cssi/SciSciGPT-SciSciNet huggingface dataset:
Use-dependent block of cardiac sodium channels by quaternary derivatives of lidocaine.

Modulation of the reduction of fast inward sodium current by local anesthetics due to changes in electrical activity has been termed use-dependent block (Courtney 1975). To determine the mechanisms responsible for use-dependent block of cardiac sodium channels and to compare use-dependent block in cardiac and nerve preparations, we investigated use-dependent block of cardiac sodium channels by the quaternary lidocaine analogues QX-314 and QX-222 (two agents previously studied in nerve). We used canine cardiac Purkinje fibers, and assessed changes in the fast inward sodium current using changes in the maximum rate of rise of the action potential upstroke ( $$\dot V_{\max }$$ ). Two microelectrode voltage clamp and current clamp techniques were used to control membrane potential prior to stimulated upstrokes. Use-dependent block was not affected by shortening the action potential duration during rapid stimulation. Partial recovery from use-dependent block was observed during rapid stimulation with brief depolarizing prepulses terminating immediately prior to the upstroke. Similar prepulses also prevented the development of use-dependent block following an abrupt increase in the stimulation rate. Hyperpolarizing prepulses during rapid stimulation caused recovery from use-dependent block; recovery was greater and more rapid with increasingly negative prepulses. Hyperpolarization during periods of electrical quiescence also caused greater recovery. These results, interpreted using the modulated receptor hypothesis (Hille 1977; Hondeghem and Katzung 1977), suggest that use-dependent block of cardiac sodium channels by quaternary local anesthetics is due to drug association with the inactivated sodium channel receptor which occurs only after these drugs gain access to the receptor site through open sodium channels.
Large Deviations for Local Times of Stable Processes and Stable Random Walks in 1 Dimension

In Chen and Li (2004), large deviations were obtained for the spatial $L^p$ norms of products of independent Brownian local times and local times of random walks with finite second moment. The methods of that paper depended heavily on the continuity of the Brownian path and the fact that the generator of Brownian motion, the Laplacian, is a local operator. In this paper we generalize these results to local times of symmetric stable processes and stable random walks.
Computation of energy dependent scattering amplitudes via analytic continuation of the fredholm determinant

Abstract A rapid method for calculating partial-wave scattering amplitudes over a range of energies is presented. Approximate values of the partial-wave Fredholm determinant are computed at a number of points in the complex energy plane from a single matrix tridiagonalization and are continued to the real axis via point-wise rational fraction analytic continuation. For two model problems accurate scattering information is obtained over a wide range of energies, and resonances are easily located by noting the zeros of the real part of the determinant.
Adsorption of ruthenium red to phospholipid membranes

We have measured the distribution of the hexavalent ruthenium red cation (RuR) between water and phospholipid membranes, have shown the critical importance of membrane negative surface charge for RuR binding, and determined the association constant of RuR for different phospholipid bilayers. The studies were performed with liposomes made of mixtures of zwitterionic L-alpha-phosphatidylcholine (PC), and one of the negatively charged phospholipids: L-alpha-phosphatidylserine (PS), L-alpha-phosphatidylinositol (PI), or L-alpha-phosphatidylglycerol (PG). Lipid composition of PC:PX membranes was 1:0, 19:1, 9:1, and 4:1. Liposomes were processed using freeze-and-thaw treatment, and their size distribution was characterized by light scattering and electron microscopy. Experimental distribution isotherms of RuR obtained by ultracentrifugation and spectrophotometry can be reproduced with the Langmuir-Stern-Grahame model, assuming that RuR behaves in the diffuse double layer as an ion with effective valency
Photoresists for 193-nm lithography

Photolithography using 193-nm light appears to be a viable route for the extension of optical lithography to the dimensions required for the manufacture of 1Gb DRAM and advanced CMOS microprocessors with 180-140-nm minimum feature sizes. In this paper, we discuss the origin of resist technology for 193-nm lithography and the current status of 193-nm photoresists, focusing on single-layer resist materials. We emphasize the photoresist design approaches under investigation, compare these with deep-UV (DUV) (248-nm) resist design and materials, and consider possible future lithography processes employing 193-nm lithography. Research and development on 193-nm photoresists by the lithography group at the IBM Almaden Research Center is highlighted.
Oculopalatal tremor, facial myokymia and truncal ataxia in a patient with neurosarcoidosis

Symptomatic palatal tremor (SPT) is the result of a structural lesion, in the form of stroke, trauma or demyelinating disease. SPT is due to contractions of the levator veli palatini and can be accompanied by simultaneous movements of the facial and ocular muscles. Facial myokymia (FM) is a persistent quivering of the facial muscles. FM is usually encountered with conditions involving the pontine tegmentum. We report, to our knowledge, the first patient with neurosarcoidosis with simultaneous SPT and FM. A 49-year-old African American woman, with non-caseating granulomas in a paratracheal lymph node biopsy, presented with progressive gait disturbances for the last 3 years. Neurological examination revealed ataxic speech, bilateral rotatory nystagmus, myokymia of the chin and perioral muscles, palatal tremor without ear click and marked truncal ataxia. MRI demonstrated a lesion involving the facial nucleus and the right middle cerebellar peduncle. Based on exclusion of alternative etiologies, a diagnosis of neurosarcoidosis was made and the patient was started on methotrexate for 9 months, with minimal improvement. She was then switched to intravenous infliximab without major adverse events. The patient's speech and gait ataxia improved and follow up MRI demonstrated resolution of the enhancing lesions. To our knowledge, this is the first reported case of the combination of palatal tremor and FM due to neurosarcoidosis. Methotrexate may fail to produce clinical or radiographic response in up to 39% of patients. Tumor necrosis factor-α inhibitors, such as infliximab, should be considered in refractory cases.
Emergency Physician Perceptions of Shared Decision-Making

Author(s): Kanzaria, Hemal K; Brook, Robert H; Probst, Marc A; Harris, Dustin; Berry, Sandra H; Hoffman, Jerome R | Abstract: ObjectivesDespite the potential benefits of shared decision-making (SDM), its integration into emergency care is challenging. Emergency physician (EP) perceptions about the frequency with which they use SDM, its potential to reduce medically unnecessary diagnostic testing, and the barriers to employing SDM in the emergency department (ED) were investigated.MethodsAs part of a larger project examining beliefs on overtesting, questions were posed to EPs about SDM. Qualitative analysis of two multispecialty focus groups was done exploring decision-making around resource use to generate survey items. The survey was then pilot-tested and revised to focus on advanced diagnostic imaging and SDM. The final survey was administered to EPs recruited at four emergency medicine (EM) conferences and 15 ED group meetings. This report addresses responses regarding SDM.ResultsA purposive sample of 478 EPs from 29 states were approached, of whom 435 (91%) completed the survey. EPs estimated that, on average, multiple reasonable management options exist in over 50% of their patients and reported employing SDM with 58% of such patients. Respondents perceived SDM as a promising solution to reduce overtesting. However, despite existing research to the contrary, respondents also commonly cited beliefs that 1) "many patients prefer that the physician decides," 2) "when offered a choice, many patients opt for more aggressive care than they need," and 3) "it is too complicated for patients to know how to choose."ConclusionsMost surveyed EPs believe SDM is a potential high-yield solution to overtesting, but many perceive patient-related barriers to its successful implementation.
Carcinoma in the retained rectum after colectomy for ulcerative colitis.

A carcinoma arising in an excluded rectal stump 18 years after ileostomy and 14 years after subtotal colectomy has been described. Extent of involvement of the colon, age of the patient at onset of colitis, and duration of symptomatology are factors which have been shown to influence the incidence of carcinoma complicating ulcerative colitis. Fifty-eight similar cases of carcinoma developing in a retained rectum were collected from the literature. The incidence of this complication is approximately 3 per cent. Rectum-sparing operations do not appear to decrease the indicence of malignant transformation in ulcerative colitis. A decision to retain the rectum after colonic resection for ulcerative colitis must take into account both the significant incidence of malignant transformation associated with all rectum-sparing procedures and also the significant incidence of recurrent symptoms following this procedure.
Microstructural factors influencing the properties of high surface area molybdenum nitride films converted from molybdenum trioxide films deposited via solution spray pyrolysis

Molybdenum trioxide (MoO 3 ) films, 15 µm thick, have been deposited on 50 µm thick polycrystalline titanium substrates from 250 to 500 °C via liquid spray pyrolysis. Molybdenum pentachloride (MoCl 5 ) dissolved in methanol was used as the molybdenum source; ambient conditions provided the oxygen source. X-ray diffraction (XRD) data indicated that amorphous MoO 3 films were produced at deposition temperatures below 400 °C. Randomly orientated polycrystalline MoO 3 films were produced at 400 °C and higher deposition temperatures. The deposition temperature also influenced the surface area of the films and their average grain size. Subsequent conversion of the MoO 3 films to high surface area (HSA) conductive films containing both γ–Mo 2 N and δ–MoN was accomplished via programmed reactions with anhydrous NH 3 and involved the formation of MoO 2 and MoO x N 1− x as intermediate phases. The degree of crystallinity, surface area, and average grain size of the MoO 3 films strongly influenced the average grain size and surface area of the resultant Mo x N films.
Free-space optical communication link and atmospheric effects: single aperture and arrays

Free space optical (FSO) communication systems offer several advantages over conventional radio frequency (RF) systems but, because of shorter wavelength, are subject to various atmospheric effects. Particularly significant in this regard is the signal fading below a prescribed threshold value owing primarily to optical scintillations associated with the received signal. In this paper we utilize some recent advances in the modeling of optical scintillation under weak-to-strong fluctuations associated with terrestrial links and examine fade probability and bit error-rate (BER) for direct detection systems using a single large aperture receiver and the BER for an array of smaller receiver apertures.
Overview: Civil-Military Relations in Central and Eastern Europe in Former Communist Societies:

This article reviews studies on civil-military relations by David Betz (Russia), Daniel Nelson (Romania and Bulgaria), Natalie Mychajlysyn (Ukraine), Marybeth Ulrich (Czech Republic), and Mark Yaniszewski (Poland and Hungary). All note minimal progress in developing a cadre of civilian defense experts who can end the monopoly of ministries of defense on policymaking. Those states that are candidates for NATO membership have made much more drastic cuts in the size of paramilitary and internal security forces than have Russia and Ukraine. They have also moved toward postures and doctrines based on coalition security policies, which have all but ruled out the internal use of armed force on the model that Milosevic developed in the former Yugoslavia and Tudjman attempted to develop in Croatia. In Russia and Ukraine, the strong presidential systems have at their disposal large internal armed forces that could be available for targeting domestic political opponents or minority groups.
Public-key cryptosystems provably secure against chosen ciphertext attacks

We show how to construct a public-key cryptosystem (as originally defined by DiNe and Hellman) secure against chosen ciphertezt attacks, given a public-key cryptosystern secure against passive eavesdropping and a noninteractive zero-knowledge proof system in the shared string model. No such secure cryptosystems were known before. A concrete implementation can be based on quadratic residuosity intractability.
Structural properties of lithium thio-germanate thin film electrolytes grown by radio frequency sputtering.

In this study, lithium thio-germanate thin film electrolytes have been successfully prepared by radio frequency (RF) magnetron sputtering deposition in Ar gas atmospheres. The targets for RF sputtering were prepared by milling and pressing appropriate amounts of the melt-quenched starting materials in the nLi2S + GeS2 (n = 1, 2, and 3) binary system. Approximately 1 μm thin films were grown on Ni coated Si (Ni/Si) substrates and pressed CsI pellets using 50 W power and 25 mtorr (∼3.3 Pa) Ar gas pressures to prepare samples for Raman and Infrared (IR) spectroscopy, respectively. To improve the adhesion between the silicon substrate and the thin film electrolyte, a sputtered Ni layer (∼120 nm) was used. The surface morphologies and thickness of the thin films were determined by field emission scanning electron microscopy (FE-SEM). The structural properties of the starting materials, target materials, and the grown thin films were examined by X-ray diffraction (XRD), Raman, and IR spectroscopy.
SU-FF-T-435: Tongue and Groove Effect in Direct Aperture Optimization IMRT Plans

Purpose: Direct Aperture Optimization (DAO) is a promising new IMRT technique whereby the MLC leaves and relative weights of the apertures are simultaneously optimized. Due to the stochastic nature of the simulated annealingoptimization algorithm, MLC leaves can have positions that are significantly different from their neighboring leaves. Opposed adjacent leaves with these positions can lead to a “ripple” in the dose distribution due to tongue‐and‐groove effect (TGE). In this work, we attempt to quantify the magnitude of the effect and commission the Pinnacle planning system to account for it. Method and Materials: To quantify TGE, we generated a two‐segment beam: one segment with every other leaf on one side extending well past the central axis and the other with every other opposed adjacent leaf extending well past the central axis. Jaws set to 20×20 bound both segments and both had equal monitor units. This beam was delivered to a flat phantom with a film placed at 10cm depth. Newer versions of Pinnacle (7.4 or greater) take into account TGE. This is modeled in the physics tool with a tongue‐and‐groove step parameter. We systematically changed this parameter and compared the resulting dose distributions to the film measurement. We imported DAO IMRT plans into the Pinnacle planning system and compared the dose distributions with and without TGE. These were also compared with verification measurements. Results: The film displayed a 23% variation from minimum to maximum dose. The Pinnacle step parameter of 0.3cm reproduced the variation. If TGE is not accounted for in the planning, an underestimation of the absolute dose is observed for DAO IMRT plans. The magnitude of the underestimation is dependent upon the aperture shapes. Conclusions: TGE affects the dose distribution for DAO plans. Limiting the distance adjacent leaves may travel can reduce the effect of TGE.
Magnetic Field Penetration in Superconducting Lead

The magnetic susceptibility of small superconducting lead spheres (radius \ensuremath{\sim}${10}^{\ensuremath{-}3}$ cm) has been determined by a self-inductance method. On the basis of relations derived from the London theory for reducing the data, the penetration depth, $\ensuremath{\lambda}$, is calculated for three different lead samples at 4.22\ifmmode^\circ\else\textdegree\fi{}K. Results indicate that $\ensuremath{\lambda}$ is 1.3\ifmmode\pm\else\textpm\fi{}0.3\ifmmode\times\else\texttimes\fi{}${10}^{\ensuremath{-}5}$ cm at this temperature. In addition, it is found that, within experimental error, $\ensuremath{\lambda}$ is not a function of the size of the sphere. It is noted that there is need for using smaller sized particles and accounting for the interaction effects if future colloid investigations designed to test the London theory are to be successful.
Comparison of heating calculations with experimental data on a modified Shuttle Orbiter

Heating-rate calculations from an "engineering" code and a "benchmark" Navier-Stokes code are compared with experimental wind-tunnel data obtained on a "modified" 0.0075 scale Shuttle Orbiter at a Mach number of 6 and a freestream Reynolds number of 1.9 X 106/m. Comparisons are presented along the windward symmetry plane, in a circumferential direction around the body, and along the wing leading edge at angles of attack of 30 and 40 deg. From these results, it is shown that both codes provide accurate predictions of the heating rate over most of the body, but because the run time for the engineering code is relatively short, it is an ideal tool for both parametric and design studies.
GENERATION AND CHARACTERISATION OF INDUCED PLURIPOTENT STEM CELLS (iPSCs) FROM ADULT CANINE FIBROBLASTS

Pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can give rise to derivatives of all three germ layers and thus have great potential in regenerative medicine. In mice and humans, it has been shown that embryonic and adult fibroblasts can be reprogrammed into pluripotency by introducing four transcription factors, Oct3/4, Klf4, Sox2 and c-Myc (OKSM). In his presentation we will describe the derivation of iPS cells from adult canine fibroblast by retroviral OSKM transduction. The isolated canine iPS cells were expanded in three different iPS culture media (FGF2, LIF and FGF2 plus LIF) and only the cells cultured in FGF2 plus LIF showed strong AP activity expressed pluripotency markers, POU5F1 (OCT4), SOX2, NANOG and LIN28 as well as ES cells-specific genes (PODXL, DPPA5, FGF5, REX1 and LAMP1). In vitro differentiation by formation of embryoid bodies (EBs) and directed differentiation showed cell derivatives of all three germ layers as confirmed by expression for AFP, CXCR4 and SOX17 (endoderm), desmin (DES), vimentin (VIM), MSX1 and BMP2 (mesoderm) and glial fibrillary acidic protein (GFAP), TUJ1, NCAM and bIII-tubulin (TUBB, ectoderm). In vivo, the putative canine iPS cells formed simple teratomas that expressed markers for all three germ layers. In summary, we were able to derive induced pluripotent cells from adult somatic cells by using four transcription factors. The isolated canine iPSCs have similar characteristics to ESCs from other species, but the exact cellular mechanisms behind their unique co-dependency on both FGF and LIF is still unknown. This work was funded by a grant from the America Kennel Club to JAP.
Global Economic Restructuring and International Migration

The purpose of this article is to explore the relationship between processes of global economic restructuring and international migration through an examination of Mexican and Central American immigration to the U.S. and the experiences of Central American and Mexican immigrants in the U.S. This relationship is analysed as one of mutual causation: on the one hand global restructuring affects conditions in both sending and receiving countries (it is not only a factor in emigration but also in the economic and political receptivity to immigrants at their point of destination); on the other international migration in turn has an important impact on countries of origin receiving countries and the relationship between them. (SUMMARY IN FRE AND SPA) (EXCERPT)
Accuracy of individual and panel visual interpretations of coronary arteriograms; Implications for clinical decisions

Abstract The visual interpretation off coronary arteriograms by individuals has been shown to be variable and inaccurate. To determine whether observer accuracy improves with experience or with use of the mean values obtained from a panel of observers, the visual readings off percent diameter stenosis and “normal” reference segment diameter were compared with the quantitative analyses of 13 randomly chosen coronary stenoses. Visual interpretation was also performed on cineangiograms of seven phantom stenoses ranging in severity from 17% to 83%. Repeated quantitative arteriography demonstrated good intraobserver variability for minimal stenosis diameter (r = 0.91, SD = 0.23 mm) and percent diameter stenosis (r = 0.93, SD = 6.4%). When the mean of the repeated quantitative analyses was used as the standard, visual interpretations of percent diameter stenosis were found to have considerable inaccuracy (r = 0.78, SD = 14.5%). Phantom percent diameter stenosis data were better correlated (r = 0.81), but accuracy remained poor (SD = 17.8%). Fifty percent narrowings were read over a range from 30% to 95%. Substantial inaccuracies were also found for observer assessment of normal reference segment diameter (r = 0.75, SD = 0.75 mm). Observer accuracy of percent stenosis did not correlate with prior angiographic experience but was progressively improved by taking the mean value off the interpretations of three and five experienced angiographers (r = 0.88, 0.89;SD = 11.3%, 8.3%, respectively). These findings suggest that arteriographic interpretations accurate enough for interventional decisions can only be obtained using quantitative arteriography or the mean value of data from a large panel of angiographers.
Recognition memory for targets from a scanned word list.

A word list was designed so that half its words would denote targets when any of a number of target classes were defined. After scanning this list for targets, subjects were unexpectedly tested on their ability to recognize the words they had scanned. Recognition memory depended on how targets had been defined: a search for members of a semantically defined target class resulted in better recognition than a search for targets structurally defined. As a group, targets were better recognized than non-targets after a search for words that (a) contained the letter A, (b) denoted living things, or (c) denoted geographical locations. Recognition memory declined by as much as 75 per cent in d' from the first quarter of testing to the last. Items prior to a word's input as well as decisions prior to its testing diminished its recognizability, whereas items following its input exerted comparatively little deleterious effect.
National Heart, Lung, and Blood Institute (NHLBI) Strategic Visioning: Setting an Agenda Together for the NHLBI of 2025

Imagine a world where we are able to prevent and pre-empt the burden of cardiovascular, lung, and blood diseases, a world where we are able to capture the promise of personalized precision medicine, where each person receives the right treatment, tailored to his or her needs, at the right time. In
Dual Role for Phospholipid:Diacylglycerol Acyltransferase: Enhancing Fatty Acid Synthesis and Diverting Fatty Acids from Membrane Lipids to Triacylglycerol in Arabidopsis Leaves

There is growing interest in engineering green biomass to expand the production of plant oils as feed and biofuels. Here, we show that PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1 (PDAT1) is a critical enzyme involved in triacylglycerol (TAG) synthesis in leaves. Overexpression of PDAT1 increases leaf TAG accumulation, leading to oil droplet overexpansion through fusion. Ectopic expression of oleosin promotes the clustering of small oil droplets. Coexpression of PDAT1 with oleosin boosts leaf TAG content by up to 6.4% of the dry weight without affecting membrane lipid composition and plant growth. PDAT1 overexpression stimulates fatty acid synthesis (FAS) and increases fatty acid flux toward the prokaryotic glycerolipid pathway. In the trigalactosyldiacylglycerol1-1 mutant, which is defective in eukaryotic thylakoid lipid synthesis, the combined overexpression of PDAT1 with oleosin increases leaf TAG content to 8.6% of the dry weight and total leaf lipid by fourfold. In the plastidic glycerol-3-phosphate acyltransferase1 mutant, which is defective in the prokaryotic glycerolipid pathway, PDAT1 overexpression enhances TAG content at the expense of thylakoid membrane lipids, leading to defects in chloroplast division and thylakoid biogenesis. Collectively, these results reveal a dual role for PDAT1 in enhancing fatty acid and TAG synthesis in leaves and suggest that increasing FAS is the key to engineering high levels of TAG accumulation in green biomass.
An introductory tour of interactive rendering

Given the depth and breadth of the field of interactive rendering, an article summarizing all the significant algorithms and hardware developments in the past few years would become a long yet shallow litany of taxonomies and terms. Instead, the author uses a selection of topics from various areas to illustrate this central theme: the influence of 3D graphics hardware on algorithm design. This article provides an understanding of consumer-level personal graphics processors and a sense of how different algorithms are developed in response to their capabilities.
Promoting L2 Vocabulary Learning through Narrow Reading

Krashen (2004) has advocated that narrow reading, i.e., reading a series of texts addressing one specific topic, is an effective method to grow vocabulary. While narrow reading has been championed to have many advantages for L2 vocabulary learning, there remains a relative dearth of empirical studies that test the impact of narrow reading on L2 learners’ lexical growth. The present study examines whether narrow reading results in L2 vocabulary learning. A total of 61 high intermediate learners read a series of texts either thematically related (narrow) or unrelated (wide) over one month. The findings showed that narrow reading considerably facilitated learners’ understanding of meanings of target words and their ability to appropriately use them. The narrow group’s responses to an exit questionnaire revealed several factors that could have accounted for this improvement in their vocabulary knowledge. Several implications for vocabulary teaching are discussed.
A Comparison of Hexahedral and Tetrahedral Finite Elements for Biphasic Analysis of Cartilage Micromechanics

Articular cartilage is a hydrated composite structure comprised of collagen type II extracellular matrix (ECM), collagen type VI pericellular matrix (PCM), and chondrocytes, each with low hydraulic permeability resulting in long viscoelastic stress relaxation times. Therefore, when subjected to fast loading, cartilage behaves as a nearly incompressible material [1]. When finite element analysis (FEA) is employed to solve mechanical problems involving nearly incompressible materials, a hexahedral finite element mesh is desirable [2]. Unfortunately, hexahedral mesh generation is difficult for complex geometries and often requires painstaking user-assisted construction which is often not feasible. Realistic chondron shapes and distributions within cartilage exhibit this complexity [3]. In these scenarios, a tetrahedral finite element discretization may need to be employed (Figure 1).Copyright © 2012 by ASME
Comparison of the Analgesic Effects of Dimethyl Sulfoxide and Morphine

Abstract : DMSO produces analgesia in rats on tests that typically only detect the analgesic effects of potent narcotic analgesic drugs (i.e. the hot-plate and tail-flick tests). There seem to be two components of this analgesic effect; one component related to a local effect and the other component related to a systemic effect. If only the feet are exposed to DMSO, the rat becomes analgesic on the hot-plate and tail-flick. If a greater surface body is exposed, the rat becomes analgesic on both the hot plate and tail flick indicating a central action, because the tail did not come into contact with the DMSO. In one study on patients the authors conclude that the analgesic effect of DMSO arises from a central, not local, analgesic effect. The analgesic effects of DMSO are not consistently blocked by naloxone indicating that these analgesic effects of DMSO are not consistently blocked by naloxone indicating that these analgesic effects of DMSO do not have the same mechanism of action as morphine.
Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and idiopathic Parkinson's disease. However, the mechanisms for activating its physiological function are not known, hindering identification of the biological role of endogenous LRRK2. The recent discovery that LRRK2 is highly expressed in cells of the innate immune system and genetic association is a risk factor for autoimmune disorders implies an important role for LRRK2 in pathology outside of the central nervous system. Thus, an examination of endogenous LRRK2 in immune cells could provide insight into the protein's function. Here, we establish that stimulation of specific Toll-like receptors results in a complex biochemical activation of endogenous LRRK2, with early phosphorylation of LRRK2 preceding its dimerization and membrane translocation. Membrane-associated LRRK2 co-localized to autophagosome membranes following either TLR4 stimulation or mTOR inhibition with rapamycin. Silencing of endogenous LRRK2 expression resulted in deficits in the induction of autophagy and clearance of a well-described macroautophagy substrate, demonstrating the critical role of endogenous LRRK2 in regulating autophagy. Inhibition of LRRK2 kinase activity also reduced autophagic degradation and suggested the importance of the kinase domain in the regulation of autophagy. Our results demonstrate a well-orchestrated series of biochemical events involved in the activation of LRRK2 important to its physiological function. With similarities observed across multiple cell types and stimuli, these findings are likely relevant in all cell types that natively express endogenous LRRK2, and provide insights into LRRK2 function and its role in human disease.
Factors, Trends, and Topics in the Evolution of Counseling Psychology Training

During all of its history, the specialty of counseling psychology has evolved constantly in response to changes in the context in which it exists. As the specialty has changed, so too has training. This article discusses six forces that have affected the content and process of counseling psychology training and will continue to do so: market forces, practitioner-educator dialogues, expectations and directives from within the profession, social and political forces, technological innovations, and the cultural context of counseling psychology. We briefly discuss prescriptive authority as a topic that will affect professional training, then conclude by introducing five particular topics that will be covered in the other articles in this issue. All will affect counseling psychology training into at least the near future.
Parental Conflict, Marital Disruption and Children's Emotional Well-Being

This article uses data from the National Longitudinal Surveys of Youth to examine the question : are children better off when they remain in two-parent families characterized by marital conflict, or are they better off when their parents dissolve their marital relationship ? The author finds that both parental marital conflict and marital disruption increase the later anxiety and depression/withdrawal of children aged 6-14 (n = 1,640). He also finds significant interactions : children remaining in high conflict environments generally exhibit lower levels of well-being than children who have experienced high levels of parental conflict but whose parents divorce or separate. These results support the possibility that marital disruption, following high conflict, may actually improve the emotional well-being of children relative to a high conflict family status
Gene regulatory networks and embryonic specification.

Eric Davidson embarked on the study of sea urchin development more than 40 years ago, with his initial efforts focused on studying the animal's nucleic acid properties through hybridization—studies that, amazingly enough, began to delineate the early logic of how to think about development (1). However, Davidson was always driven by biology: in his case, by a desire to understand the molecular basis of sea urchin development. In the intervening years, Davidson and his colleagues came to understand the biology of sea urchin development at a uniquely deep level, and this knowledge was the driver and integrator of subsequent developmental studies. Over the past 15 years or so, Davidson arrived at the realization that development was hardwired in the gene regulatory logic of the genome and that determination of this logic would require a systems approach (i.e., global analyses, rather than the study of one or a few genes or proteins at a time). He also came to understand that the systems approach to development required (i) determination of the complete sea urchin genome sequence, to compile a complete “parts list” of sea urchin genes, especially those encoding transcription factors; (ii) an understanding of the deep logic of how individual genes are regulated by transcription factors through their cis-regulatory elements; and (iii) a delineation of the dynamics of complete gene regulatory networks (GRNs) specifying the distinct stages of sea urchin development. Complete GRNs—the dynamic network relationships of all relevant transcription factors—are essential because the genomic regulatory logic is so complex that inferences from incomplete networks can be misleading or inadequate. For each of these challenges, Davidson and his colleagues carried out groundbreaking work. Davidson was almost single-handedly responsible for initiating the sea urchin genome project, and he certainly inspired what was perhaps the most thorough annotation of any genome at that time (2). His group specified, in detail, the cis regulation of the developmentally regulated endo-16 gene and demonstrated the fascinating logic and complexity of this regulatory circuit (3). Finally, Davidson and his associates pioneered the preliminary delineation of a variety of GRNs and their specification of sea urchin larval development (see ref. 4).
ANTIGENICITY OF THE M PROTEINS OF GROUP A HEMOLYTIC STREPTOCOCCI III. ANTIBODY RESPONSES AND CUTANEOUS HYPERSENSITIVITY IN HUMANS

Highly purified M proteins were used for determining cutaneous hypersensitivity and type-specific circulating antibodies in normal adults and infants. 80% of 91 adults and 8% of 59 infants exhibited a transient delayed cutaneous reaction to at least two of types 12, 14, and 24 M proteins. Antibodies assayed by passive hemagglutination were observed in 90% of the adults and 13% of the infants. Vaccines of 10 µg of alum-precipitated M protein or 20 µg of the soluble antigen were administered to adults not exhibiting delayed hypersensitivity. Within 2 wk hemagglutination liters increased significantly in 31 of 33 subjects. Preimmunization antibody levels indicated that these responses were probably anamnestic reactions from previous exposures to homologous serotypes of group A streptococci. Sera exhibiting large increments in antibody titers resulting from M protein inoculations also had type-specific bactericidal properties. "Attenuated" M proteins, produced by partial degradation with trypsin induced only minimal cutaneous reactions in hypersensitive adults, but still retained most of the antigenic specificity when assayed in vitro and in vivo. The utility of M protein vaccines for human use is discussed in reference to the low incidence of cutaneous hypersensitivity in infants, the potentials of polyvalent attenuated M protein vaccines and the apparent absence of immune cross-reactivity between pure M proteins and human heart and kidney tissues.
Mobilization with movement applied to the elbow affects shoulder range of movement in subjects with lateral epicondylalgia

Abstract Clinical observations have suggested a relationship between shoulder range of movement (ROM) and lateral epicondylalgia. This study reports the effect of a single intervention of a mobilization with movement (MWM) applied to the elbow, on shoulder rotation ROM in subjects with lateral epicondylalgia. Twenty-three subjects with lateral epicondylalgia were included. In a one-group pretest-post-test design, ROM of shoulder internal and external rotation were measured by goniometer before and after the application of the MWM, of both the unaffected and the affected limbs. Significant differences in pre-intervention external rotation ROM were found between unaffected and affected shoulders of subjects with lateral epicondylalgia, but no significant difference remained post-intervention. It may be concluded that restriction of shoulder rotation ROM is present in patients with lateral epicondylalgia, probably due to a facilitated level of shoulder rotator muscle tone. Shoulder internal and external rotation ROM increases significantly following MWM to the elbow, in subjects with unilateral lateral epicondylalgia. Surprisingly, these ROM increases are also apparent on the ‘unaffected’ limb. These findings suggest that the MWM causes a neurophysiologically mediated decrease in resting muscle tone.
An introduction to IBM general business simulation environment

IBM general business simulation environment (GBSE) is a supply chain simulation tool developed by IBM China Research Lab. It can capture supply chain dynamics with finest level of granularity and provides great insights to a supply chain?s real operations. GBSE is designed for tactical level decision making; it is proper for supply chain what-if analysis and risk analysis. GBSE implements multiple supply chain processes to considerable details, such as order handling process, inventory control process, manufacturing process, transportation process, procurement process, and planning. The environment is created as a desktop software tool based on Eclipse platform. The backbone framework consists of Presentation Layer, Controller Layer, Service Layer, and Data Layer.
Experimental, cancer-induced retinopathy

Autoantibody reactions with various ocular components have been described in different types of paraneoplastic vision loss, and are considered indicators of an activated, and potentially harmful im...
CELLULAR DIFFERENTIATION OF THE IMMUNE SYSTEM OF MICE IV. LACK OF CLASS DIFFERENTIATION IN THYMIC ANTIGEN-REACTIVE CELLS

Thymocytes and marrow cells of unprimed donor mice were mixed in vitro and transplanted into X-irradiated syngeneic mice. 18 hr later, sheep erythrocytes were injected to induce immune responses. Splenic plaque-forming cells (PFC) secreting IgM (direct PFC) or IgG (indirect PFC) hemolytic antibody were enumerated at the time of peak responses. By transplanting graded and limiting numbers of thymocytes with 4 x 10(7) marrow cells, inocula were found which contained one or a few thymic antigen-reactive cells (ARC) reaching the recipient spleens, interacting with marrow cells, and inducing PFC formation. The frequency values of ARC inferred from direct and indirect plaque assays were very similar, 1 in approximately 10(7) thymocytes. Furthermore, statistical analysis indicated that the formation of direct PFC was not independent of the formation of indirect PFC. This was interpreted to mean that ARC were not specialized themselves and did not determine the molecular class of antibody to be secreted after interaction with marrow cells. Spleens of thymus-marrow grafted mice containing one or two ARC and non-limiting numbers of marrow precursors of PFC (P-PFC), had direct and indirect PFC clustered in several focal areas. Assuming that each focal area represented the progeny of one P-PFC that had interacted with ARC, these results confirmed the statistical evidence for lack of class differentiation in thymic ARC, and also indicated that each ARC or its progeny cells interacted with more than one P-PFC of either class.
TurKit: tools for iterative tasks on mechanical Turk

Mechanical Turk (MTurk) is an increasingly popular web service for paying people small rewards to do human computation tasks. Current uses of MTurk typically post independent parallel tasks. We are exploring an alternative iterative paradigm, in which workers build on or evaluate each other's work. We describe TurKit, a new toolkit for deploying iterative tasks to MTurk, with a familiar imperative programming paradigm that effectively uses MTurk workers as subroutines.
Computational cognitive neuroscience of early memory development

Numerous brain areas work in concert to subserve memory, with distinct memory functions relying differentially on distinct brain areas. For example, semantic memory relies heavily on posterior cortical regions, episodic memory on hippocampal regions, and working memory on prefrontal cortical regions. This article reviews relevant findings from computational cognitive neuroscience on why different neural regions might be specialized for different types of memory, and how this might impact early memory development. These findings demonstrate computational trade-offs among different memory functions, such that a single system cannot specialize on more than one function. Instead, the anatomical and physiological specializations of posterior cortical, hippocampal, and prefrontal cortical regions support their associated functions. This computational framework provides a mechanistic way of understanding memory distinctions described at the conceptual level. The developmental relevance of this framework is discussed—in the context of specific models, where available—for category learning, infantile amnesia and developmental amnesics, and the development of flexible behavior.
PROTEIN ANALYSIS BY HYDROGEN EXCHANGE MASS SPECTROMETRY

Mass spectrometry has provided a powerful method for monitoring hydrogen exchange of protein backbone amides with deuterium from solvent. In comparison to popular NMR approaches, mass spectrometry has the advantages of higher sensitivity, wider coverage of sequence, and the ability to analyze larger proteins. Proteolytic fragmentation of proteins following the exchange reaction provides moderate structural resolution, in some cases enabling measurements from single amides. The technique has provided new insight into protein-protein and protein-ligand interfaces, as well as conformational changes during protein folding or denaturation. In addition, recent studies illustrate the utility of hydrogen exchange mass spectrometry toward detecting protein motions relevant to allostery, covalent modifications, and enzyme function.
Novel anti-tuberculosis drug designs by data mining for similarity in substituent substitution and structure modification

Mycobacterium tuberculosis (TB) is among the most common of infectious diseases that cause death, and as many as one-third of the world’s population may be infected. This work presents 17 novel hydrazide agents formed by focused in silico data mining utilizing search parameters restricted to substituent replacement only. Substituent substitution has been highly successful in design of novel antibacterial and antiviral drugs. This diverse set of hydrazide constructs possess molecular properties indicating favorable bioavailability with excellent intestinal absorption for oral administration. All agents have zero violations of the Rule of 5, indicating favorable druglikeness. Important pharmaceutical properties including polar surface area, Log P, and formula weight were determined and compared to that of the parent structure of isoniazid by hierarchical cluster analysis and discriminant analysis. The average Log P with range is -0.258 and -2.165 to 1.373, respectively. The average polar surface area (PSA) with range is 75.19 A 2 and 55.121 A2 to 94.036 A2, respectively. The diverse range of PSA and Log P, with other descriptors, portend a versatile group of hydrazide drugs having substantial potential to expand the application and effectiveness forclinical treatment of multi-organ infected TB patients. Analysis of similarity indicated that all 17 agents are significantly similar to isoniazid, however discriminant analysis and hierarchical cluster analysis are able to differentiate isoniazid based upon molecular properties. Molecular weight and number of atoms were highly correlated by Pearson r (r>0.9000), with Log P moderately correlated (r>0.5500) to number of atoms, molecular weight, and volume. Seventeen hydrazide compounds (success rate of approximately 38%) having diverse pharmaceutical properties resulted from substituent data mining with potential for clinical application.
Spatial restriction of α4 integrin phosphorylation regulates lamellipodial stability and α4β1-dependent cell migration

Integrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from α4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient α4-mediated migration requires spatial control of α4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated α4 accumulated along the leading edge. Blocking α4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced α4-dependent migration and lamellipodial stability. α4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-α4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated α4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with α4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.
Report on an interdisciplinary program for allied health.

A B S T R A C T Context: A central recommendation from the Pew Health Commission to educators has been to empower future care providers to function effectively as teams. Administrators and faculty members within a school of allied health sciences thus established an interdisciplinary program where students would learn to function as team members and demonstrate competencies required for practice in diverse, demanding, and continually changing health care environments. Students from five disciplines have participated in featured events, mentored activities and capstone projects, earning credit in an interdisciplinary course of study that complements offerings in their home disciplines. Goal: This follow-up article reports on the progress and development since 2002 of an interdisciplinary program known as Team IDEAL. Formative evaluation measures used to assess satisfaction with the program are presented alongside a discussion of new directions. Conclusion: Team IDEAL will move forward in a streamlined form that reflects its central aim. IDEAL leadership will remain cognizant of the effects of discipline-specific curricular changes, complex programming, and student perspectives on the process interdisciplinary education.
Relation of Athletic Sports to International Peace

(1915). Relation of Athletic Sports to International Peace. American Physical Education Review: Vol. 20, No. 3, pp. 143-147.