cssi/SciSciGPT-SciSciNet huggingface dataset:
Waiving the MPA Entrance Exam: Impact on Performance

For decades, graduate schools around the country have used various graduate entrance exams as one of the key factors in determining graduate school admission. Although many people would argue that ...
Physical Properties of Short-Chain and Long-Chain Fractions of Lipopolysaccharide

The toxicity of lipopolysaccharide (LPS) isolated from different organisms varies greatly, as does the toxicity of different salt forms of a single LPS isolate (4). Thus, it seems probable that the “endotoxic effects” of LPS are due to the presence of particular chemical groups, and to the accessibility of these groups. The accessibility may, in turn, depend on the aggregate structure.
Buddhist Ultimates? A Difficult Question

If there are “ultimates” in Buddhism, they are not some separate sphere or entity, but rather the depth dimension of this very life. Nor are they conceptual for Buddhists; the words are merely the inadequate results of trying to verbalize profound experiences. The two leading candidates for Buddhist ultimates are “interdependence” or “conditioned genesis,” and “emptiness.” Though these two are often presented separately, they are, in fact, much the same thing. Conditioned genesis shows how all phenomena arise dependent on their causal matrix and cease when that matrix changes. Because the matrix changes moment by moment, phenomena are very short-lived. But because phenomena are dependent on their causal nexus, they are “empty” of inherent existence. Thus phenomena are not real in the way we usually assume they are. Therefore, they are not worth the emotional charge they usually carry, which imprisons us in painful habitual patterns. To complete the cast of characters of Buddhist ultimates, we need only point to widespread teachings that everyone has the capacity to realize interdependence and emptiness, and thus free themselves from entanglement in self-perpetuating pain.
Technical Tips: The Visual Evoked Potential—How Important Is Pupil Size?

ABSTRACT.We present a case in which pupillary asymmetry produced latency changes in the visual evoked potential (VEP), leading to an erroneous diagnosis of a demyelinating optic nerve lesion. The latency asymmetry disappeared when the small pupil was iatrogenically dilated. This finding underscores the importance of pupil size on the VEP latency. Increased awareness of the inverse relationship between pupillary diameter and VEP latency will help to avoid diagnostic pitfalls and potentially unnecessary procedures.
Polymer–drug conjugate therapeutics: advances, insights and prospects

Polymer–drug conjugates have long been a mainstay of the drug delivery field, with several conjugates successfully translated into clinical practice. The conjugation of therapeutic agents to polymeric carriers, such as polyethylene glycol, offers several advantages, including improved drug solubilization, prolonged circulation, reduced immunogenicity, controlled release and enhanced safety. In this Review, we discuss the rational design, physicochemical characteristics and recent advances in the development of different classes of polymer–drug conjugates, including polymer–protein and polymer–small-molecule drug conjugates, dendrimers, polymer nanoparticles and multifunctional systems. Current obstacles hampering the clinical translation of polymer–drug conjugate therapeutics and future prospects are also presented. The conjugation of therapeutic agents to polymer carriers, such as polyethylene glycol (PEG), can control drug delivery, enhance solubilization, increase efficacy and improve pharmacokinetics. Here, Grinstaff, Colson and Ekladious discuss recent advances in the preclinical and clinical development of different classes of polymer–drug conjugates and highlight current challenges and future directions.
Current-only Directional Overcurrent Protection Using Postfault Current

Directional overcurrent relays play an important role in protecting the transmission and distribution systems. Conventionally, voltage profile is utilized as a polarizing reference quantity for the directional protection. During the close-in-faults, the conventional relaying technique loses its voltage reference signal. Moreover, the implementation cost of the method increases in distribution systems as it requires installation of potential transformers. In this paper, a novel method for identification of fault direction is proposed that only requires postfault current signal and does not require voltage signal. According to the case study results, the proposed method can determine the direction of faults precisely even in the case of change in the prefault power flow direction.
Widespread activation of awake mouse cortex by electrical stimulation

Electrical stimulation is a highly-effective, temporally-precise technique to evoke neural activity in the brain, and thus is critically important for both research and clinical applications. Here, we set out to understand the time-course and spatial spread of neural activation elicited by electrical stimulation. By imaging the cortex of awake, chronically-implanted, transgenic mice during electrical stimulation, we found that a broad range of stimulation parameters led to widespread neural activation. In general, increasing current amplitude and the number of stimulation pulses progressively produced higher maximum activity and activated larger areas of cortex. However, increasing stimulation frequency above 30 Hz primarily shifted the timing, not amplitude, of peak activity. Our results demonstrate that even weak electrical stimulation widely activates neurons within awake mouse cortex.
Additive manufacturing of catalytically active living material hydrogels

Herein, we describe a yeast-laden hydrogel ink that can be printed using a direct-write 3D printer and used for the production of a peptide. A poly(alkyl glycidyl ether)-based triblock copolymer was synthesized and formulated as a hydrogel that was characterized via rheometry to evaluate the printability of the hydrogel ink. An engineered yeast strain with an upregulated α-factor production pathway was incorporated into the hydrogel ink and 3D printed. The immobilized yeast cells exhibited adequate viability of 87.5% within the hydrogel. The production of the up-regulated α- factor was detected using a detecting yeast strain and quantified at 268 nM (s = 34.6 nM) over 72 h. The reusability of these systems was demonstrated by immersion of the yeast-laden hydrogel lattice in fresh SC media and confirmed by the detection of similar amounts of up-regulated α-factor 259 nM (s = 45.1 nM). These yeast-laden materials represent an attractive opportunity for whole-cell catalysis of other high-value products in a sustainable and continuous manner.
Additive manufacturing in repair: Influence of processing parameters on properties of Inconel 718

Abstract Laser engineered net shaping (LENS™), a metal additive manufacturing process, was employed to repair internal defects in Inconel 718. The technique involves milling slot/s around defect zone and subsequently refill the cavities with a material. This study investigates the effectiveness of two slots with different geometric shapes, rectangular and trapezoidal, to repair internal cracks and understand the influence of deposition orientation on mechanical properties of the repaired components. Trapezoidal shaped cross-section showed good fusion between deposit material and the part along the sidewalls without any void inclusion. Build-direction, especially diagonal-deposition, influenced coefficient of friction and compound-wear for non-heat-treated samples.
Breast cancer malpractice litigation: A 10-year analysis and update in trends.

Abstract Purpose The purpose of this study is to evaluate factors contributing to medical malpractice claims relating to breast cancer and the field of breast imaging. Method and materials A retrospective analysis of jury verdict and settlement reports in US state and federal courts on the Westlaw legal database was performed. The database was searched for ‘malpractice’ and ‘breast cancer’ related terms from 2005 to 2015. 253 cases were evaluated for factors including case outcome, award amounts, type of physician defendants, plaintiff age, stage at diagnosis, length of delay in diagnosis, and symptomatology, among other factors. Data were summarized using descriptive statistics. Logistic regression was used to evaluate associations between factors and plaintiff award. Results Median plaintiff age was 46 (IQR 39, 56). In cases that resulted in plaintiff payment, the award amount was $978,858 ± 2,308,598. Delay in diagnosis was cited as a reason for claimed negligence in 82% of cases. Mean length of delay was 17 ± 13 months. Named defendants were radiologists (43%), surgeons (27%), obstetrician/gynecologists (26%), and internal medicine/family practice (15%). Age, defendant type, and cancer stage were not significant predictors of case outcome. Failure to refer to a surgeon was twofold (OR [95% CI]: 2.44 [1.085, 5.489]) more likely to be resolved with payment compared to those cases without that factor. Cases with a delay in diagnosis of ≥12 months were twofold (OR [95% CI]: 2.129 [1.086, 4.175]) more likely to be resolved with payment compared to a delay Conclusion Plaintiffs involved in breast cancer imaging related medical malpractice cases tend to be younger than the median age of diagnosis of breast cancer for US women (62 per NCI Surveillance, Epidemiology and End Results data). Breast cancer imaging suits involve physicians from multiple specialties, radiology being the most common. Delay in diagnosis ≥12 months, lack of surgeon referral, and lack of recommended follow up are related to plaintiff payments and may be areas of professional practice to target as radiology professionals. Clinical relevance/application Medical malpractice relating to breast cancer and breast imaging remains very prevalent and costly for all involved. Radiologists are being named in these lawsuits more frequently than in the past.
Police leadership of tomorrow: comprehensive compstat performance management moving from stagnation to innovation

In 1994 New York City began its police performance management system called Compstat – compare statistics. It is now used by many law enforcement agencies throughout the world. Its use, however, is...
Custom tissue engineered aneurysm models with varying neck size and height for early stage in vitro testing of flow diverters

Endovascular techniques for treating cerebral aneurysms are rapidly advancing and require testing to optimize device configurations. The purpose of this work was to customize tissue-engineered aneurysm “blood vessel mimics” (aBVMs) for early stage in vitro assessment of vascular cell responses to flow diverters and other devices. Aneurysm scaffolds with varying neck size and height were created through solid modeling, mold fabrication, mandrel creation, and electrospinning. Scaffold dimensions and fiber morphology were characterized. aBVMs were created by depositing human smooth muscle and endothelial cells within scaffolds, and cultivating within perfusion bioreactors. These vessels were left untreated or used for flow diverter implantation. Cellular responses to flow diverters were evaluated at 3 days. Custom scaffolds were created with aneurysm neck diameters of 2.3, 3.5, and 5.5 mm and with aneurysm heights of 2, 5, and 8 mm. A set of scaffolds with varying neck size was used for aBVM creation, and dual-sodding of endothelial and smooth muscle cells resulted in consistent and confluent cellular linings. Flow diverters were successfully implanted in a subset of aBVMs, and initial cell coverage over devices was seen in the parent vessel at 3 days. Direct visualization of the device over the neck region was feasible, supporting the future use of these models for evaluating and comparing flow diverter healing. Tissue-engineered aneurysm models can be created with custom neck sizes and heights, and used to evaluate cellular responses to flow diverters and other endovascular devices.
Mathematical Model and Experimental Design of Nanocomposite Proximity Sensors

A mathematical model of fringe capacitance for a nano-based proximity sensor, which takes the presence of different resistivities into account, is developed. An analytical solution obtained for a rectangular-shape sensor with applying of Gauss, Conversation of Charge and Ohm laws into Laplace's equation ∇ 2 V (x, y, z, t) = 0 gives the electric potential distribution by which the fringe capacitance in a 2D domain area can be calculated. The calculated capacitance evidently decreases drastically due to the fringe phenomena while object moves toward the polymeric sensor. The model also asserts that the change of capacitance is under a noticeable influence of sensor resistivity, particularly in the range of 10 3 -10 5 Ω.m, the initial capacitance varies from 0.045pF to 0.024 pF. The fabricated flexible nanocomposite sensors, Thermoplastic Polyurethane (TPU) reinforced by 1wt.% Carbon Nanotubes (CNTs) having resistivity 105Ω.m, are capable of detecting presence of an external object in a wide range of distance and indicating remarkable correlation with the mathematical solution. Our proximity sensor fabrication is straightforward and relatively simple. An unprecedented detection range of measurement reveals promising ability of this proximity sensor in applications of motion analysis and healthcare systems.
Clearance rates of freshwater bivalves Corbicula fluminea and Utterbackia imbecillis in the presence and absence of light

Light affects bivalve behavior and gaping activity, but its potential effects on bivalve filtration remain poorly investigated. In this study, clearance rates of two bivalve species: the Asian clam, Corbicula fluminea and the paper pondshell, Utterbackia imbecillis, were assessed in light (6.5 ± 0.5 µmol m−2 s−1) and dark (0.0 µmol m−2 s−1) conditions. We found that clearance rates remained similar between C. fluminea (50 ± 18 mL g−1 h−1) and U. imbecillis (41 ± 10 mL g−1 h−1) during light conditions. However, C. fluminea (110 ± 15 mL g−1 h−1) filtered significantly faster than U. imbecillis (24 ± 6 mL g−1 h−1) in the dark condition (p < 0.05). The results indicated that light might affect the filtration activity in freshwater bivalves differently, depending on species.
Insights into the practical effectiveness of RT-PCR testing for SARS-CoV-2 from serologic data, a cohort study

Background: Virologic detection of SARS-CoV-2 through Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) has limitations for surveillance. Serologic tests can be an important complementary approach. Objective: Assess the practical performance of RT-PCR based surveillance protocols, and the extent of undetected SARS-CoV-2 transmission in Shenzhen, China. Design: Cohort study nested in a public health response. Setting: Shenzhen, China; January-May 2020. Participants: 880 PCR-negative close-contacts of confirmed COVID-19 cases and 400 residents without known exposure (main analysis). Fifty-seven PCR-positive case contacts (timing analysis). Measurements: Virological testing by RT-PCR. Measurement of anti-SARS-CoV-2 antibodies in PCR-negative contacts 2-15 weeks after initial testing using total Ab ELISA. Rates of undetected infection, performance of RT-PCR over the course of infection, and characteristics of seropositive but PCR-negative individuals were assessed. Results: The adjusted seropositivity rate for total Ab among 880 PCR-negative close-contacts was 4.1% (95%CI, 2.9% to 5.7%), significantly higher than among residents without known exposure to cases (0.0%, 95%CI, 0.0% to 1.0%). PCR-positive cases were 8.0 times (RR; 95% CI, 5.3 to 12.7) more likely to report symptoms than the PCR-negative individuals who were seropositive, but otherwise similar. RT-PCR missed 36% (95%CI, 28% to 44%) of infected close-contacts, and false negative rates appear to be highly dependent on stage of infection. Limitations: No serological data were available on PCR-positive cases. Sample size was limited, and only 20% of PCR-negative contacts met inclusion criteria. Conclusion: Even rigorous RT-PCR testing protocols may miss a significant proportion of infections, perhaps in part due to difficulties timing testing of asymptomatics for optimal sensitivity. Surveillance and control protocols relying on RT-PCR were, nevertheless, able to contain community spread in Shenzhen.
Ethics in Pandemics: The Lawyer for the (Crisis) Situation

Lawyers often respond to client crises. But a client crisis is not necessarily a crisis for the lawyer when the lawyer is competent, prepared, and trained to handle that crisis. More and more, though, lawyers are asked to face novel crises that are so pervasive that they impact the ability of the lawyer to provide competent, effective, and zealous advocacy for her client. Today, lawyers are sheltering-in-place while their clients suffer immense hardship, either in prison or detention where the Coronavirus is spreading like wildfire, or homebound, forced to remain with an abuser. The Model Rules of Professional Conduct provide some limited guidance to lawyers dealing with emergency situations, and there has been some tinkering along the margins of the rules in response to recent crises, particularly as the rules address the unauthorized practice of law in jurisdictions where emergencies arise. Some scholarship addresses how lawyers have dealt with crises in discrete areas, with a great deal of attention being directed toward the national security context in particular. More and more though, lawyers are asked to assist clients in novel and widespread crises that affect many areas of practice, and the Model Rules do not address the ways in which such crises can impact the practice of law more generally. The main approach this Article takes is to assess the extent to which scholarship and the current rules governing the practice of law and their underlying principles account for some of the unique aspects of practice in novel, pervasive crises. To date, legal scholarship has not considered the ways in which what I call crisis lawyering may be a mode of practice many, if not all lawyers, will face throughout the course of their careers. Moreover, one of the purposes of the Model Rules includes providing guidance to lawyers but they also serve as a means by which we can measure lawyer conduct to ensure there is some degree of lawyer accountability to clients, adversaries, the legal system, and the general public. By using the Model Rules as a starting point for the analysis, this Article explores the somewhat disjointed ways in which the rules that govern the practice of law offer guidance to the lawyer facing novel, pervasive crises. It also addresses the needs of lawyers operating in fields where they may confront crisis situations and seeks to recognize that crisis lawyering may be a form of practice that is, itself, trans-substantive, demonstrating distinct similarities across different areas of practice. This Article attempts to address the absence of scholarship addressing crisis lawyering and analyzes the extent to which the current rules governing the practice of law are or are not adequate to the task of providing guidance—and accountability—to lawyers dealing with such situations. It also offers recommendations for how we may consider amendments to those rules to better reflect the needs, interests, and obligations of lawyers dealing with crisis situations so that lawyers may serve their clients better and more effectively when faced with such crises.
The Voice: Popular Culture and the Perpetuation of Ideology

Since American Idol, aspiring singers have viewed television singing competitions as a way to bypass playing in bars to achieve success in the music industry. Many musicians define success in the music industry as obtaining a record contract. As the reigning singing competition on television, ABC’s The Voice positions itself as a way to “coach” singers to become celebrities. Through a cultural study of the show, legal documents and news reports, Arditi argues the show advances ideology about record contracts while it exploits contestants. Whereas contestants labor for up to eight months without pay, show executives and coaches earn millions each season. Meanwhile, the show seduces viewers at home who come to believe the show provides a pathway to musical success. This affects the attitudes viewers and aspiring musicians have about the recording industry, allowing industry executives to perpetuate the exploitation of musicians.
Psychological wellness of internal medicine hospitalists during the COVID-19 pandemic

Patients with COVID-19 infection requiring in-hospital care are frequently managed by Internal Medicine hospitalists, comprised of physicians, nurse practitioners and physician assistants. There is...
Young Man with Cardiac Arrest Secondary to Undiagnosed Mediastinal Mass: A Case Report.

Author(s): Mallett, Ian; Watsjold, Bjorn; Chipman, Anne K. | Abstract: Introduction: A 20-year-old man with a reported history of asthma presented to the emergency department in cardiac arrest presumed to be caused by respiratory failure. Case Report: The patient was discovered to have central airway obstruction and concomitant superior vena cava compression caused by a large mediastinal mass—a condition termed mediastinal mass syndrome. While the patient regained spontaneous circulation after endotracheal intubation, he was challenging to ventilate requiring escalating interventions to maintain adequate ventilation. Conclusion: We describe complications of mediastinal mass syndrome and an approach to resuscitation, including ventilator adjustments, patient repositioning, double-lumen endotracheal tubes, specialty consultation, and extracorporeal life support.
PREEMPT: Scalable Epidemic Interventions Using Submodular Optimization on Multi-GPU Systems

Preventing and slowing the spread of epidemics is achieved through techniques such as vaccination and social distancing. Given practical limitations on the number of vaccines and cost of administration, optimization becomes a necessity. Previous approaches using mathematical programming methods have shown to be effective but are limited by computational costs. In this work, we present PREEMPT, a new approach for intervention via maximizing the influence of vaccinated nodes on the network. We prove submodular properties associated with the objective function of our method so that it aids in construction of an efficient greedy approximation strategy. Consequently, we present a new parallel algorithm based on greedy hill climbing for PREEMPT, and present an efficient parallel implementation for distributed CPU-GPU heterogeneous platforms. Our results demonstrate that PREEMPT is able to achieve a significant reduction (up to 6.75×) in the percentage of people infected and up to 98% reduction in the peak of the infection on a city-scale network. We also show strong scaling results of PREEMPT on up to 128 nodes of the Summit supercomputer. Our parallel implementation is able to significantly reduce time to solution, from hours to minutes on large networks. This work represents a first-of-its-kind effort in parallelizing greedy hill climbing and applying it toward devising effective interventions for epidemics.
Dynamic fault weakening during earthquakes: Rupture or friction?

Abstract An earthquake is an event of dynamic, unstable slip that releases elastic energy stored in the earth's crust. This abrupt energy release requires the weakening of the slipping fault that is manifested by a strength drop from a static level to a dynamic level. The fault weakening occurs in two general zones: The rupture-front at the earthquake tip, and the frictional zone in the wake of the propagating front. Here, we analyze the weakening processes of the rupture-front in experimental stick-slips, and compare these processes to the weakening in the frictional zone. Our experimental analysis focuses on high-speed monitoring (1 MHz) of the strain-fields associated with spontaneous, unstable ruptures propagating bilaterally from a nucleation site along a circular fault. The ruptures propagated at velocities ranging from slow (∼100 m/s) to supershear, and the fault weakening by the rupture-front, defined by WS = [strength drop/peak strength], is proportional to the rupture propagation velocity. WS ranged 0.08-0.58 during tiny slip-displacements of 3.7-43 microns, in agreement with similar weakening intensity in a few sets of dynamic rupture experiments. In contrast, frictional weakening, which is traditionally analyzed in constant-velocity experiments, requires slip-displacements in the range of 0.1-10 m to reach similar weakening intensity. Therefore, in terms of slip-displacements, rupture-front weakening is more efficient than frictional weakening by orders of magnitude. Further, we observed that a rupture-front transported its intense weakening from a nucleation site to the entire experimental fault, and we argue that the equivalent process can occur along natural faults. If the rupture of a tiny earthquake, e.g., M
Reclaiming the mission of academic medicine: An examination of institutional responses to (anti)racism.

Purpose The utility of institutional statements is said to provide clarity and reinforcement of an institution's goal. Unfortunately, it can also be argued that these statements are in clear misalignment between the words described and the environments that faculty, students, trainees, and staff of color face. The purpose of this study was to analyze academic medicine institutional statements that responded to 2020 racial tensions following the murders of George Floyd, among others, and the subsequent nationwide protests against police brutality. Methods We conducted a manifest content analysis of institutional statements generated by academic medical centers after George Floyd's murder. We used manifest content analysis to gain insights into how institutional statements connect structural racism to the mission of academic medicine. We collected and examined institutional statements from 26 academic medicine centers. Selection parameters included statements that were publicly available and published by the institutions during a 2-week period. We conducted a four-stage analysis: decontextualization, recontextualization, categorization, and compilation. To better understand the collection of statements, we plotted these institutional statements according to the most salient discussed themes. Results Overall, institutional statements discussed racism through three subthemes: identifying the racial implications of health disparities, issuing a call to action to address racism, and decentering race. Absent language is also noted. Second, institutional statements evoked institutional values by expressing an explicit connection with the academic medicine mission, naming the value of social justice, and emphasizing the concept of community. Finally, institutional statements largely discussed public health in connection with racism or with institutional values. Conclusion Our study determines a much-needed reconnection to the mission of academic medicine. Reclaiming the social mission will be a major step toward recentering the foundation of institutional actions. This call is what ultimately will improve the health and well-being of marginalized populations.
Novel Preosteoclast Populations in Obesity-Associated Periodontal Disease.

Although there is a clear relationship between the degree of obesity and periodontal disease incidence, the mechanisms that underpin the links between these conditions are not completely understood...
PROBABILITY-BASED SHIP STRUCTURAL SAFETY ANALYSIS

This paper provides a demonstration on the use of probability- bases ship structural safety analysis and enumerates the benefits in comparison with traditional methods. Reliability techniques are developed to determine safety levels of existing vessels, taking into consideration uncertainties in loads, strength and calculation procedures. Ultimate, serviceability and fatigue limit states are developed and applied to an existing tanker. The corresponding load models are examined and, in some instances, further developed. Safety indices associated with yielding, buckling, and fatigue are calculated. Conclusions are drawn regarding the benefits and drawbacks of using probability-based ship safety analysis.
Animal experimentation defended

From my colleagues at the University of Michigan I bring cordial greetings to our friends and hosts in ARTEM and the Istituto di Ricerche Farmacologiche ‘Mario Negri’, and associated organizations. The intellectual objectives, and the methods of humane inquiry, for researchers on all continents are in essential harmony; I take this opportunity to express satisfaction in our mutual support. My remarks regarding the use of animals as subjects in biomedical experiments are presented under four headings.
The Invention of Free Verse

The invention deserves commemoration. We must put up our plaque, however, not anywhere in New York or London, not even in Boston or Dublin, but in ?unlikeliest of places ? Crawfordsville, Indiana, some where in the environs of Wabash College. The year was 1907. The poet was more or less improvising, we may suppose, in the character of one of the old poets whom he had recently studied with such fondness and apti tude.
PATIENT CLASSIFICATION AND HOSPITAL COSTS OF CARE FOR STROKE IN 10 EUROPEAN COUNTRIES

Stroke is a major cause of death and disability around the world, and the care of stroke patients ties up a great amount of resources in healthcare systems. Stroke severity and the given care may vary substantially between patients, and there is remarkable variation in both the costs and length of stay (LoS) of stroke patients. Using patient level data from 10 European countries on costs and LoS, we explored the ability of the diagnosis-related group (DRG) systems to explain variance in the costs and length of stay of stroke patients. In addition, we evaluated whether the existing DRGs for stroke patients would benefit from additional patient-related and treatment-related factors that are commonly found in the administrative databases across countries. Cost analyses were run using OLS fixed effects models, and LoS analyses with negative binomial models. The descriptive statistics showed that the stroke patients differ remarkably across countries. Large variations in the classification of stroke patients raise concerns about whether all systems rely on the most appropriate classification variables. In all the countries, the DRG classifications' performance could be improved with the introduction of the patient characteristics analysed here. Copyright © 2012 John Wiley & Sons, Ltd.
Abstract 1898: The combination of gemcitabine/nab-paclitaxel and anti-DLL4 (demcizumab) produces synergistic growth inhibition, delays tumor recurrence and reduces tumor initiating cells in pancreatic cancer

Clinical management of pancreatic cancer is challenging and this disease remains the fourth most common cause of cancer-related death. Conventional chemotherapeutic agents, including gemcitabine, commonly used in the treatment of pancreatic cancer, have low response rates and limited effects on improving patient survival. A recent Phase III clinical trial has demonstrated that nab-paclitaxel (Abraxane, a protein-bound paclitaxel) in combination with gemcitabine significantly improved response rate and overall survival compared to patients receiving gemcitabine alone. We previously demonstrated that targeting Notch signaling by anti-DLL4 (demcizumab) inhibits tumor growth, reduces tumor initiating cell frequency and induces differentiation in patient-derived pancreatic xenograft tumors. To further explore the utility of demcizumab in the setting of pancreatic cancer, we evaluated anti-DLL4 combination with gemcitabine/ nab-paclitaxel in a panel of pancreatic xenograft models. We found that anti-DLL4 in combination with gemcitabine plus nab-paclitaxel resulted in striking tumor regression, whereas tumors treated with chemotherapeutic agents alone grew continuously. The effect of the triple combination in some tumors was quite durable and persisted after both antibody and chemotherapeutic treatments were discontinued. The significant growth inhibitory effect by the combination of anti-DLL4 with gemcitabine/nab-paclitaxel was associated with a decrease in cancer stem cell frequency and an increase in apoptosis and tumor cell differentiation. The triple combination of anti-DLL4, gemcitabine and nab-paclitaxel was generally more efficacious compared with anti-DLL4 plus gemcitabine alone. Notably, in a xenograft established from a patient that previously did not respond to demcizumab plus gemcitabine, the triple combination was highly effective. We are currently evaluating demcizumab in combination with gemcitabine plus nab-paclitaxel in a Phase 1b clinical trial in pancreatic cancer. Citation Format: Wan-Ching Yen, Marcus Fischer, John Lewicki, Austin Gurney, Timothy Hoey. The combination of gemcitabine/nab-paclitaxel and anti-DLL4 (demcizumab) produces synergistic growth inhibition, delays tumor recurrence and reduces tumor initiating cells in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1898. doi:10.1158/1538-7445.AM2014-1898
Role of endothelial PPARγ: Protection against vascular dysfunction induced by IL-1β

Peroxisome proliferator-activated receptor gamma (PPARγ) has been proposed to mediate anti-inflammatory actions by promoting the degradation of the p65 subunit of nuclear factor kappa B (NFκB). We ...
Interpreting cohesive forms in the context of discourse inference

In this thesis, we present analyses and algorithms for resolving a variety of cohesive phenomena in natural language, including VP-ellipsis, gapping, event reference, tense, and pronominal reference. Past work has attempted to explain the complicated behavior of these expressions with theories that operate within a single module of language processing. We argue that such approaches cannot be maintained; in particular, the data we present strongly suggest that the nature of the coherence relation operative between clauses needs to be taken into account. We provide a theory of coherence relations and the discourse inference processes that underly their recognition. We utilize this theory to break the deadlock between syntactic and semantic approaches to resolving VP-ellipsis. We show that the data exhibits a pattern with respect to our categorization of coherence relations, and present an account which predicts this pattern. We extend our analysis to gapping and event reference, and show that our analyses result in a more independently-motivated and empirically-adequate distinction among types of anaphoric processes than past analyses. We also present an account of VP-ellipsis resolution that predicts the correct set of strict and sloppy readings for a number of benchmark examples that are problematic for past approaches. The correct readings can be seen to result from a general distinction between referring and copying in anaphoric processes. The account also extends to other types of reference, such as event reference and 'one'-anaphora. Finally, we utilize our theory of coherence in analyses that break the deadlock between definite-reference and coherence-based approaches to tense and pronoun interpretation. We present a theory of tense interpretation that interacts with discourse inference processes to predict data that is problematic for both types of approach. We demonstrate that the data commonly cited in the pronoun interpretation literature also exhibits a pattern with respect to coherence relations, and make some preliminary proposals for how such a pattern might result from the properties of the different types of discourse inference we posit.
"Thrombin" receptor-directed ligand accounts for activation by thrombin of platelet phospholipase C and accumulation of 3-phosphorylated phosphoinositides.

Using three experimental approaches, we have addressed the questions of whether the presence of saturably bound thrombin plays a role in potentiating the activation of platelet phospholipase C (PLC) and/or accumulation of the 3-phosphorylated phosphoinositides (3-PPI), i.e. phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, and whether the generation of tethered ligand (Vu, T-K.H., Hung, D. T., Wheaton, V. I., and Coughlin, S. R. (1991) Cell 64, 1057-1068) by thrombin can account fully for thrombin's proteolytic effects in activating platelets, as gauged by the above parameters. We have 1) measured PLC activation or 3-PPI after we have exposed platelets to thrombin for various periods and either blocked thrombin's proteolytic activity without interrupting its binding or blocked both binding and proteolytic activity of thrombin; 2) attempted to potentiate 3-PPI accumulation, using combinations of protein kinase C stimulation, Ca2+ elevation, and saturating but proteolytically inactive thrombins; and 3) compared the activation of platelets by thrombin with activation by the "thrombin" receptor-directed peptide, SFLLRNPNDKYEPF (SFLL; a portion of the tethered ligand created by thrombin's proteolytic activity), and examined the effect of thrombin on this latter activation. We conclude that the initial and sustained effects of thrombin in stimulating PLC and the accumulation of 3-PPI are completely attributable to thrombin's proteolytic activity. Further, thrombin's effects in promoting these responses can be accounted for by the actions of SFLL peptide, and by implication, formation of tethered ligand.
Adaptive locally optimal detection using RBF neural network

This paper addresses the application of locally optimum (LO) signal detection techniques to environments in which the noise density is not known a priori. For small signal levels, the LO detection rule is shown to involve a nonlinearity which depends on the noise density. The estimation of the noise density is a major part of the computational burden of LO detection rules. In this paper, adaptive estimation of the noise density is implemented using a radial basis function (RBF) neural network. Unlike existing algorithms, the present technique places few assumptions on the properties of the noise, and performs well under a wide variety of circumstances. Experimental results are shown which illustrate the system performance as a variety of noise densities are encountered. >
Mental health literacy among young people in a small US town: recognition of disorders and hypothetical helping responses

Aim: Mental health literacy may be a factor in early detection and prompt treatment for mental, emotional and behavioural disorders among young people. Building on previous research in Australia, this study assessed aspects of mental health literacy among adolescents in classrooms in a small town in the eastern USA. Methods: The students were provided brief, hypothetical, gender-matched scenarios about adolescents experiencing negative emotions and exhibiting related behaviours; some scenarios depicted diagnosable disorders. The respondents were asked to characterize each scenario as describing a mental health problem or other teen problem and indicate how they would respond to a peer who had such a problem. Results: Overall levels of recognition of mental disorders were low (27.5% identified anxiety and 42.4% identified depression as ‘a mental health problem or illness’). However, the respondents who recognized a disorder were three to four times more likely than those who did not to say they would take some helping action, such as telling an adult about the problem (depression: odds ratio 3.27; CI 1.43–7.46, anxiety: OR 4.43; CI 2.23–8.79). Few students (27.7%) remembered in-class discussions of mental health, a mandated health topic for schools in their area. Conclusions: There appears to be substantial room for improvement in mental health literacy among young people, and the development of interventions to enhance mental health literacy among students may be justified.
Algorithm evaluation for synchronous data compression

Summary form only given. As part of an industry standardization effort, we have evaluated compression algorithms for throughput enhancement in a synchronous communication environment. Synchronous data compression systems are link layer compressors used between digital transmission devices in internetworks to increase effective throughput. Compression is capable of speeding such links, but achievable performance is effected by interaction of algorithm, the networking protocols, and implementation details. The compression environment is different from traditional file compression in inducing a trade-off between compression ratio, compression time, and the performance metric (network throughput). In addition, other parameters and behavior are introduced, including robustness to data retransmission and multiple interleaved streams. Specifically, we have evaluated the following issues through both synchronous queuing and direct network simulation: (1) relative algorithm capability; (2) throughput improvement for various algorithms as a function of compression processor capability; (3) the impact of multiple compression context; (4) protocol interactions; and (5) specialized algorithms.
PIR1, a novel phosphatase that exhibits high affinity to RNA . ribonucleoprotein complexes.

Protein tyrosine phosphatases are involved in the regulation of important cellular processes such as signal transduction, cell cycle progression, and tumor suppression. Here we report the cloning and characterization of PIR1, a novel member in the dual-specificity phosphatase subfamily of the protein tyrosine phosphatases. PIR1 also contains two stretches of arginine-rich sequences. We have shown that the recombinant PIR1 protein possessed an intrinsic phosphatase activity on phosphotyrosine-containing substrate. A unique feature of this phosphatase is that it binds directly to RNAin vitro with high affinity. In addition, we have found that PIR1 interacted with splicing factors 9G8 and SRp30C, possibly through an RNA intermediate during a yeast two-hybrid screen. PIR1 exhibited a nuclear-staining pattern that was sensitive to RNase A, but not to DNase I, suggesting that PIR1 in the cells are associated with RNA and/or ribonucleoprotein particles. Furthermore, a fraction of PIR1 showed a speckle-staining pattern that superimposed with that of the splicing factor, SC35. Taken together, our data suggest that PIR1 is a novel phosphatase that may participate in nuclear mRNA metabolism.
A novel role of RGS9: inhibition of retinal guanylyl cyclase.

Cyclic GMP plays a key role in retinal phototransduction and its photoreceptor concentration is precisely controlled by the cooperative action of cGMP phosphodiesterase (PDE) and retinal guanylyl cyclase (retGC). However, studies of the relationship between these two systems have focused only on a Ca2+-mediated, indirect connection. This article summarizes our studies strongly suggesting that RGS9-1 is directly involved in the cooperative action of PDE and retGC, and that this ingenious mechanism plays an important role in tuning of cGMP concentration in photoreceptors. (Mol Cell Biochem 230: 125–128, 2002)
A Mathematical Modeling of Pure, Recursive Algorithms

This paper follows previous work on the Formal Language of Recursion FLR and develops intensional (algorithmic) semantics for it: the intension of a term t on a structure A is a recursor, a set-theoretic object which represents the (abstract, recursive) algorithm defined by t on A. Main results are the soundness of the reduction calculus of FLR (which models faithful, algorithm-preserving compilation) for this semantics, and the robustness of the class of algorithms assigned to a structure under algorithm adjunction.
Specific placement of tryptophan in the catalytic sites of Escherichia coli F1-ATPase provides a direct probe of nucleotide binding: maximal ATP hydrolysis occurs with three sites occupied.

Abstract Residue beta Y331 of Escherichia coli F1-ATPase is known from previous affinity labeling, mutagenesis, and lin-benzo-ADP binding experiments to interact directly with the adenine moiety of substrates bound in catalytic sites. Here we mutagenized beta Y331 to tryptophan. Mutant cells grew well on succinate or limiting glucose; purified mutant F1 had kappa cat/Km and lin-benzo-ADP binding characteristics similar to wild type. Fluorescence from beta W331 residues exhibited a maximum at 349 nm, indicating a polar environment in unoccupied sites. ATP, ADP, or AMPPNP caused virtually complete quenching of beta W331 fluorescence, so that the fluorescence of mutant F1 with occupied catalytic sites resembled that of wild-type enzyme. Therefore the beta W331 fluorescence provided a direct probe of nucleotide binding to catalytic sites under true equilibrium conditions. We measured ATP binding and hydrolysis in parallel experiments and found that occupancy of one or two catalytic sites per F1 molecule did not yield significant rates of hydrolysis while occupancy of all three sites yielded Vmax rates. Km(ATP) was similar to Kd3, the Kd for ATP binding to the third catalytic site. We also measured AMPPNP and ADP binding parameters. For ADP, the "on" rate at the first catalytic site was much faster (> or = 5 x 10(5) M-1 s-1) than seen previously by centrifuge column procedures, although the Kd was not much changed. For AMPPNP, the "on" rate at the first site was 2 orders of magnitude less than for ADP or ATP, and the Kd was similar to that for ADP.
Female Transfer: A Technique to Produce Genetically Identifiable Families with Tilapia Aurea

(1985). Female Transfer: A Technique to Produce Genetically Identifiable Families with Tilapia Aurea. The Progressive Fish-Culturist: Vol. 47, No. 3, pp. 190-192.
Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

Background: Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. Objective: The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel®; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. Methods: A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. Results: Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. Conclusions: Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination of amlodipine/ benazepril can be successfully accomplished in the majority of patients.