cssi/SciSciGPT-SciSciNet huggingface dataset:
Abstract GMM-053: ROLE OF LATS AND DYRK1A KINASES IN THE PATHOGENESIS AND TREATMENT OF HGSOC

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with 75% of women presenting with metastatic disease at the time of diagnosis. High Grade Serous Ovarian Carcinoma (HGSOC) is the most common and aggressive type of epithelial ovarian cancer, with 5-year survival rate of 30% for most patients. Developing of accurate experimental models of HGSOC is necessary to elucidate the disease pathogenesis and to evaluate new treatments. Our study is aimed at determining the roles of the Large Tumor Suppressor 1 and 2 kinases (LATS1/2), and their downstream effector Dual-specificity tyrosine(Y)-Regulated Protein Kinase 1A (DYRK1A), in HGSOC pathogenesis and treatment sensitivity. The Cancer Genome Atlas study revealed copy number losses of the LATS1, LATS2 and DYRK1A genes in 65%, 59% and 38% of HGSOC cases, respectively. Previous studies found that LATS1/2 and DYRK1A mediate a crosstalk between the Hippo tumor suppressor pathway and the G0/G1 cell cycle checkpoint. However, the role of these kinases in HGSOC pathogenesis is not known. We found that loss of both LATS1 and LATS2, or DYRK1A results in increased proliferation of SKOV3 ovarian cancer cells in 2D or 3D cultures, mediated in part by disruption of the DREAM complex that represses cell cycle-regulated genes. Interestingly, we observed upregulation of cyclin D1 and increased phosphorylation of retinoblastoma (RB) family proteins in SKOV3 cells depleted of LATS1/2 or DYRK1A kinases, indicative of aberrant activation of CDK4/6. Similar changes were observed upon depletion of LATS1/2 or DYRK1A using non-transformed human fallopian epithelial cells, suggesting that genetic losses of these kinases could contribute to the HGSOC pathogenesis. Furthermore, we tested whether an aberrant activation of CDK4/6 in SKOV3 cells with low levels of LATS1/2 or DYRK1A could increase their sensitivity to pharmacological CDK4/6 inhibitors such as palbociclib. Using metabolic cell proliferation assays, we found that loss of LATS1/2 or DYRK1A resulted in a significant decrease of palbociclib IC50 in SKOV3 cells. Interestingly, palbociclib treatment increased the DREAM assembly in these cells, resulting in downregulation of DREAM-regulated cell cycle factors such as cyclin A or B-Myb. Our results show that loss of LATS1/2 or DYRK1A could contribute to HGSOC pathogenesis by CDK4/6-mediated disruption of RB family function. Further studies are underway to validate our findings in vivo using orthotopic ovarian tumor xenografts in mice and a bioluminescence imaging approach. In addition, these models will be used for validation of novel therapeutic approaches for HGSOC, such as palbociclib, as well as for the mechanistic studies of the EOC pathogenesis. Citation Format: Fatmata Sesay, Siddharth Saini, Larisa Litovchick. ROLE OF LATS AND DYRK1A KINASES IN THE PATHOGENESIS AND TREATMENT OF HGSOC [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-053.
Finding a Common Voice: Lessons Learned from a Pilot Mental Health Literacy Intervention for Secondary Students with Disabilities

The current study evaluates lessons learned from a feasibility and acceptability trial of the Think, Be, Do, curriculum (a mental health literacy curriculum) for transition age students (14–21) in ...
Should Firms Accelerate Product Development During Market Emergence

This study challenges the notion that speeding products to market is beneficial by examining conditions under which accelerating product development as a strategy can be suboptimal. I argue that th...
Post-Acute COVID-19 Syndrome for Anesthesiologists: A Narrative Review and a Pragmatic Approach to Clinical Care

Abstract Post-acute coronavirus disease 2019 (COVID-19) syndrome is a novel, poorly understood clinical entity with life-impacting ramifications. Patients with this syndrome, also known as "COVID-19 long-haulers," often present with nonspecific ailments involving more than one body system. The most common complaints include dyspnea, fatigue, brain fog, and chest pain. There currently is no single agreed-upon definition for post-acute COVID-19 syndrome, but most agree that criterion for this syndrome is the persistence of mental and physical health consequences after initial infection. Given the millions of acute infections in the United States over the course of the pandemic, perioperative providers will encounter these patients in clinical practice in growing numbers. Symptoms of the COVID-19 long-haulers should not be minimized, as these patients are at higher risk for postoperative respiratory complications and perioperative mortality for up to seven weeks after initial illness. Instead, a cautious multidisciplinary preoperative evaluation should be performed. Perioperative care should be viewed through the prism of best practices already in use, such as avoidance of benzodiazepines in patients with cognitive impairment and use of lung-protective ventilation. Recommendations especially relevant to the COVID-19 long-haulers include assessment of critical care myopathies and neuropathies to determine suitable neuromuscular blocking agents and reversal, preoperative workup of insidious cardiac or pulmonary pathologies in previously healthy patients, and, thorough medication review, particularly of anticoagulation regimens and chronic steroid use. In this article, the authors define the syndrome, synthesize the available scientific evidence, and make pragmatic suggestions regarding the perioperative clinical care of COVID-19 long-haulers.
The new Russian minorities: a statistical overview.

A prominent Sovietologist and pioneer in the study of the human geography of the former Soviet Union in the West presents a succinct review of the newly constituted Russian minorities situated in the former Soviet republics. Based on census data series (1897 to 1989) and original computations, the paper covers location (highest proportion of Russians in Kazakhstan, Latvia, and Estonia), concentration (predominantly urban), occupational structure (largely in industry and science), and related data on issues such as language affinities and migration. 4 tables, 9 maps, 6 graphs, 44 references.
Influence of tourniquet application on patellar tracking in total knee arthroplasty.

Objective To explore, the influence of tourniquet application on patellar tracking with using the surgical transepieondylar axis as distal femur alignment in total knee arthroplasty (TKA). Methods From December 2002 to August 2008, 349 cases (526 knees) of primary TKA were performed. There were 124 males and 225 females with an average age of 68 years from 33 to 84 years. A total of 387 knees had varus deformity and 94 had valgus deformity. All of prosthesis were rotating platform with posterior cruciate ligament retaining provided by Gemini MK Ⅱ. All patients underwent anterior medial parapatellar approach. The surgical transepieondylar axis had been principally used as the distal femur alignment. Patellar tracking was checked with no thumb test. For maltracking ones, we prefered to use a single retinacular closing stitch at the superior medial arthrotomy and deflate tourniquets. Patellar tracking was checked again. Finally, later-al retinaeular releases (LRR) had been performed to obtain optimizing patellar tracking. Results Intraoper-atively, no thumb test were positive in 138 knees, including patellar subluxation (vaigus deformity) in 12 knees and patellar inclining (74 of valgns deformity and 52 of varus deformity) in 126 knees. After using a single retinacular closing stitch at the superior medial arthrotomy and deflating tourniquets, no thumb test were positive in 40 knees, including patellar subluxation (valgus deformity) in 8 knees and patellar inclining (29 of valgns deformity) in 32 knees. The total rate of LRR was 7.6% (40/526), the rate of LRR in valgus deformity was 39.4% (37/94) and that in yarns deformity and no deformity was 0.7% (3/432). Conclusion There was significant influence of tourniquet application on patellar tracking during the TKA. We were not falsely correcting patellar tracking problems with using a single retinaeular closing stitch at the superior me-dial arthrotomy anti deflating tourniquets intraoperatively and reducing the rate of LRR. Key words: Arthroplasty; replacement; knee; Tourniquets; Patella; Treatment outcome
Is There a Difference in Pain Management of Patients with Upper Extremity Injuries in Relation to Age

Timely and appropriate analgesia for the treatment of long bone fractures is a primary goal of Emergency Departments. Despite incentives from the Centers of Medicare and Medicaid and accreditation agencies studies have found the existence of pain management disparities. The purpose of this research study was to conduct a retrospective chart review to investigate if patients with an upper extremity long bone fracture received pain medication within 60 minutes of arrival to the ED and to identify if there was a difference in the pain management of patients, with identical injuries, by age. Katharine Kolcaba’s comfort theory was used to guide the implementation of this project. Pain medication was provided within 60 minutes in 63% of the participants aged 69 and under and 56% of those aged 70 and older. A larger disparity occurred between the groups being medicated appropriately according to the World Health Organization’s guidelines for pain management with 63% of participants aged 18-69 receiving the appropriate pain medication compared to 45 % of participants in the 70 and over age group. The APRN has the opportunity to educate the nurses and members of the interdisciplinary team through evidence based practice in the safe and effective methods for treating acute pain across the lifespan. Acknowledgments The last three years has been an exciting time for me both personally and professionally as I have worked to fulfill a lifetime goal of becoming a NP. Without the support from the Rhode Island College MSN faculty, and my friends and family I would not have been able to complete the program. I am appreciative and thankful to Dr. Debra Servello and Dr. Cynthia Padula for their encouragement and guidance throughout the program. I would like to thank my advisor Dr. Margaret Mock for telling me “to just do it” when I questioned my ability to handle more than one class a semester, without her push I would have another full year to go before graduating. I would also like to thank my committee chair, Claire Creamer PhD, RN, CNP-PC and committee member Patricia Calvert MSN, GCNS-BC for their tireless effort and help completing this project. I would like to thank my “work family” Kara Beck BSN, RN, Jessica Janeiro and Rita Pedro BSN, RN for covering my work duties while I was completing 600 clinical hours, without their willingness to be flexible I would not have been able to finish the required hours. I would also like to thank Denise Brennan MSN, RN, CNL and Nancy Robin RN, M. Ed, CEN for encouraging me to return to school in the first place. Lastly and most importantly I would like to thank my husband Marc and daughter Alyssa who have been patient, supportive, encouraging and loving throughout the last three years. They have never once doubted my ability and have been there to pick me up after 14 day stretches of school, studying and work. I love them dearly.
Evaluation and Intervention in the Paretic Upper Extremity Following Hemiparetic Stroke using the ACT 3D System

The effect of gravity on the expression elbow/shoulder synergy patterns results in discoordination during movements following stroke. This is believed to be related to the shoulder abduction torques generated when lifting the arm against gravity, which results in a concurrent elbow flexion (i.e., the flexion synergy). The Arm Coordination Training 3-D (ACT ) robotic system is a novel way of recording movement patterns while a subject generates varying amounts of shoulder abduction torque. This system is used to show increased shoulder abduction forces reduce a stroke subject's available work area in a way that is consistent with the flexion synergy. The system can also be used in interventions that target reducing this abnormal synergy; a case study is presented
Law and Everyday Life

Historically, law and everyday life have been defined in opposition to one another. Over the past century, the boundary separating law from everyday life has become blurred. Increasingly, socio-legal scholars understand law and everyday life to be mutually constituted in a dynamic and emergent process wherein law is produced and applied in the everyday domain of social action. At the same time, the practices, relationships, and meanings that make up the everyday are themselves, in part, constructed by law or legality.
Temperature effects during the sorption and desorption of water vapor in high polymers. I. Fibers with particular reference to wool

The sorption-desorption method of measuring diffusion constants for water in polymers is often complicated by the accompanying heat effects. This is particularly true in the case of wool and other protein fibers because of the large heats of sorption. Corrections for this effect have been reported by CASSIE et al. assuming that the water vapor was taken up to equilibrium essentially instantaneously. Simple experiments have demonstrated that the diffusivity must also be taken into account and the correction equations have been modified to include the rate of diffusion. The necessary parameters have been determined experimentally for wool fabric and the extent of the corrections demonstrated. The correction factors increase with increasing water content and rapidly become several hundred percent. At very high water contents the correction parameters become so large that the equations become too sensitive for accurate corrections to be made. Measurements of untreated and styrene grafted wool have been made, the diffusivity of water is less in the grafted wool and is also less affected by the concentrations in keeping with its more hydrophobic nature. Die Sorption-Desorptionsmethode zur Messung von Diffusionskonstanten von Wasser in Polymeren fuhrt oft zu Schwierigkeiten infolge von Warmeeffekten, besonders bei Wolle und anderen Proteinfasern wegen ihrer grosben Sorptionswarmen. CASSIE und Mitarbb. gaben hierfur Korrekturen an unter der Annahme, das die Sorption des Wasserdampfes zum Gleichgewicht augenblicklich erfolgt. Einfache Experimente haben gezeigt, das auch die Diffusionskonstante in Betracht gezogen werden mus; die Korrekturformeln wurden entsprechend abgeandert. Es werden die Korrekturen fur Wolle angegeben. Die notigen Parameter wurden experimentell bestimmt. Die Korrekturfaktoren nehmen zn mit steigendern Wassergehalt und erreichen sehr rasch Werte von einigen hundert Prozent. Fur sehr hohen Wassergehalt werden die Korrekturparameter so gros, das die Gleichungen zu empfindlich werden, um genaue Korrekturen zu ermoglichen. Messungen an unbehandelter und an mit Styrol gepfropfter Wolle ergaben, das fur gepfropfte Wolle die Diffusionskonstante von Wasser kleiner ist. Auserdem hangt sie in geringern Mase von der Konzentration ab, was mit der grol3eren Hydrophobie der gepfropften Wolle ubereinstimmt.
Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target.

BACKGROUND Specific tyrosine kinase receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a tyrosine kinase receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model. METHODS RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6pl, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON. RESULTS Immunohistochemical staining revealed RON overexpression in 93% of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6pl cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of β-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60%. CONCLUSIONS RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression. Cancer 2007 © 2007 American Cancer Society.
Reinventing "The People": The Progressive Movement, the Class Problem, and the Origins of Modern Liberalism

Review of: "Re-inventing "The People": The Progressive Movement, the Class Problem, and the Origins of Modern Liberalism," by Shelton Stromquist.
Physics Results from the National Spherical Torus Experiment

The National Spherical Torus Experiment (NSTX) at the Princeton Plasma Physics Laboratory is designed for studying toroidal plasma confinement at very low aspect-ratio, A=R/a = 0.85m/0.68m {approximately} 1.25, with cross-section elongation up to 2.2 and triangularity up to 0.5, for plasma currents up to 1 MA and vacuum toroidal magnetic fields up to 0.6 T on axis. Conducting plates are installed close to the plasma on the outboard side to stabilize kink modes. This should permit operation with toroidal-{beta} approaching 40%. The plasmas will be heated by up to 6 MW High-Harmonic Fast Waves (HHFW) at a frequency 30 MHz and by 5 MW of 80 keV deuterium Neutral Beam Injection. Inductive plasma startup can be supplemented by the process of Coaxial Helicity Injection (CHI).
The detection of extremely rare DNA modifications. Methylation in dam- and hsd- Escherichia coli strains.

Abstract DNA methylation in Escherichia coli plays a role in many key cellular processes, including DNA replication, repair, restriction, and transcription. However, several mutant bacterial strains exist which are deficient in DNA methylase activities. Thus, it has been suggested that methylation produced by the dam (DNA adenine methylase) gene is required for the viability of E. coli and that dam- strains still produce low levels of methylation. Current experimental methods are not sensitive enough to detect a few potentially essential methylated sites per genome. Here we describe a method for the detection of N6-methyladenine at specific sites with a sensitivity of one site in more than 10 megabases. We show that methylation produced by both the dam and hsd (EcoK) genes is not required for the growth of E. coli and identify the site of EcoK modification. Minor adaptations of the technique should enable the identification of other rare DNA modifications.
Regret and Moral Maturity: A Response to Michael Ing and Manyul Im

My intention in writing “Confucius’ Complaints” was to “complicate” the ways we conceptualize the good life as it is represented in the Analects and, especially, in the life of Confucius qua exemplar. I argued that our understanding of Confucius’ “good life” has been insufficiently attentive to the subtle psychological complexity evident in the Analects. Both Michael Ing and Manyul IM suggest that the complexities I originally limned are only a start, that the life of Confucius may be yet more complicated than I represented it. I am in the happy position of agreement with them. Indeed, there is much more to chart than I first mapped out and I am grateful to both Ing and Im for pushing farther into this territory than I myself went. Taken together, Ing and Im perhaps most invite reflection on regret, both as it might situate in Confucius’ own life and as it could feature more broadly in developed moral maturity. In what follows, I want to consider two modes of regret: regret concerning compromises of conscience and end-of-life regret. The latter can naturally include elements of the former, but may nonetheless have special features not exhausted by it. My sense is that the model of Confucius is consistent with versions of both of these forms of regret. However, I also think that where the Analects is concerned, much of what we might say about regret will inevitably be somewhat speculative. In consequence, I want simply to explore further the suggestions Ing and Im make. I propose no resolution or final view, but seek instead simply to tarry in some of the additional complexities they raise. Dao (2015) 14:579–587 DOI 10.1007/s11712-015-9469-3
An integrated operator advisor system for plant monitoring, procedure management, and diagnosis

This paper reports on an integrated operator advisor system (OAS) built using generic task methodology. The operator's activities of plant monitoring, data interpretation, procedure execution, and diagnosis have been implemented as the four generic tasks in the system. The OAS is capable of identifying the abnormal functioning of the plant in terms of threats to safety, preenumerated abnormal events, and deviations from normality. After the identification of abnormal functioning, the system will identify the procedures to be executed to mitigate the consequences of abnormal functioning and will help the operator by displaying the procedure steps and monitoring the success of actions taken. The system also is capable of diagnosing the cause of abnormal functioning. The diagnosis is done in parallel to the task to procedure execution.
Soil Nitrogen Transformations Associated with Small Patterned-Ground Features along a North American Arctic Transect

Small patterned-ground features (PGFs) in the Arctic have unique soil properties that vary with latitude and may greatly affect tundra biogeochemistry. Because nitrogen availability can strongly limit arctic vegetation growth, we examined how soil nitrogen transformations differ between PGFs and the surrounding inter-PGF tundra along an arctic latitudinal gradient. We collected soils at eight sites from the Alaskan Low Arctic to the Canadian High Arctic. The soils were incubated for 21days at 9 C and 15 C and analysed for changes in total inorganic nitrogen, nitrate and extractable organic nitrogen (EON). We found greater nitrogen immobilisation in the surrounding inter-PGF soils than in the PGF soils. Along the latitudinal gradient, differences in net nitrogen mineralisation and EON cycling between PGF and inter-PGF soils were strongly influenced by the presence of a pH boundary within the Low Arctic and the transition between the High and Low Arctic, with greater immobilisation in the nonacidic and Low Arctic sites, respectively. Incubation temperature affected EON flux but did not affect net nitrogen mineralisation or nitrification. These results show that spatial heterogeneity at several scales can influence soil nitrogen dynamics, and is therefore an important influence on arctic ecosystem function. Copyright © 2012 John Wiley & Sons, Ltd.
An Active Asset Management Investment Process for Drawdown-Averse Investors

The contribution of this article is to present an investment process that allows the asset manager to limit risk exposure to macro-factors - including expectations on correlation dynamics - whilst allowing for selective exposure to risk factors using factor-portfolios that emulate the risk and return profile of market micro-factors.
Comparison between shear deformable and Kirchhoff theories for bending, buckling and vibration of antisymmetric angle-ply laminated plates

Abstract A generalized Levy-type solution in conjunction with the state space concept is developed for the bending, buckling and vibration of antisymmetric angle-ply laminated plates. The exact solutions are applicable to rectangular plates with two opposite edges simply supported and the remaining ones subjected to a combination of clamped, simply supported and free boundary conditions. The solutions are obtained for the classical Kirchhoff theory and the numerical results are compared with their counterparts using the first order transverse shear deformation theory. The comparisons show that the results obtained within the classical laminated theory can be significantly inaccurate.
Progressive acquisition of relevant cues in visual pattern discrimination by monkeys.

Three monkeys, on a self-shaping regimen, learned a 6+ vs 4– simultaneous visual pattern discrimination. The stimuli were projected randomly upon translucent panels at 2 of 16 possible locations for each trial. In tabulating all panel presses during acquisition, it is shown that decreased preference for non-illuminated (blank) panels is attended by an increased preference for both the positive and the negative stimuli. Criterion-level preference exclusively for the positive stimulus thus does not occur until a markedly increased preference for the negative stimulus is eliminated.
A Three-Phase Centrifuge To Minimize Waste From Production Tank Bottoms And Sludges: An Economic Analysis

The performance of a three-phase centrifuge process in separating tank bottoms into salable oil, brine and solids was scaled using the sigma method. The profitability was analyzed for a range of processed volumes for three business scenarios: producer owned, service company and a disposal facility. Centrifuge processes operated at full capacity in these situations may be very profitable investments but any investment decision should be heavily influenced by the annual volume to be processed, the quality of the feed and the price received for separated oil.
From Passive Periphery to Active Agents: Emerging Perspectives in the Archaeology of Interregional Interaction

Traditional archaeological approaches to interregional interaction or culture contact have relied on unidirectional, Eurocentric interpretive frameworks such as the world systems and acculturation models. More recently, researchers from diverse fields such as prehistoric archaeology, the archaeology of ancient literate societies, and historical archaeology have begun to develop a new perspective on interregional interaction. Problems with these more traditional approaches to the archaeology of interregional interaction are summarized, and the main elements are outlined for a new research perspective to study culture contact. A set of methods are suggested to translate this theoretical framework into effective field research. Finally, the expansion of Mesopotamia in the fourth millennium B.C. Uruk period is presented as a case study to illustrate some of the ways that models derived from this emerging perspective can be used to better understand interregional interaction in the world's earliest known colonial system. [Keywords: interregional interaction, culture contact, colonies, trade diasporas, Mesopotamia]
ENTROPY PRODUCTION IN AN EXPANDING GAS‐FILLED UNIVERSE*

The entropy generated in an expanding gas-filled universe is calculated for an expansion that takes place in a series of steps during which the gas is collisionless. At the end of each step the gas is allowed to thermalize before undergoing its next expansion step. The results of the calculation show that entropy is generated only during a brief period in the evolution of the gas and that the total dimensionless entropy per baryon generated (∼10) is insufficient to explain the existence of the 108 per baryon of dimensionless entropy that appears to exist in the universe.
Evaluating the benefits and costs of regulatory reforms: What questions need to be asked?

Abstract In 1984, Portney argued that “[w]e should scrutinize proposed reforms of the rulemaking process every bit as carefully as the regulations that process produces.” In the 23 years since then, the regulatory process on the federal level has been continuously reformed by statute, by executive order, and by directives from the OMB. Despite the extensive debate on the need for these reforms, there has been very little analysis of the reforms themselves. This paper updates Portney's work on analyzing cost–benefit analysis and expands it to evaluate reforms of the regulatory process. I use as my primary example the recent peer-review guidelines issued by OMB. I argue that we may have reached a point of diminishing returns in regulatory reforms, that the peer-review guidelines likely have costs that exceed their benefits, and that further regulatory reforms merit closer evaluation.
The mechanism of gene targeting in human somatic cells

Gene targeting in human somatic cells is of importance because it can be used to either delineate the loss-of-function phenotype of a gene or correct a mutated gene back to wild-type. Both of these outcomes require a form of DNA double-strand break (DSB) repair known as homologous recombination (HR). The mechanism of HR leading to gene targeting, however, is not well understood in human cells. Here, we demonstrate that a two-end, ends-out HR intermediate is valid for human gene targeting. Furthermore, the resolution step of this intermediate occurs via the classic DSB repair model of HR while synthesis-dependent strand annealing and Holliday Junction dissolution are, at best, minor pathways. Moreover, and in contrast to other systems, the positions of Holliday Junction resolution are evenly distributed along the homology arms of the targeting vector. Most unexpectedly, we demonstrate that when a meganuclease is used to introduce a chromosomal DSB to augment gene targeting, the mechanism of gene targeting is inverted to an ends-in process. Finally, we demonstrate that the anti-recombination activity of mismatch repair is a significant impediment to gene targeting. These observations significantly advance our understanding of HR and gene targeting in human cells.
Failure of Combinations of Orotic Acid, Thioctic Acid, Adenosine and Mevalonic Acid to Stimulate Chick Growth

Abstract MENGE and Combs (1952) reported that orotic acid stimulated only very slight and inconsistent growth responses when fed to chicks. Similar results were obtained by Chin and Norris (1953). In contrast Combs, Arscott and Jones (1954) obtained increased growth in chicks fed practical type diets supplemented with orotic acid. Rasmussen et al. (1954) also reported that orotic acid promoted chick growth. DeBusk and Williams (1955) observed a growth response in chicks on addition of thioctic acid to the diet. Stokstad, Broquist and Patterson (1953), Morrison and Norris (1956), Stokstad et al. (1956), Reid et al. (1956), Supplee, Combs and Romoser (1956) and Briggs and Fox (1957) on the other hand, were unable to show that thioctic acid increased chick growth under a variety of environmental and dietary conditions. Barnett et al. (1956) reported a growth increase in chicks on the addition of adenosine to a purified diet. Ritchey, Scott and…
Physiological Comparisons of Pith Callus With Crown-Gall and Genetic Tumors of Nicotiana glauca, N. langsdorffii, and N. glauca-langsdorffii Grown in Vitro. II. Nutritional Physiology

Explants of genetic tumors, tumors initiated by Agrobacterium tumefaciens strains B-6 and T-37, and excised pith plugs from Nicotiana glauca, N. langsdorffii, and N. glauca-langsdorffii were cultured on Murashige and Skoog medium. All cultures, pith callus and tumors with the exception of N. langsdorffii pith grew on this medium. Addition of glutamine to the medium resulted in highly organoid growth in N. langsdorffii pith. In order to have material comparable to other pith cultures, N. langsdorffii was initiated on 2,4-dichlorophenoxyacetic acid medium, after which it grows on complete medium as amorphous pith callus. Except for the initiation of N. langsdorffii (and N. glauca) pith, the 2,4-dichlorophenoxyacetic acid medium, caused bleaching in cultures of T-37 induced tumors and death of B-6 induced tumors. Tumor cultures, except for the seedling tumor, grew well on a minimal medium lacking kinetin, indoleacetic acid, vitamins, glycine, and inositol. Glycine was necessary only in the growth of N. langsdorffii pith callus. A tissue culture model is presented which permits comparison of the various tissue types.
A Surgical Procedure for Resecting the Mouse Rib: A Model for Large-Scale Long Bone Repair

This protocol introduces researchers to a new model for large-scale bone repair utilizing the mouse rib. The procedure details the following: preparation of the animal for surgery, opening the thoracic body wall, exposing the desired rib from the surrounding intercostal muscles, excising the desired section of rib without inducing a pneumothorax, and closing the incisions. Compared to the bones of the appendicular skeleton, the ribs are highly accessible. In addition, no internal or external fixator is necessary since the adjacent ribs provide a natural fixation. The surgery uses commercially available supplies, is straightforward to learn, and well-tolerated by the animal. The procedure can be carried out with or without removing the surrounding periosteum, and therefore the contribution of the periosteum to repair can be assessed. Results indicate that if the periosteum is retained, robust repair occurs in 1 - 2 months. We expect that use of this protocol will stimulate research into rib repair and that the findings will facilitate the development of new ways to stimulate bone repair in other locations around the body.
The paradox of expertise: is the Wikipedia Reference Desk as good as your library?

Purpose – The purpose of this paper is to examine the quality of answers on the Wikipedia Reference Desk, and to compare it with library reference services. It aims to examine whether Wikipedia volunteers outperform expert reference librarians and exemplify the paradox of expertise.Design/methodology/approach – The study applied content analysis to a sample of 434 messages (77 questions and 357 responses) from the Wikipedia Reference Desk and focused on three SERVQUAL quality variables: reliability (accuracy, completeness, verifiability), responsiveness, and assurance.Findings – The study reports that on all three SERVQUAL measures quality of answers produced by the Wikipedia Reference Desk is comparable with that of library reference services.Research limitations/implications – The collaborative social reference model matched or outperformed the dyadic reference interview and should be further examined theoretically and empirically. The generalizability of the findings to other similar sites is questiona...
Reassessment of the genus Catillochroma (lichenized Ascomycota, Ramalinaceae)

The species assigned to the genus Catillochroma are reassessed. The two characters used to characterize Catillochroma, exciple anatomy and thalline chemistry, are shown to be variable and contradictory with a number of intermediates. Consequently, Catillochroma is reduced to synonymy with Megalaria, and the species previously placed in Catillochroma transferred, or returned, to Megalaria. As such, the following new combinations are proposed: Megalaria anaglyptica, M. endo- chroma, M. intermiscensand M. leptocheila. The genus Lopezariais also shown to be related to Megalaria and to be closely related to the type species of Catillochroma, C. endochroma, and so is also reduced to synonymy with Megalaria. A number of species found to have been misplaced in Catillaria are also transferred to Megalaria: M. leucochlora, M. melanopotamica, M. obludens, M. pannosa and M. phaeolomiza. Megalaria imshaugii is reduced to synonymy with M. obludens, Megalaria pannosa is reported for the first time from North America and Lopezaria isidiza is reported for the first time from outside Asia from Jamaica.
SUPPORTED IR AND PT CLUSTERS : REACTIVITY WITH OXYGEN INVESTIGATED BY EXTENDED X-RAY ABSORPTION FINE STRUCTURE SPECTROSCOPY

Extended X-ray absorption fine structure (EXAFS) spectroscopy was used to investigate the effects of oxidation and reduction on supported noble metal clusters. After long-term exposure to laboratory air at room temperature, platinum clusters with an average diameter of approximately 7 A inside the pores of BaKLTL zeolite were almost completely fragmented. The EXAFS data indicate small, highly disordered platinum−platinum contributions but no bulk platinum oxides. Treatment in H2 at 450 °C led to the formation of platinum clusters about 10 A in average diameter, and exposure of these to air at room temperature led to the formation of a disordered platinum-oxide-like phase covering a core of platinum atoms. The reactivity of platinum clusters with oxygen is size-dependent, and platinum cluster growth by oxidation−reduction cycles may be inhibited by the size of the zeolite pores. Similarly, iridium clusters on MgO, approximated as Ir4, were fragmented by treatment in O2, but treatment of the oxidized iridiu...
Halide coordination to zinc porphyrin sensitizers anchored to nanocrystalline TiO2.

The coordination of halide ions to 5-(3,5-dicarboxyphenyl)-10,15,20-tri-p-tolylporphinatozinc(II) anchored to mesoporous nanocrystalline (anatase) TiO2 thin films (TiO2/ZnP) immersed in propylene carbonate was quantified. The addition of tetrabutylammonium halide salts to the external propylene carbonate electrolyte resulted in a red shift in the absorption spectrum with the maintenance of five isosbestic points. The absorption spectra were within experimental error the same for ZnP and ZnP−X− compared to TiO2/ZnP and TiO2/ZnP−X−: ASoretZnP = 427 nm (e = 574 000 M−1 cm−1), ASoretZnP−Cl− = 435 nm (e = 905 000 ± 12 000 M−1 cm−1), ASoretZnP−Br− = 436 nm (e = 776 000 ± 30 000 M−1 cm−1), and ASoretZnP−I− = 437 nm (e = 620 000 ± 56 000 M−1 cm−1). Titration studies with the halides revealed sharp isosbestic points consistent with formation of a 1:1 halide/porphyrin adduct. Equilibrium constants for ZnP were found to be 1670 M−1 for Cl−, 96 M−1 for Br−, and 5.5 M−1 for I−, and the corresponding values for TiO2/Zn...
The Structural Basis of Cholesterol Accessibility in Membranes

Although the majority of free cellular cholesterol is present in the plasma membrane, cholesterol homeostasis is principally regulated through sterol-sensing proteins that reside in the cholesterol-poor endoplasmic reticulum (ER). In response to acute cholesterol loading or depletion, there is rapid equilibration between the ER and plasma membrane cholesterol pools, suggesting a biophysical model in which the availability of plasma membrane cholesterol for trafficking to internal membranes modulates ER membrane behavior. Previous studies have predominantly examined cholesterol availability in terms of binding to extramembrane acceptors, but have provided limited insight into the structural changes underlying cholesterol activation. In this study, we use both molecular dynamics simulations and experimental membrane systems to examine the behavior of cholesterol in membrane bilayers. We find that cholesterol depth within the bilayer provides a reasonable structural metric for cholesterol availability and that this is correlated with cholesterol-acceptor binding. Further, the distribution of cholesterol availability in our simulations is continuous rather than divided into distinct available and unavailable pools. This data provide support for a revised cholesterol activation model in which activation is driven not by saturation of membrane-cholesterol interactions but rather by bulk membrane remodeling that reduces membrane-cholesterol affinity.
General Hybrid Parallel Profiling

A hybrid parallel measurement system offers the potential to fuse the principal advantages of probe-based tools, with their exact measures of performance and ability to capture event semantics, and sampling-based tools, with their ability to observe performance detail with less overhead. Creating a hybrid profiling solution is challenging because it requires new mechanisms for integrating probe and sample measurements and calculating profile statistics during execution. In this paper, we describe a general hybrid parallel profiling tool that has been implemented in the TAU Performance System. Its generality comes from the fact that all of the features of the individual methods are retained and can be flexibly controlled when combined to address the measurement requirements for a particular parallel application. The design of the hybrid profiling approach is described and the implementation of the prototype in TAU presented. We demonstrate hybrid profiling functionality first on a simple sequential program and then show its use for several OpenMP parallel codes from the NAS Parallel Benchmark. These experiments also highlight the improvements in overhead efficiency made possible by hybrid profiling. A large-scale ocean modeling code based on OpenMP and MPI, MPAS-Ocean, is used to show how the TAU hybrid profiling tool can be effective at exposing performance-limiting behavior that would be difficult to identify otherwise.
Dependence upon conditions of the properties of specifically located fluorescent probes on wheat germ calmodulin

The single tyrosine, Tyr-139, of wheat germ calmodulin provides an intrinsic fluorescent probe to monitor Ca2+-binding domain 4, while the single cysteine, Cys-27, provides a site for the attachment of an extrinsic fluorescent label to monitor the N-terminal lobe. This has resulted in a means of comparing the response of the N- and C- terminal regions to pH, ionic strength, and Ca2+ level. Ca2+ ligation decreases the mobility sensed by Tyr-139 at neutral pH, while a shift in pH to 5.2 results in a further decrease.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
Clarithromycin Transport by Gingival Fibroblasts and Epithelial Cells

Macrolide antibiotics penetrate cells, but the mechanism by which this occurs is unclear. The objective of this study was to characterize the mechanisms of clarithromycin uptake by gingival fibroblasts and oral epithelium. Cultured human gingival fibroblasts and SCC-25 cells were incubated with [3H]-clarithromycin. We assayed clarithromycin transport by measuring cell-associated radioactivity over time. Fibroblasts and epithelial cells rapidly accumulated clarithromycin, attaining steady-state intracellular concentrations within 15 minutes. Incubation in medium containing 2 μg/mL clarithromycin yielded steady-state intracellular concentrations of 75.8 μg/mL in fibroblasts and 6.6 μg/mL in SCC-25 cells. Clarithromycin transport exhibited Michaelis-Menten kinetics and was inhibited below 37°C. The Michaelis constants for fibro-blasts and SCC-25 cells were 78.4 and 227 μg/mL, respectively, while the maximum transport velocities were 264 and 381 ng/min/106 cells, respectively. Thus, both types of cells take u...
The compression of the alkali metals to 45 kbar

Abstract The volume compressions of lithium, sodium, potassium, and rubidium, have been determined in a piston cylinder apparatus to 45 kbars pressure. The results are at considerable variance with Bridgman's 1948 measurements. The bulk moduli and some of their pressure derivatives have been estimated by fitting a Murnaghan equation to the pressure volume data, and the results are compared with values obtained from ultrasonic measurements. The static compressions have also been compared with isothermal compressions calculated from the shock Hugoniot measurements.
MR demonstration of an anomalous muscle in a patient with coexistent carpal and ulnar tunnel syndrome case report and literature summary

Abstract An aberrant muscle is demonstrated by magnetic resonance (MR) imaging in a patient presenting with focal wrist swelling and compression neuropathy of median and ulnar nerves following 4 months of carpentry work. The muscle originated from the palmaris longus tendon and ulnar antebrachial fascia at the lower half of the forearm as a single belly, then diverged medially from palmaris longus tendon and bifurcated. Both portions of the split muscle extended into the distal ulnar tunnel or Guyon's canal. One segment joined with the abductor digiti minimi muscle and the other with the flexor retinaculum. MR was able to clearly delineate this hypertrophied, symptomatic muscle anomaly. It may be helpful when mass effect is suspected in either tunnel, or in patients with atypical work-related carpal tunnel syndrome with evidence of significant ulnar neuropathy for evaluation of underlying anomalous musculature. Normal MR images of the wrist are included for comparison and the literature is reviewed.
Sodium ion interactions with aqueous glucose: Insights from quantum mechanics, molecular dynamics, and experiment

In the last several decades, significant efforts have been conducted to understand the fundamental reactivity of glucose derived from plant biomass in various chemical environments for conversion to renewable fuels and chemicals. For reactions of glucose in water, it is known that inorganic salts naturally present in biomass alter the product distribution in various deconstruction processes. However, the molecular-level interactions of alkali metal ions and glucose are unknown. These interactions are of physiological interest as well, for example, as they relate to cation-glucose cotransport. Here, we employ quantum mechanics (QM) to understand the interaction of a prevalent alkali metal, sodium, with glucose from a structural and thermodynamic perspective. The effect on β-glucose is subtle: a sodium ion perturbs bond lengths and atomic partial charges less than rotating a hydroxymethyl group. In contrast, the presence of a sodium ion significantly perturbs the partial charges of α-glucose anomeric and ring oxygens. Molecular dynamics (MD) simulations provide dynamic sampling in explicit water, and both the QM and the MD results show that sodium ions associate at many positions with respect to glucose with reasonably equivalent propensity. This promiscuous binding nature of Na(+) suggests that computational studies of glucose reactions in the presence of inorganic salts need to ensure thorough sampling of the cation positions, in addition to sampling glucose rotamers. The effect of NaCl on the relative populations of the anomers is experimentally quantified with light polarimetry. These results support the computational findings that Na(+) interacts similarly with α- and β-glucose.