cssi/SciSciGPT-SciSciNet huggingface dataset:
Sequential Logic Circuits

A sequential circuit consists of logic gates and flip-flops. A flip-flop (ff) is a bistable device that has two outputs. One output indicates the true variable of the output, and the other indicates its complement. Such a device is used to store one bit of information. In concept, a sequential circuit uses logic gates to provide the control functions, and it uses flip-flops to store the digital signals. If the output of an ff changes as soon as its input changes, it is called an asynchronous ff. If the output of an ff changes as its input changes but is controlled by a clock, it is a synchronous ff. An asynchronous ff requires no clock, but a synchronous one does. A synchronous ff has a clock input in addition to its data inputs. Thus, the data inputs and clock input jointly control the timing of the change in its output voltage. By grouping an ordered set of flip-flops, we obtain a register. Thus, a register is used to store many bits where each ff is a one-bit storage cell in a register. The length of a register is the number of bits that can be stored. Precisely, an eight-bit register can store eight bits, a 16-bit register can store 16 bits, and a 32-bit register can store 32 bits. If the output of register A is connected to the input of register B, the presence of a clock at the input can transfer the bits from register A to register B. The bits in register A remain after the operation.
Relationship Between Cardiac Work and Cardiac Growth: Some General Thoughts on Cardiac Hypertrophy

The fundamental relation between myocardial work conditions and energetics can be expressed as: $$E = A + f(P,t) + \alpha .\bar \Delta L + W$$ (1)
Bovine and Feline Immunodeficiency Viruses

Both bovine immunodeficiency virus (BIV) and feline immunodeficiency virus (FIV) are prevalent worldwide and cause clinical diseases in their natural host. The genomic sequences are quite different between BIV and FIV. Both viruses infect lymphocytes and cause disease associated with lymphocyte dysfunction. The severity of the clinical diseases caused by BIV infection in cattle is milder and less consistent than those caused by FIV infection in domestic cats. In addition, FIV-infected cats have major CD4 + T-cell loss like HIV-1-infected humans. Consequently, FIV infection of cats is considered to be an excellent small animal model for HIV-1/AIDS. Commercial BIV vaccine and antiviral drug against BIV are currently unavailable. Thus, prevention and control of BIV infection is dependent on the management practices and policies set by cattle industry. Although commercial antiviral drug against FIV is still unavailable, commercial FIV vaccine was released in USA in 2002 and in Australia and New Zealand in 2005. FIV causes an important disease in domestic pet cats. Since stray are the major reservoir of FIV infection, commercial vaccine should be useful in preventing the spread of FIV infection in pet cat population.
Finessing King Neptune: Fisheries Management and the Limits of International Law

The shared uses of the world's oceans includes a broad spectrum of activities. Ships routinely navigate off the shores of virtually every coastal nation and their activities run the gamut from fishing to commerce, recreation, navigation, and military activities - all of which rely on the principle of mare liberum, or freedom of the high seas. Regulating the activities of these many vessels, flying the flags of different sovereign states, on the high seas - the paridigmatic international commons - poses a unique set of challenges for the international legal system. Of these many challenges, managing the mobile fish stocks that straddle zones of national jurisdiction and the international commons is perhaps the most complicated. Managing these resources raises practical questions about who has the authority to make and enforce rules as well as more theoretical questions about the contours of a State's sovereignty over vessels flying its flags. Taken to its logical end, mare liberum implies a right to fish straddling stock to extinction. Each State has an equal right to exploit the resources of the high seas, and no State has authority to regulate the activities of another State's nationals on the high seas. States vary in their commitment to fisheries protection, and no State wants to disadvantage its nationals in the international arena. Unless international law devises a legal framework capable of imposing consistent conservation measures on high seas straddling stocks, mare liberum will drive these stocks towards extinction, either actual or commercial. This paper uses the interaction between the competing international norms of mare liberum and environmental stewardship in the context of high seas fisheries management to explore fundamental questions of sovereignty and of international law. In particular, I ask whether the fisheries management regime proposed by the 1995 Straddling Stock Agreement can solve this regulatory puzzle in a manner consistent with generally accepted notions of national sovereignty in an international context. In answering that question, I propose a new vision of high seas fisheries management, one that reconciles the apparent contradiction between mare liberum and environmental stewardship.
Imaging of Cerebrospinal Fluid Shunts, Drains, and Diversion Techniques

This chapter reviews the diagnostic imaging findings related to the procedures and devices used for managing cerebrospinal fluid diversion, including external ventricular drains, ventriculoperitoneal shunts, atypical ventricular shunts, ventriculosubgaleal shunts, ventriculo-cisternal shunts, percutaneously accessed cerebrospinal fluid reservoirs, subduralperitoneal shunts, cystoperitoneal and cystoventriculostomy shunts. cystoperitoneal and cystoventriculostomy shunts, cystoperitoneal and cystoventriculostomy shunts, third ventriculocisternostomy, endoscopic septum pellucidum and intraventricular cyst fenestration, aqueductoplasty, endoscopic choroid plexus cauterization, complications related to cerebrospinal fluid diversion surgeries, and Chiari decompression surgery and associated complications.
Mixed H 2 /H ∞ Data-Driven Control Design for Hard Disk Drives

A frequency based data-driven control design considering mixed $H_{2}$ / $H$ ∞ control objectives is developed for multiple input-single output systems. The main advantage of the data-driven control over the model-based control is its ability to use the frequency response measurements of the controlled plant directly without the need to identify a model for the plant. In the proposed methodology, multiple sets of measurements can be considered in the design process to accommodate variations in the system dynamics. The controller is obtained by translating the mixed $H_{2}$ / $H$ ∞ control objectives into a convex optimization problem. The H∞ norm is used to shape closed loop transfer functions and guarantee closed loop stability, while the $H$ 2 norm is used to constrain and/or minimize the variance of signals in the time domain. The proposed data-driven design methodology is used to design a track following controller for a dual-stage Hard Disk Drive (HDD), based on the sensitivity decoupling structure.
Nonlinear Imaging using Object-Dependent Illumination

Nonlinear imaging systems can surpass the limits of linear optics, but nearly all rely on physical media and atomic/molecular response to work. These materials are constrained by their physical properties, such as frequency selectivity, environmental sensitivity, time behavior, and fixed nonlinear response. Here, we show that electro-optic spatial light modulators (SLMs) can take the place of traditional nonlinear media, provided that there is a feedback between the shape of the object and the pattern on the modulator. This feedback creates a designer illumination that generalizes the field of adaptive optics to include object-dependent patterns. Unlike physical media, the SLM response can provide a wide range of mathematical functions, operate over broad bandwidths at high speeds, and work equally well at high power and single-photon levels. We demonstrate the method experimentally for both coherent and incoherent light.
Pathologic complete response and serial circulating tumor cell monitoring during neoadjuvant therapy in nonmetastatic triple-negative breast cancer patients.

e12111Background: ARTEMIS (A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival) is a randomized trial to determine if precision guided neoadjuvant chemotherapy (NAC)...
Biogeochemical and physical controls on methane fluxes from two ferruginous meromictic lakes

Meromictic lakes with anoxic bottom waters often have active methane cycles whereby methane is generally produced biogenically under anoxic conditions and oxidized in oxic surface waters prior to reaching the atmosphere. Lakes that contain dissolved ferrous iron in their deep waters (i.e., ferruginous) are rare, but valuable, as geochemical analogues of the conditions that dominated the Earth's oceans during the Precambrian when interactions between the iron and methane cycles could have shaped the greenhouse regulation of the planet's climate. Here, we explored controls on the methane fluxes from Brownie Lake and Canyon Lake, two ferruginous meromictic lakes that contain similar concentrations (max. >1 mM) of dissolved methane in their bottom waters. The order Methanobacteriales was the dominant methanogen detected in both lakes. At Brownie Lake, methanogen abundance, an increase in methane concentration with respect to depths closer to the sediment, and isotopic data suggest methanogenesis is an active process in the anoxic water column. At Canyon Lake, methanogenesis occurred primarily in the sediment. The most abundant aerobic methane-oxidizing bacteria present in both water columns were associated with the Gammaproteobacteria, with little evidence of anaerobic methane oxidizing organisms being present or active. Direct measurements at the surface revealed a methane flux from Brownie Lake that was two orders of magnitude greater than the flux from Canyon Lake. Comparison of measured versus calculated turbulent diffusive fluxes indicates that most of the methane flux at Brownie Lake was non-diffusive. Although the turbulent diffusive methane flux at Canyon Lake was attenuated by methane oxidizing bacteria, dissolved methane was detected in the epilimnion, suggestive of lateral transport of methane from littoral sediments. These results highlight the importance of direct measurements in estimating the total methane flux from water columns, and that non-diffusive transport of methane may be important to consider from other ferruginous systems.
Knee synovial fluid complement C3-β chain levels correlate with clinical symptoms of knee osteoarthritis.

Aim Early research found innate immune factor complement C3 in the synovial fluid (SF) and activated in serum of osteoarthritis (OA) patients. Whether synovial C3 comes from circulation, or is produced locally, is still unknown. It is also unclear whether synovial and circulating C3 is responsible to OA symptoms. A native C3 molecule consists of two chains, C3-α and C3-β. Small fragments breaking down from C3-α chain in serum and SF were reported to be related to OA severity. Little is known if C3-β chain is involved in the pathogenesis. Method In this study, we evaluated these important areas by biochemical analyses of C3-α and C3-β chains in both the SF and plasma of OA patients. Results Our results showed that C3-α and C3-β levels in SF did not correlate with those in plasma, suggesting that synovial C3 is independently and locally produced, rather than being "leaked" from circulation. Synovial C3-β but not C3-α levels correlated with pain, other OA symptoms, function in daily living, and sports/recreational activities. Plasma C3-β levels only marginally correlated with pain, and plasma C3-α levels did not correlate with any of these OA symptoms. Conclusion We present first-hand evidence that the clinical symptoms of OA are mainly associated with C3 in the local SF rather than systemic circulation, suggesting local factors in the etiopathogenesis. Future local targeted therapies for pain management may be more effective and safer.
War Zones and Depraved Violence: Exploring the Framing of Urban Neighborhoods in News Reports of Violent Crime:

This study examines the role that the news media play in casting certain urban neighborhoods as particularly violent areas. It is possible that the news media serve as a key source of information a...
1 – Finite Differences

Publisher Summary Digital computer is not suited to perform computation by way of calculus. The automatic programming of the fundamental theorem of the integral calculus on the digital computer is a formidable, if not impossible, task of providing the computer with a symbolic list of functions and the corresponding antiderivatives, that is, a table of indefinite integrals, establishing a procedure for enlarging upon this list through combinations and substitutions, and having the computer decide when the integral can or cannot be expressed in terms of the listed functions. Moreover, even if the computer succeeds in expressing the integral in terms of these functions, a considerable amount of arithmetic still lies ahead as the integral that can become vastly involved need to be evaluated at the limits of integration. Integral calculus is most potent, and hence its triumph in the precomputer days, in mental and hand computations of reasonable integrals that can be expressed in terms of common elementary functions. It is utterly unsuitable for automatic programming on the digital computer. This chapter describes finite difference schemes. Replacement of differentials by finite differences is the paramount step in the algebraization of the differential equation. The chapter presents error analysis, in which Taylor's theorem plays the central role. Errors are inherent in replacing differentials by finite differences. The chapter discusses the factors these errors depend on.
We Need a Better System

Mental health is a topic of growing interest but there is no crisis. Rates of mental illness are stable, while demand is escalating. Increases in help-seeking could be a function of rising perceived value of mental health and wellness programming. However, at the same time, there are signs that some forms of stigma could be increasing. In this chapter, I suggest that the risk paradigm, which dominates our cultural narratives and political policy, is restricting opportunities to capitalize on the growing interest in wellness. I introduce Stepped Care 2.0 as an efficient and sustainable model for shifting beyond the risk paradigm. Stepped Care 2.0 shows promise for eliminating treatment wait-lists and ensuring more upstream support for anyone who is interested in improving their mental health.
Precipitated Δ9-THC withdrawal reduces motivation for sucrose reinforcement in mice.

Abstract Withdrawal from Δ9-tetrahyrocannibidol (THC) is associated with a host of dysphoric symptoms that increase probability of relapse. To date, many animal models of THC withdrawal rely on withdrawal-induced somatic withdrawal signs leaving withdrawal-suppressed behavior relatively unexplored. As compared with withdrawal-induced behaviors, ongoing behavior that is suppressed by withdrawal is a useful behavioral endpoint because it 1) more effectively models the subjective aspects of withdrawal and 2) identifies pharmacotherapies that restore behavior to baseline levels, rather than eliminate behavior induced by withdrawal. The current study assessed effects of spontaneous and rimonabant-precipitated THC withdrawal in mice responding on a progressive-ratio (PR) schedule of sucrose water reinforcement. Once behavior stabilized, male and female mice were administered THC (10 mg/kg, s.c.) or vehicle for five or six days. THC was either discontinued and behavior monitored for three days during abstinence, or the CB1 antagonist rimonabant (2 mg/kg, i.p.) was used to precipitate withdrawal. Whereas spontaneous THC withdrawal had no effect on PR performance, THC-treated mice were differentially sensitive to rimonabant administration via large decreases in break point, overall response rate, and run rate relative to vehicle-treated mice. Importantly, pretreatment with the CB1 positive allosteric modulator ZCZ011 (10 mg/kg, i.p.) did not prevent precipitated-withdrawal-induced behavioral impairment. These extend findings of earlier studies suggesting operant baselines are useful tools to study subjective effects of cannabinoid withdrawal. Additionally, operant baselines allow withdrawal pharmacotherapies to be tested in a restoration-of-function context, which may be more sensitive, selective, and clinically relevant.
Computationally modeling mammalian succinate dehydrogenase kinetics identifies the origins and primary determinants of ROS production.

Succinate dehydrogenase (SDH) is an inner mitochondrial membrane protein complex that links the Krebs cycle to the electron transport system. It can produce significant amounts of superoxide ( O 2 · ¯ ) and hydrogen peroxide (H2O2); however, the precise mechanisms are unknown. This fact hinders the development of next-generation antioxidant therapies targeting mitochondria. To help address this problem, we developed a computational model to analyze and identify the kinetic mechanism of O 2 · ¯ and H2O2 production by SDH. Our model includes the major redox centers in the complex, namely FAD, three iron-sulfur clusters, and a transiently bound semiquinone. Oxidation state transitions involve a one- or two-electron redox reaction, each being thermodynamically constrained. Model parameters were simultaneously fit to many data sets using a variety of succinate oxidation and free radical production data. In the absence of respiratory chain inhibitors, model analysis revealed the 3Fe-4S iron-sulfur cluster as the primary O 2 · ¯ source. However, when the quinone reductase site is inhibited or the quinone pool is highly reduced, O 2 · ¯ is generated primarily by the FAD. In addition, H2O2 production is only significant when the enzyme is fully reduced, and fumarate is absent. Our simulations also reveal that the redox state of the quinone pool is the primary determinant of free radical production by SDH. In this study, we showed the importance of analyzing enzyme kinetics and associated side reactions in a consistent, quantitative, and biophysically detailed manner using a diverse set of experimental data to interpret and explain experimental observations from a unified perspective.
Fatigue performance of additive manufactured metals under variable amplitude service loading conditions including multiaxial stresses and notch effects: Experiments and modelling

Abstract Additive manufacturing technology has gained significant attention in recent years. However, due to lack of sufficient understanding of their fatigue behavior under service loading conditions, design of critical load carrying parts using this technique is still at early stages. These conditions include multiaxial stress states, notches and stress concentrations, and variable amplitude load cycles. Some of the distinguishing features of AM metals as compared to the conventionally fabricated metals include defects, surface roughness, anisotropy and build orientation effects, and residual stresses due to the fast solidification during the fabrication process. These factors resulting from AM processes may significantly affect the fatigue performance of AM parts under multiaxial variable amplitude loading. In this work, unnotched and notched fatigue behavior of two commonly used AM metals with different surface roughness conditions were studied under variable amplitude multiaxial loads. Both crack initiation approach using critical plane-based model and fracture mechanics approach using crack growth from the rough surface or surface defects at the notch were used to estimate the fatigue lives. Fatigue estimations are then compared to the experimental results.
Poverty Suburbanization, Job Accessibility, and Employment Outcomes

The last decade of urbanization throughout many cities have seen a perceptible shift in the demand for centralized urban amenities while poverty has increasingly decentralized. Yet, the opportunity landscape of these shifting geographies of poverty and prosperity are not well understood. In this article, we examine how access to employment for low-income households has been impacted as a result of these changing geographies. Using a case study on the Charlotte metropolitan area we examine whether the suburbanization of poverty and reinvestment in the center city has reshaped the job opportunity landscape for low-wage residents. The objectives of this article are twofold. First, we calculate and map autobased accessibility from all neighborhoods in the Charlotte metropolitan area to job locations, differentiated by wage categories, in 2010 and 2017 to identify potential changes in the mismatch between low-income households and access to employment. We use a point-level employment dataset for these two years and calculate accessibility originating from census block groups. Second, we estimate the extent to which access to employment has affected employment rates and household incomes at the neighborhood level using a first-difference, spatial two-stage least squares model with instrumental variables. Our findings suggest that changes in accessibility had no significant effect on changes in neighborhood employment rates. However, we find evidence that increasing accessibility for lower-income households could have a positive effect on neighborhood median household incomes. Overall, the polycentric nature of Charlotte appears to have reduced the spatial mismatch between low-income workers and low-wage jobs.
Foreign Demand and Local House Prices: Evidence from the US

We test whether foreign demand matters for local house prices in the US using an identification strategy based on the existence of 'home bias abroad' in international real estate markets. Following an extreme political crisis event abroad, a proxy for a strong and exogenous shift in foreign demand, we show that house prices rise disproportionately more in neighbourhoods with a high concentration of population originating from the crisis country. This effect is strong, persistent, and robust to the exclusion of major cities. We also show that areas that were already expensive in the late 1990s have experienced the strongest foreign demand shocks and the biggest drop in affordability between 2000 and 2017. Our findings suggest a non-trivial causal effect of foreign demand shocks on local house prices over the last 20 years, especially in neighbourhoods that were already rather unaffordable for the median household.
Future of Education or Present Reality

Context - The main focus of education in most pathology residency and subspecialty pathology fellowships is the light microscopic examination of pathology specimens. Classes with multiheaded scopes are the most popular among pathology trainees. Until recently, it was difficult to us to imagine that this educational approach could change. In the beginning of March 2020 our country faced a serious challenge, which all of us now known as coronavirus disease 2019 (COVID-19) pandemic. The rules of social distancing and work from home were applied. These types of restrictions were implemented in almost all parts of our life including work and pathology education. Objective - To share our experience in the Department of Hematopathology at The University of Texas MD Anderson Cancer Center during COVID-19 pandemic. We describe our experience in modifying our approaches to education. We show how we overcame many obstacles to learning by building one of the largest virtual hematopathology educational platforms via Cisco WebEx and using social media, in particular Twitter. These tools facilitated the learning of hematopathology by medical students, pathology trainees, and practicing pathologists from all over the world. Data Sources - During the three months of the pandemic (April, May and June 2020), we evaluated the visitors' attendance to MD Anderson Cancer Center Hematopathology Virtual Educational Platform using data collected by Cisco WebEx website. For examination of the impact of the hematopathology community on Twitter on medical education the analytic metrics obtained from Symplur LLC (www.symplur.com, 04/27/2020) were used via its Symplur Signals program. Conclusions - Our experience using the MD Anderson Hematopathology Virtual Platform showed that there is substantial, global interest and desire for virtual hematopathology education, especially during the pandemic time.
Case Report: Dual Target Deep Brain Stimulation With Externalized Programming for Post-traumatic Complex Movement Disorder.

Introduction: Movement disorders can be common, persistent, and debilitating sequelae of severe traumatic brain injury. Post-traumatic movement disorders are usually complex in nature, involving multiple phenomenological manifestations, and can be difficult to control with medical management alone. Deep brain stimulation (DBS) has been used to treat these challenging cases, but distorted brain anatomy secondary to trauma can complicate effective targeting. In such cases, use of diffusion tractography imaging and inpatient testing with externalized DBS leads can be beneficial in optimizing outcomes. Case Description: We present the case of a 42-year-old man with severe, disabling post-traumatic tremor who underwent bilateral, dual target DBS to the globus pallidus internus (GPi) and a combined ventral intermediate nucleus of the thalamus (Vim)/dentato-rubro-thalamic tracts (DRTT) target. DRTT fiber tracts were reconstructed preoperatively to assist in surgical targeting given the patient’s distorted anatomy. Externalization and survey of the four leads extra-operatively with inpatient testing allowed for internalization of the leads that demonstrated benefit. Six months after surgery, the patient’s tremor and dystonic burden had decreased by 67% in the performance sub-score of The Essential Tremor Rating Scale (TETRAS). Conclusion: A patient-tailored approach including target selection guided by individualized anatomy and tractography as well as extra-operative externalized lead interrogation was shown to be effective in optimizing clinical outcome in a patient with refractory post-traumatic tremor.
Securing stent during multi-stage laryngotracheoplasty--an evolved technique.

Abstract Background Multi-stage laryngotracheoplasty (LTP) typically requires a stent be secured to the airway for 2–6 weeks. Our technique has evolved over time to securing the stent to the strap muscles and tying a series of knots long enough to leave the suture tail protruding through the skin incision, which simplifies stent removal. Methods Retrospective chart review. Results Twenty-four patients underwent multi-stage LTP at our institution from 2007 to 2013. Eight patients were excluded from the study because they either did not have a stent placed (n = 4), or they had a t-tube placed which was not sutured in place (n = 4). Of the remaining 16 patients, 62.5% (n = 10) had their stent secured via sutures which were buried below the skin, and 37.5% (n = 6) via a long suture tail which was left protruding through the end of the skin incision. An incision was required for stent removal 100% of buried sutures patients, and 33% of exposed suture patients (p = 0.0009). Average operative time for stent removal was 60 min in the buried sutures group, and 25 min in the exposed sutures group (p = 0.0075). Conclusions Securing stents via an exposed suture technique decreases the need for making a skin incision during the second stage of the operation, and significantly decreases the operative time of the second stage.
Catecholamine metabolism and digital circulation after histamine and its analogue. Krypton clearance and calorimetric blood flow.

In 1959 (1) we reported the paradoxical effects on the digital circulation of histamine administered parenterally and of an orally ingested histamine analogue* (2). Both histamine and its analogue produced vasodilatation of the capillaries as manifested by flushing contrasted with vasoconstriction of the arteriovenous anastomoses (AVAS). It was postulated at that time that the AVA constricted in response to heat loss produced by histamine-mediated precapillary sphincter and hence capillary vasodilatation. The question as to whether the AVA constriction was a neural reflex or produced by some other mechanism such as the release of catecholamines (CM) from nerve endings and/or chrcmaff in tissues remained unanswered (3).
Data dependent concentration bounds for sequential prediction algorithms

We investigate the generalization behavior of sequential prediction (online) algorithms, when data are generated from a probability distribution. Using some newly developed probability inequalities, we are able to bound the total generalization performance of a learning algorithm in terms of its observed total loss. Consequences of this analysis will be illustrated with examples.
Scenario Analysis of Hybrid Class 3-7 Heavy Vehicles

The effects of hybridization on heavy-duty vehicles are not well understood. Heavy vehicles represent a broader range of applications than light-duty vehicles, resulting in a wide variety of chassis and engine combinations, as well as diverse driving conditions. Thus, the strategies, incremental costs, and energy/emission benefits associated with hybridizing heavy vehicles could differ significantly from those for passenger cars. Using a modal energy and emissions model, they quantify the potential energy savings of hybridizing commercial Class 3-7 heavy vehicles, analyze hybrid configuration scenarios, and estimate the associated investment cost and payback time. From the analysis, they conclude that (1) hybridization can significantly reduce energy consumption of Class 3-7 heavy vehicles under urban driving conditions; (2) the grid-independent, conventional vehicle (CV)-like hybrid is more cost-effective than the grid-dependent, electric vehicle (EV)-like hybrid, and the parallel configuration is more cost-effective than the series configuration; (3) for CV-like hybridization, the on-board engine can be significantly downsized, with a gasoline or diesel engine used for SUVs perhaps being a good candidate for an on-board engine; (4) over the long term, the incremental cost of a CV-like, parallel-configured Class 3-4 hybrid heavy vehicle is about %5,800 in the year 2005 and $3,000 in 2020, while for a Class 6-7 truck, it is about $7,100 in 2005 and $3,300 in 2020; and (5) investment payback time, which depends on the specific type and application of the vehicle, averages about 6 years under urban driving conditions in 2005 and 2--3 years in 2020.
Corneal endothelial cell survival in organ cultures under acute oxidative stress: effect of VIP.

PURPOSE Human corneal endothelium, a neural crest-derived tissue, has a very limited regenerative capacity and may depend on trophic factors for its survival throughout life, as well as after injury and during storage before transplantation. The purpose of this study was to determine whether vasoactive intestinal peptide (VIP), a 28-amino acid neurotrophic factor present in human aqueous humor, promotes the survival of corneal endothelium in corneal organ cultures, and whether VIP is produced by the corneal endothelium. METHODS Thirteen viable human donor corneas that had been received from the Central Florida Lions Eye Bank and stored in preservation medium (Optisol-GS; Chiron Vision, Irvine, CA) at 4 degrees C for 8 to 17 days were bisected. Each half was treated with either 0 or 10 nM VIP (15 minutes) and subjected to H(2)O(2) (1.4 mM, 30 minutes) treatment at 37 degrees C. The numbers of live and dead corneal endothelial (CE) cells isolated from the corneas were then determined under fluorescence microscopy using a live-dead viability-cytotoxicity assay conducted by an observer uninformed of the treatment. The effect of VIP (10(-16) to 10(-6) M) on CE cell survival was also studied in fresh bovine corneas in situ, by using the same assay. The presence of VIP in the corneal endothelium in fresh human donor and bovine eyes was examined by immunocytochemistry, in situ hybridization, and Western blot analysis, whereas VIP in the bovine aqueous humor was assessed by radioimmunoassay. RESULTS VIP (10 nM) significantly increased CE survival in 10 of 13 human corneas. The mean survival of CE cells (+/-SEM) was 42% +/- 3% in control corneas versus 59% +/- 3% in VIP-treated corneas (P < 0.001). In bovine corneas, VIP at concentrations as low as 10(-10) M demonstrated a significant protective effect. The mean number of dead CE cells on bovine corneas was maximally decreased by 10(-6) M VIP from 46 +/- 5 to 18 +/- 3 per field. In CE cells from fresh human and bovine corneas, VIP immunoreactivity and mRNA were detected. VIP was also present in bovine aqueous humor at 40 +/- 8 pM. CONCLUSION VIP may be an autocrine trophic factor that protects CE cells from H(2)O(2) in normal aqueous humor and possibly from other oxidative insults.
A probabilistic model for analysing species co-occurrence

Aim To develop a new probabilistic model that can be used to test for statistically significant pair-wise patterns of species co-occurrence. The model gives the probability that two species would co-occur at a frequency less than (or greater than) the observed frequency if the two species were distributed independently of one another among a set of sites. The model can be used to classify species associations as negative, positive or random. Innovation Historically, the analysis of species co-occurrence has involved the use of data randomization. An observed species presence–absence matrix is compared with randomized matrices to determine if the observed matrix has structure, either an excess or deficit of species positively or negatively associated with each other. The computer algorithms used to randomize matrices can sometimes produce Type I and Type II errors (when the randomization algorithm produces a biased set of all possible matrices) due to the randomization process itself. The probabilistic model does not rely on any data randomization, hence it has a very low Type I error rate and is powerful having a low Type II error rate. Main conclusions When applied to 10 different data sets the probabilistic model revealed significant positive and negative species associations in most of the data sets. Compared with previous analyses the model tended to find fewer significant associations; this may indicate a generally low rate of Type I error in the model. The model is easy to implement and requires no special software. The model could potentially transform the way that ecologists test for species co-occurrence in a wide range of ecological studies.
Pathophysiology of allergic inflammation

Allergic inflammation is due to a complex interplay between several inflammatory cells, including mast cells, basophils, lymphocytes, dendritic cells, eosinophils, and sometimes neutrophils. These cells produce multiple inflammatory mediators, including lipids, purines, cytokines, chemokines, and reactive oxygen species. Allergic inflammation affects target cells, such as epithelial cells, fibroblasts, vascular cells, and airway smooth muscle cells, which become an important source of inflammatory mediators. Sensory nerves are sensitized and activated during allergic inflammation and produce symptoms. Allergic inflammatory responses are orchestrated by several transcription factors, particularly NF-κB and GATA3. Inflammatory genes are also regulated by epigenetic mechanisms, including DNA methylation and histone modifications. There are several endogenous anti-inflammatory mechanisms, including anti-inflammatory lipids and cytokines, which may be defective in allergic disease, thus amplifying and perpetuating the inflammation. Better understanding of the pathophysiology of allergic inflammation has identified new therapeutic targets but developing effective novel therapies has been challenging. Corticosteroids are highly effective with a broad spectrum of anti-inflammatory effects, including epigenetic modulation of the inflammatory response and suppression of GATA3.
Animal models of inhibitors.

Summary. Antibody responses to clotting factorconcentrates remain a major treatment limitation.In conjucation with ongoing clinical studies, thepathogenesis and potential treatment of clottingfactor immune responses is being evaluated in avariety of animal models.Keywords: Hemophilia, inhibitors, immunity, factorVII, animal models Introduction In 2010, the most important treatment-related com-plication of coagulation factor replacement is thedevelopment of neutralizing antibodies to the ther-apeutic protein. This complication occurs in approx-imately 25% of haemophilia A (HA) patients and3% of haemophilia B subjects. While signiﬁcantprogress has been made in our understanding of thepathogenic mechanisms involved in this phenome-non, much remains to be learnt.The investigation of the immune response tocoagulation factor exposure in human haemophili-acs is limited by a number of biological andpractical considerations. Thus, while it remainscritical to continue the evaluation of this treatmentcomplication in human populations, this experimen-tal approach will need to be complemented withobservations made in animal models of haemo-philia.This chapter focuses on three speciﬁc aspects of theimmuneresponse tofactors VIII (FVIII) and factor IX(FIX): the development of novel transgenic mousemodels to facilitate the characterization of thisprocess, the study of tolerance mechanisms in haem-ophilic mice and ﬁnally, the association of inhibitorswith haemophilia gene therapy studies.
Heat capacity of Ba1-xKxFe2As2, x=0 and 0.41

Heat-capacity measurements on exceptionally high-quality samples of Ba1-xKxFe2As2 give the values of a number of parameters relevant to the electronic structure, the structural/magnetic transition in the undoped parent compound, and the superconducting transition in the near optimally doped, x = 0.41 sample. In BaFe2As2 the changes in the lattice and magnetic structure appear as a single, sharp first-order transition at 140 K; the Sommerfeld coefficient is γ = 5.1 mJ K−2 mol−1. For the superconducting, x = 0.41, sample, the residual density of electron states in the superconducting states is essentially zero. The specific-heat anomaly at Tc suggests extreme strong coupling, with Δ(0)/kBTc ≈ 2.6, and a normal-state Sommerfeld coefficient γn ≈ 45 mJ K−2 mol−1.
Selective Packaging of Host tRNA's by Murine Leukemia Virus Particles Does Not Require Genomic RNA

Abstract The 4S RNA contained in RNA tumor virus particles consists of a selected population of host tRNA's. However, the mechanism by which virions select host tRNA's has not been elucidated. We have considered a model which specifies that 35S genomic RNA determines which tRNA's are to be encapsidated as well as the relative amounts of these tRNA's within the virion. The model was tested by comparing the free 4S RNA composition of normal murine leukemia virus (MuLV) particles and noninfectious virions from actinomycin D (ActD)-treated cells, which are deficient in genomic RNA (ActD virions). Viral 4S RNA was analyzed by two-dimensional polyacrylamide gel electrophoresis. Surprisingly, the patterns obtained for control and ActD 4S RNA were identical to each other and were clearly distinct from the cell 4S RNA pattern. The viral patterns had three prominent areas of radioactivity. One of the spots was identified on the basis of its oligonucleotide fingerprint as tRNA Pro, the primer for MuLV RNA-directed DNA synthesis. These results were obtained with two different MuLV strains, AKR and Moloney, each grown in SC-1 cells. The demonstration that ActD virions contain primer tRNA and in general exhibit the characteristic MuLV tRNA pattern rather than the complete representation of cell 4S RNA leads to the conclusion that genomic RNA is not the major determinant in selective packaging of host tRNA's. A possible role for one or more viral proteins, including reverse transcriptase, is suggested.
Multi-representation interaction for physically based modeling

For simulations involving complex objects, a number of different properties must be represented. An example of this is in modeling an object undergoing combustion---heat amounts, fuel consumption, and even object shape must be modeled and changed over time. Ideally we would put everything into a unified representation, but this is sometimes not possible/feasible due to measurement limitations or the suitability of a specific representation. In this paper we define a multi-representation framework for dealing with multiple properties and their interactions within an object. This model is especially useful in physically based modeling, where the time variation of some properties affect other properties including geometry or topology. As a motivating example case, we present a method for modeling decomposition of a burning object.
Topical steroid risk analysis: Differentiating between physiologic and pathologic adrenal suppression

AbstractBackground: Topical corticosteroids are a mainstay of therapy for inflammatory skin disorders. Hypothalamic–pituitary–adrenal (HPA) axis suppression is a potential systemic risk of topical steroid use. Our aim was to review available data on the risk of HPA axis suppression associated with long-term topical steroid use and to distinguish between pathologic and physiologic adrenal suppression.Methods: We performed a PubMed search for literature that evaluated the risk of HPA axis suppression associated with topical steroid use.Results: Fifteen of sixteen clinical trials reviewed did not report any pathologic adrenal suppression. In the single clinical trial that reported pathologic adrenal suppression, the patients used twice the maximum recommended amount of clobetasol propionate continuously for as long as 18 months. Physiologic adrenal suppression was seen as early as 1–2 weeks after treatment with class I–IV topical corticosteroids. In about half of these patients, cortisol levels spontaneously...
The structure of inosine 5'-monophosphate dehydrogenase and the design of novel inhibitors.

Abstract The enzyme IMPDH is a homotetramer of ∼55 kDa subunits and consists of a (β/α)8 barrel core domain and a smaller subdomain. The active site has binding pockets for the two substrates IMP and NAD. The enzymatic reaction of oxidation of IMP to XMP proceeds through a covalent mechanism involving an active site cysteine residue. This enzyme is a target for immunosuppressive agents because it catalyzes a key step in purine nucleotide biosynthesis which is important for the proliferation of lymphocytes. Several X-ray structures of inhibitors bound to IMPDH have been published. The uncompetitive IMPDH inhibitor MPA is the active metabolite of the immunosuppressive agent mycophenolate mofetil (CellCept®) which is approved for the prevention of acute rejection after kidney and heart transplantation. The bicyclic ring system of MPA packs underneath the hypoxanthine ring of XMP*, thereby trapping this covalent intermediate of the enzymatic reaction. Ribavirin monophosphate, the active metabolite of the antiviral agent ribavirin, is a substrate mimic of IMP. The structure of the two inhibitors 6-Cl-IMP and SAD binding in the IMP and NAD pockets of IMPDH, respectively, gives information for the binding mode of the di-nucleotide cofactor to the enzyme. At Vertex Pharmaceuticals a structure-based drug design program for the design of IMPDH inhibitors was initiated. Several new lead compound classes unrelated to other IMPDH inhibitors were found. Integrating structural information into an iterative drug-design process led to the design of VX-497. VX-497 is a potent uncompetitive enzyme inhibitor of IMPDH. The phenyl-oxazole moiety of the molecule packs underneath XMP*, analogous to MPA. VX-497 also makes several new interactions that are not observed in the binding of MPA. VX-497 is a potent immunosuppressive agent in vitro and in vivo. A Phase I clinical trial has been successfully concluded and the compound is currently in Phase II trials in psoriasis and hepatitis C. The rapid progress from initiation of the drug design program to a compound entering clinical trials illustrates the power of structure-based drug design to accelerate the drug discovery process. The structural information on IMPDH has also significantly increased our knowledge about the mechanistic details of this fascinating enzyme.
Human-Impacted Water Resources: Domain Stratification and Mapping To Determine Hydrologically Similar Units

Geographic Information Systems (GIS) and multivariate statistical analyses were used to partition the United States into Human Influenced Water Environmental Classes (HIWECs) for the purpose of determining hydrologically similar units within the conterminous United States. Such a framework could be used to investigate various categories of watersheds throughout the country or to establish observatory sites in variant hydrologies. These HIWECs represent areas that are relatively homogeneous with respect to the human influence variables of land cover, population density, and water use; the climate variables of temperature and precipitation; and the physical variables of slope, bedrock permeability, and soil permeability. These variables combine to characterize hydrologic condition and collectively represent the major hydrologic variability that exists across the U.S. GIS was first used to break each of the variables into low to high ranges. Multivariate statistics were then used to identify and cluster areas that share similar characteristics in multivariate data space. HIWECS can serve as a framework for development of water research and management; observatory sites can be selected to capture variant hydrologies that incorporate the human influence element with the criteria that each type of human-influenced hydrologic condition, or class, be represented.
The impact of decentralization on health workforce development in Papua New Guinea

Papua New Guinea decentralized a wide range of health functions to provincial governments between 1977 and 1983. The national Department of Health (DOH) was given no role in provincial budget and staffing decisions, and the national health budget was fragmented into the health components of provincial budgets. The impact of decentralization on health workforce development was particularly severe and largely unforeseen. Many difficulties were inherent in the manner in which decentralization regulations structured power relationships. Others arose as a result of the administrative confusion and inflamed relationships that accompanied the forceful transfer of power from a very reluctant national DOH to the provinces. Even though policy formulation and planning were retained as national functions, decentralization hampered their effective execution. Human resource data bases deteriorated, responsibility for planning became confused, and the ability of the DOH to implement its planning decisions was compromised. In reality, health workforce planning was carried out by the Departments of Finance and Planning, and Personnel Management through the annual budgetary process of provincial financial limits and staff ceilings, without any attempt to assess health service needs, either in the country as a whole or between the provinces. Decentralization brought a need for new management skills, and it complicated administrative relationships between training institutions and the provinces. The Papua New Guinea experience has shown that in a decentralized health service, there is a great potential for conflict between national goals and the aspirations of individual provinces. To achieve an equitable, appropriate and effective staffing of services, standards must be formulated as the basis for planning and conflict resolution. Effective linkages between central government departments and between the national and provincial health authorities must be developed, and management and technical skills of health managers improved.