The cracking state of each concrete element is described using an original concept—local relative crack density (LRCD). Furthermore, a numerical relationship between LRCD and the moisture transport property is proposed to consider the accelerating influence of crack propagation on moisture diffusion. Finally, a global relative crack density is suggested to denote the cracking state of the entire concrete structure, which may serve as an appropriate index to evaluate the overall deterioration level of the structure. A finite element-based computational methodology is developed to simulate the coupled thermohydrochemomechanical deterioration processes, and is expanded further to implement the simulation of crack propagation. The proposed method establishes a reasonable analytical basis for quantitative long-term durability assessment of ...
Ventricular arrhythmia discriminator programming and the impact on the incidence of inappropriate therapy in patients with implantable cardiac defibrillators.

Background: The incidence of inappropriate therapy from implantable cardioverter defibrillators (ICDs) has been reduced by programming ventricular arrhythmia discriminators (VAD) on at the time of implant. Objective: To determine which VAD is most effective in preventing inappropriate therapy. Methods and Results: Dual chamber ICD (n=48) or cardiac resynchronization therapy defibrillator (CRT-D) (n=55) implantation was performed in 103 patients (M=94, F=9). Patients were followed prospectively for therapy events (shock or anti-tachycardia pacing) for a mean 362±289 days. Events were correlated with clinical characteristics and VAD programming. Of the 103 pts followed, 11 received inappropriate therapy (IT), 15 received appropriate therapy (AT), and 77 received no therapy (NT). In the AT and IT groups, a total of 207 events (ATP=171, shock=36) were observed. A total of sixty-four electrograms (EGMs) were analyzed. Programming VADs "ON" versus "OFF" reduced the incidence of IT events compared to those receiving AT or NT events (p<.01), with a trend in fewer patients receiving IT (31.3% "ON" vs 55.6% "OFF", p = 0.131). Programming atrial fibrillation (AF) detection ON resulted in fewer patients receiving IT compared to those receiving AT or NT (3.6% vs 19%, p<.05). Furthermore, programming AF or AFL algorithms "ON", resulted in overall fewer episodes of IT therapy (p<.01). Conclusions: AF or AFL discriminators significantly reduced the incidence of IT, and were predominantly responsible for the benefits from VAD programming observed in this study. Activating these features as part of routine ICD or CRT-D programming may provide a simple and effective alternative to the use of more complex and multiple VAD strategies.
Cable TV Deregulation Reconsidered: An Exploration of Three Theses

Why did the Federal Communications Commission deregulate cable television between 1974 and 1980? This article attempts to answer this question through a comparative consideration of three theoretical explanations: the policy discourse explanation, the policy systems explanation, and the organizational capacity explanation. Ultimately, the article concludes that none of these perspectives, standing alone, adequately explains the FCC's deregulation of cable television. The article also provides a more integrative explanation for policy change.
The effect of temperature and density on the amplitude of vertical migration of Daphnia magna

The amplitude of vertical migration of Daphnia magna from warm to cold water was inhibited in thermally stratified columns in acrylic tubes. Changes in water density alone did not affect vertical movement. Abolition of the descending blue dance could not explain the results because the light source had a spectrum shifted to the red region. The magnitude of vertical migration may be reduced by an avoidance reaction to cold temperatures commonly observed in temperate lakes during summer stratification.
Oromandibular reconstruction with vascularized free flaps: a review of 50 cases

Fifty cases of oromandibular reconstruction using vascularized free flaps to evaluate functional parameters of results were evaluated. There were 23 iliac crest flaps, 17 fibula flaps, 30 ulnar forearm flaps, and 3 radial forearm flaps with bone. Thirteen female and 37 male patients comprised the study, with a mean age of 57.66 years. Squamous-cell carcinoma (SCC) constituted 86% of cases, of which 60% were T4 lesions and 13.9% were recurrent. Anterolateral mandibular defects constituted 48.7%, and the mean bone gap was 8.13 cm. Functional evaluation was based on the University of Washington Questionnaire (UWQ) through phone calls and personal communication. The mean hospital stay was 12.42 days. The external carotid (75%) and facial (18.3%) were the main recipient arteries. The internal jugular (47.05%) was the main recipient vein. Overall flap survival was 95.9%. Three flaps were lost due to unsalvageable venous thrombosis. Major local complications such as partial flap loss, hematoma, and orocervical fistula constituted 10% of cases. Speech was classified as "excellent" and "good" in 43.3% of cases. Swallowing was identified as "excellent" and "good" in 53.3% of cases. Cosmetic acceptance was rated "good" in 63.3% of cases. Vascularized free flap reconstruction of oromandibular defects provides excellent functional and aesthetic results. The majority of patients are able to tolerate a regular diet. Intelligible speech and acceptable appearance are restored, providing patient satisfaction.
THREE‐ALTERNATIVE MULTIPLE CHOICE TESTS: AN ATTRACTIVE OPTION

Traditionally, multiple choice tests have included four or five alternatives. Data from public sector employment tests are presented that indicate that tests composed of multiple choice items containing three alternatives have psychometric properties similar to those offered by tests composed of items containing five alternatives. Given the similarity of the psychometric properties and the likely reductions in cost of development and administration time, three-alternative multiple choice items may be preferable to five-alternative multiple choice items for some testing purposes.
Determination of water mass ages using radium isotopes as tracers: Implications for phytoplankton dynamics in estuaries

Abstract Despite a relatively short residence time of water in many shallow, semi-enclosed estuaries, phytoplankton blooms in nutrient enriched systems are a common phenomenon. This poses the question how is it possible to have phytoplankton populations bloom in response to local conditions of shallow estuaries, if the water residence times are similar to cell division times? To address this paradox we used the radium quartet as a tool to measure water mass age in coastal systems (Waquoit Bay, MA, USA) subject to different degrees of land-derived nitrogen load and hence differences in phytoplankton biomass. Recently, the radium quartet has been used as geochemical tracers to determine age of water masses. Based on a number of samples collected over the course of one year, the average radium-derived age (± stdev) of water in three sub-estuaries of Waquoit Bay (Childs River, Quashnet River, and Sage Lot Pond) was ~ 7 (± 4.7), 11 (± 6.2), and 17 (± 7.5) days, respectively. These values are significantly longer than previous estimates based on more traditional hydrodynamic methods. Furthermore, peak chlorophyll concentrations were associated with older water masses in the heavily freshwater-influenced sub-estuaries (Childs and Quashnet). Our results suggest that water age, temperature, and nutrients all play a role in controlling phytoplankton biomass however, water age was more important at the time of the year when temperature limits phytoplankton growth (late spring, early summer). We conclude that radium-derived age models, which are similar to artificial tracer-based approaches, may be the most appropriate method for studying the role of hydrodynamics on estuarine ecology.
Super-Gaussian Loading for Robust Beamforming

It is well known that the performance of adaptive beamformers may degrade in the presence of steering errors. In this context, diagonal loading is one of the most popular methods used for robust beamforming, and can be derived from an l2 norm constraint. Equivalently, this method assumes a white Gaussian prior on the beamforming vector, similar to ridge regression in statistical point of view. By changing the loading level, which can be treated as confidence of this prior distribution, a trade-off between robustness and adaptivity is obtained. In this article, we generalize this approach via lp norms. We find that under different settings, it is not optimal to set p = 2 compared with other p ∈ [1, 2] with the loading level chosen in such a way that the prior variance is maintained. We derive an iterative form to calculate the beamformer, as well as an iterative online implementation. Convergence is observed in empirical simulations and discussed under certain conditions.
Treating Patients With Asthma: The Impact of Individual and Family Dynamics

Asthma is an increasingly common chronic medical condition that affects not only patients but their families. Because this condition has significant psychosocial impact, effective treatment requires an integration of psychosocial treatment—including individual, couples, and family counseling—with conventional medical treatment. Individual psychological dynamics as well as couple and family dynamics that influence the treatment process are described along with implications for family counseling. An illustrative case example is included.
Antisense Inhibition of AT1 Receptor in Vascular Smooth Muscle Cells Using Adeno-Associated Virus-Based Vector

Abstract —Vascular smooth muscle cells (VSMCs) are the main peripheral target for vasoconstriction and growth-promoting activity of angiotensin II (Ang II), acting through angiotensin type 1 receptors (AT 1 -R). Current antihypertension treatments include daily reductions in the effects of Ang II. To decrease an effect of Ang II in a prolonged fashion, we have developed an adeno-associated virus (AAV) vector with antisense DNA for AT 1 -R. AAV has many advantages over other viral vectors. AAV is nonpathogenic, does not stimulate inflammation or immune reaction and enters nondividing cells, and provides stable long-term gene expression. To test AAV in VSMCs, we constructed and tested plasmid AAV (pAAV) and recombinant AAV (rAAV) with AT 1 -R antisense DNA. rAAV was constructed with a cassette containing a cytomegalovirus promoter and the cDNA for the AT 1 -R inserted in the antisense direction. The cassette was packaged into the virion. Transfection of VSMCs with the pAAV antisense to AT 1 -R produced a significant reduction in the amount of AT 1 -R ( P 1 -R-AS at MOI of 5 also showed significant reduction of AT 1 -R and long-lasting expression of the transgene for at least 8 weeks. The reduction of AT 1 -R number in VSMCs was concomitant with a decrease in the Ang II–stimulated increase of intracellular calcium. The results show that AAV vector delivers AT 1 -R antisense to inhibit AT 1 -R in VSMCs. For the purpose of gene therapy for hypertension, it is necessary to demonstrate the effectiveness of a vector system in VSMCs. This study provides support for the potential use of AAV AT 1 -R antisense in VSMCs.
Management of Orbital Lymphoma

In this chapter dealing with management of orbital lymphomas, the term “orbital” will refer to lymphomas occurring in the conjunctiva, lacrimal gland, and eyelid as well as the orbit. As orbital lymphomas are relatively rare tumors, the author has relied heavily on information from the three largest collected series of 115 patients from the United Kingdom (Bessell et al. 1988), 108 cases from the United States (Jakobiec and Knowles 1989), and 42 cases from Canada (Fitzpatrick and Macko 1984).
Late Glacial and Holocene glacier fluctuations at Nevado Huaguruncho in the Eastern Cordillera of the Peruvian Andes

Discerning the timing and pattern of late Quaternary glacier variability in the tropical Andes is important for our understanding of global climate change. Terrestrial cosmogenic nuclide (TCN) ages (48) on moraines and radiocarbon-dated clastic sediment records from a moraine-dammed lake at Nevado Huaguruncho, Peru, document the waxing and waning of alpine glaciers in the Eastern Cordillera during the past ∼15 k.y. The integrated moraine and lake records indicate that ice advanced at 14.1 ± 0.4 ka, during the first half of the Antarctic Cold Reversal, and began retreating by 13.7 ± 0.4 ka. Ice retreated and paraglacial sedimentation declined until ca. 12 ka, when proxy indicators of glacigenic sediment increased sharply, heralding an ice advance that culminated in multiple moraine positions from 11.6 ± 0.2 ka to 10.3 ± 0.2 ka. Proxy indicators of glacigenic sediment input suggest oscillating ice extents from ca. 10 to 4 ka, and somewhat more extensive ice cover from 4 to 2 ka, followed by ice retreat. The lack of TCN ages from these intervals suggests that glaciers were less extensive than during the late Holocene. A final Holocene advance occurred during the Little Ice Age (LIA, ca. 0.4 to 0.2 ka) under colder and wetter conditions as documented in regional proxy archives. The pattern of glacier variability at Huaguruncho during the Late Glacial and Holocene is similar to the pattern of tropical Atlantic sea-surface temperatures, and provides evidence that prior to the LIA, ice extent in the eastern tropical Andes was decoupled from temperatures in the high-latitude North Atlantic.
Formulation and Properties of an Alcohol-Free, Pharmaceutical Microemulsion System

An alcohol-free, water-in-oil microemulsion was formulated using two high molecular weight, pharmaceutically acceptable surfactants: sorbitan monolaurate (Arlacel 20 or Span 20) and sodium dioctyl sulfosuccinate (AOT). The amount of water solubilized depended on the oil chain length, the relative amounts of the two surfactants and the salinity of the water as well as the total surfactant weight. The optimal system contained equal weights of AOT and Arlacel 20 in hexadecane. With this system, one can obtain an isotropic dispersion containing equal volumes of oil and water with 21% total surfactants and no alcohol. With AOT and Arlacel 20 at a 1:1 weight ratio in hexadecane, the molecular ratio of water to total surfactant present was approximately 50. Addition of electrolytes drastically reduced water solubilization in the microemulsion system. Maximum water solubilization corresponded to a low interfacial tension between the oil and water. For a given oil chain length, a specific molar ratio of AOT to Arlacel 20 was required for maximum solubilization of water in the oil. Since the emulsifiers used are pharmaceutically acceptable, this microemulsion is promising for pharmaceutical and cosmetic applications.
Thomas H. Jukes (1906–1999)

TOM Jukes accepted our invitation to write a Perspectives on the early history of molecular evolution, and in August 1999 he sent a rough beginning containing some now-forgotten early history. He planned an extensive revision and continuation, but on November 1 his death intervened. We have decided
Pharmacokinetics and Clinical Utility of Valproic Acid Administered via Continuous Infusion.

Valproic acid is a versatile antiepileptic drug that is often used in the acute care setting. Intravenous valproic acid lends itself well to a continuous infusion as it exhibits a relatively short half-life. We evaluated the pharmacokinetics and clinical efficacy of continuous infusion valproic acid in hospitalized patients with migraine and seizures. A retrospective cohort study was performed utilizing information from the medical records of patients receiving an intravenous continuous infusion of valproic acid. Patients were included if they were aged 1 month to 85 years and they received a continuous infusion of valproic acid. Therapeutic response, common adverse effects, and the pharmacokinetic profile of valproic acid were evaluated. Continuous infusion valproic acid led to a concentration within the desired range (50–100 μg/ml) in 83.4 % of patients, a rate that was higher in pediatric patients. The clinical response rate was also higher in pediatric patients with seizures or migraines and appeared to be better when the concentration was >75 μg/ml. Analysis of safety parameters suggests similar safety considerations to valproic acid when administered via intermittent infusion. Continuous infusion valproic acid appears to be a safe, effective, and predictable manner by which to administer valproic acid to pediatric and adult patients admitted to the hospital.
Elbow "tRASH" (The radiographic appearance seemed harmless) lesions

A small subset of serious injuries to the pediatric elbow, deemed "TRASH" lesions, are easily missed on radiograph because of their benign appearance. These lesions however, represent a group of osteochondral injuries, which if treated insufficiently result in chronic long-term consequences. Epiphyseal separations, a displaced intra-articular medial condyles before ossification of the secondary center, capitellar shear fractures, radial head fractures with radiocapitellar subluxation and osteochondral fractures of the olecranon, radial head or distal humerus with joint incongruity comprise the group of "TRASH lesions". These injuries are usually seen in children less than 10 years of age who sustain high-energy trauma. The challenge is a prompt diagnosis requiring a high level of suspicion and early additional imaging. Many of these injuries are displaced and unstable requiring anatomic reduction, internal fixation with or without soft tissue repair for further stability. These injuries when diagnosed late, missed completely or treated improperly without aggressive surgical care can result in long-term complications. Surgical reconstruction of the late presenting malunion is difficult.
Laryngeal sarcoidosis: report of 13 patients

Of 220 patients with sarcoidosis of the head and neck region, representing 9% of 2,319 patients with sarcoidosis seen at the Mayo Clinic from 1950 through 1981, we identified 12 who had laryngeal sarcoidosis. Edematous, pale, diffuse enlargement of the supraglottic structures was the most common laryngeal manifestation. The diagnosis is made by a group of clinical, radiologic, and laboratory findings, confirmed by the finding of noncaseating granuloma on biopsy. Sarcoidosis is a disease with frequent remissions and exacerbations and generally burns itself out; glucocorticoids may be indicated in particularly severe disease. When laryngeal sarcoidosis is suspected, the laryngologist should collaborate with other clinicians in a thorough evaluation of the patient.
Synthesis of 3,4‐dihydro‐1(2H)‐isoquinolinonesxs

Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large-scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high-temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)-isoquinolinone (9). Catalytic hydrogenation of 9 provided the desired 3,4-dihydro-5-methyl-1(2H)-isoquinolinone (2) in 65 % overall yield. Similar reduction of a commercially available 5-hydroxy-1(2H)-isoquinolinone precursor 10 followed by an O-alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4-dihydro-1(2H)-isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.
Myocardial deformation in fetuses with coarctation of the aorta: a case-control study.

Objective To study myocardial deformation by speckle tracking echocardiography in fetuses with coarctation of the aorta (CoA) compared with gestational age-matched normal controls. Methods This was a retrospective study of 12 fetuses with postnatally confirmed CoA and 12 gestational age-matched controls seen at a tertiary fetal cardiology unit between January 2013 and July 2014. Two-dimensional speckle tracking in standard grayscale four-chamber view of the fetal heart was performed to assess left and right myocardial deformation. Global longitudinal strain, strain rate and velocities, and regional longitudinal strain were analyzed and compared with controls. Results Median gestational age at echocardiography was 25 + 4 weeks. Fetuses with CoA presented with a narrower, but not shorter, left ventricle when compared with controls (mitral valve diastolic diameter, 5.90 vs 8.50 mm; P = 0.002; left ventricular diastolic length, 16.50 vs 18.50 mm; P = 0.05). Global longitudinal systolic strain (P = 0.004), systolic strain rate (P = 0.01) and diastolic strain rate (P = 0.004) of the left ventricle were significantly lower in fetuses with CoA compared with controls. Similar findings were observed for longitudinal systolic (P = 0.03) and diastolic (P = 0.01) velocities of the left ventricle. Right ventricular parameters were not different between groups. Conclusions Fetuses with CoA have lower left ventricular longitudinal systolic strain, systolic strain rate and diastolic strain rate when compared with gestational age-matched control fetuses. These differences in deformation might explain, at least in part, the cardiac asymmetry observed in fetuses with CoA. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Trends in the Diagnosis and Outcomes of Traumatic Carotid and Vertebral Artery Dissections among Medicare Beneficiaries

Background Early identification of carotid and vertebral artery dissections has been advocated to reduce stroke among trauma patients. We sought to characterize trends in the diagnosis of traumatic carotid and vertebral artery dissections and association changes in stroke rate among Medicare beneficiaries. Methods Using Medicare claims, we created a cohort of 5,961 beneficiaries admitted with a new traumatic carotid or vertebral artery dissection from 2001 to 2012. We calculated rates of stroke during hospitalization and 90 days of discharge. We calculated rates of carotid imaging using computed tomography-angiography, carotid duplex, and plain angiography index hospitalization. To study concurrent secular trends, we created a secondary cohort of patients admitted after any traumatic injury from 2001 to 2012 and determined rates of stroke and carotid imaging within this cohort. Results From 2001 to 2012, incidence of traumatic carotid dissection increased 72% among Medicare beneficiaries (1.1–1.76 per 100,000 patients; rate ratio [RR], 1.72; 95% CI, 1.6–1.9, P P = 0.094). Likewise, there was little change in mortality (10.3%; RR, 1.01; 95% CI, 0.95–1.06; P = 0.88). Among all trauma patients, the use of computed tomography angiography has increased 16-fold (2–35 per 100,000 patients; RR, 16.7; 95% CI, 13–19; P Conclusions Despite increased diagnosis of carotid or vertebral artery dissection, there has been little change in stroke risk among trauma patients. Efforts to more effectively target imaging and treatment for these patients are necessary.
Pressure field induced in the water column by acoustic‐gravity waves generated from sea bottom motion

An uplift of the ocean bottom caused by a submarine earthquake can trigger acoustic-gravity waves that travel at near the speed of sound in water and thus may act as early tsunami precursors. We study the spatiotemporal evolution of the pressure field induced by acoustic-gravity modes during submarine earthquakes, analytically. We show that these modes may all induce comparable temporal variations in pressure at different water depths in regions far from the epicenter, though the pressure field depends on the presence of a leading acoustic-gravity wave mode. Practically, this can assist in the implementation of an early tsunami detection system by identifying the pressure and frequency ranges of measurement equipment and appropriate installation locations.
Coarse-Grained Information Flow Control on Hybrid Clouds

Recently, more and more enterprises have adopted hybrid cloud strategies to simultaneously enjoy the security of on-premise clouds and the low cost of public clouds. The key challenge of hybrid clouds, though, stems from the difficulty of specifying where the data should be stored and where the information could flow efficiently. In order to meet security concerns and performance requirements, we introduce a coarse-grained information flow control (CIFC) model to limit storing, accessing, and disclosing of confidential data in public clouds. The CIFC model aims at providing information control implicitly, without the large overhead of periodically checking access privileges. Moreover, since the CIFC model may request redistributing data whenever the secrecy level of a dataset changes, we formulate the data redistribution problem as an optimization problem and propose the Partition Biased Sampling Algorithm (PBSA) for its solution. We implemented the CIFC model on top of Spark, and our results show that Spark applications can achieve 1.4 to 2.1 times better performance by utilizing the additional computational capacity of public cloud to process non-sensitive data. Furthermore, we integrate the PBSA algorithm into Spark and demonstrate a saving of more than 35% in execution time, compared to the Spark default data distribution strategy.
How safe is same-day discharge after laparoscopic sleeve gastrectomy?

Abstract Background Laparoscopic sleeve gastrectomy (LSG) is associated with low morbidity and mortality and a short length of stay. Studies on the safety of same-day discharge after LSG are limited. Objective To compare outcomes between same-day versus first-postoperative-day (POD1) discharge after LSG. Setting Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database. Methods The 2015 to 2016 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database was analyzed for elective LSG cases with same-day or POD1 discharge. Open, revisional, and converted cases were excluded. Multivariate analysis was performed to compare adjusted 30-day mortality, morbidity, readmission, and reoperation for same-day versus POD1 discharge. Results We examined 85,321 LSG cases, including 4728 same-day discharges and 80,593 POD1 discharges. Compared with POD1 discharges, same-day discharges were associated with higher overall morbidity (1.31% versus .84%, respectively; adjusted odds ratio [AOR] 1.72; P = .0002), a higher readmission rate (2.14% versus 1.64%, respectively; AOR 1.40; P = 0.0034), and a higher reoperation rate (.61% versus .27%, respectively; AOR 2.35; P Conclusion Same-day discharge after LSG is associated with increased complications, readmissions, and reoperations compared with POD1 discharge. Further studies are needed to examine objective criteria for safe same-day discharge after LSG.