cssi/SciSciGPT-SciSciNet huggingface dataset:
Toll-like Receptor 9 Activation Accelerates Inhibitor Formation in Response to Factor VIII

Inhibitor (neutralizing anti-drug antibody) formation against factor VIII (FVIII) is currently the most serious complication of FVIII replacement therapy for hemophilia A. The role of innate immune signals in this adaptive immune response is unclear. Lipopolysaccharide (LPS, the major component of the outer membrane in Gram-negative bacteria), which activates the innate immune sensor toll-like receptor 4 (TLR4), enhances inhibitor formation in hemophilia A mice. Intriguingly, earlier data suggested that activation of the endosomal DNA sensor TLR9 may actually suppress inhibitor formation. However, we demonstrated that a TLR9 agonist induced inhibitor formation against a factor IX transgene product in gene therapy for hemophilia B, which resulted from activation of monocyte-derived dendritic cells (moDCs) and enhancement of T follicular helper (Tfh) cell responses. Tfh cells drive germinal center (GC) formation and T cell help-dependent antibody formation. The aim of this study was to elucidate the role of TLR9 signaling in FVIII inhibitor formation in hemophilia A mice. Hemophilia A (F8e16-/-) B6/129 mice were co-injected IV (n=4) with FVIII (1.5 IU) and ODN-1826 (a class B CpG oligodeoxynucleotide, 50 µg), which is a TLR9 agonist, or injected on two consecutive days (n=3), first with ODN-1826 and then with FVIII on the next day. Control mice received FVIII only (n=5). Injections were performed once weekly for 4 weeks. Blood samples, spleens and subiliac (superficial inguinal) lymph nodes were collected for ELISA and Bethesda assays, and flow cytometry analysis. In our analysis, Tfh were defined as CD4+CXCR5+PD1+Bcl6- cells, while GC B cells were defined as CD19+GL7+CD95+. Tfh cell response and GC formation in the spleen were robustly enhanced by the TLR9 agonist compared to mice injected with FVIII only (2-fold for Tfh frequencies and 6-fold for GC B cells when co-injected; P 400-fold (on average from 6.4 to 2746.5 BU/ml). In contrast, anti-FVIII IgG1 levels increased only 2.5-fold. The differences between mice injected on two consecutive days and the FVIII-only group were not statistically significant. A time-course experiment was also carried out to monitor progress of immune response to FVIII (1.5 IU administered once weekly) in the absence of TLR9 agonist over time: 4 (n=4), 6 (n=4) and 8 weeks (n=5) after the initial antigen challenge. Inhibitor titers continued to rise beyond the fourth week of antigen challenges, reaching 46-fold higher values at eighth week (from 3 BU/ml in the fourth week to 138 BU/ml in the eighth week, p Disclosures No relevant conflicts of interest to declare.
Parents' Perspectives: An Expanded View of Occupational and Co-Occupational Performance in the Neonatal Intensive Care Unit.

Importance: One limitation of occupation-based neonatal practice is the lack of clarity surrounding what parent and infant occupations exist in the neonatal intensive care unit (NICU). Without clear definitions and examples of these constructs, occupational therapists may not recognize or value them as part of practice. Objective: To explore concepts of occupational and co-occupational performance in the NICU and provide richly expanded descriptions of parent and infant occupations in this setting. Design: Phenomenological study with convenience sampling. Participants engaged in semistructured interviews. Inductive content analysis, in vivo and process coding methods, and cross-case analysis were used. Member checking and expert review of emergent themes were used to ensure authenticity. Setting: A metropolitan 48-bed Level 3 NICU with single-family rooms in the midwestern United States. Participants: Fourteen parents (mean age = 29.7 yr; range = 19–37 yr) volunteered for the study. Results: Five themes of active occupational engagement emerged: (1) perceiving “they” versus “I”; (2) maintaining proximity; (3) expressing emotions, values, and beliefs; (4) addressing health issues; and (5) analyzing. A matrix framework displayed emergent themes with definitions of parent occupations, infant occupations, and parent–infant co-occupations. Examples of both directly observable and hidden occupations were found at matrix intersections. Conclusions and Relevance: Occupational performance prevalently reflected attempts to balance power differentials and pursue meaningful engagement through observable and hidden participation in caregiving. Findings suggest that beyond typical occupations (e.g., feeding, socializing), neonatal therapists can address the doing, being, and becoming occupations expressed by parents in this study. What This Article Adds: Parents described five broad thematic categories of NICU-based occupation and co-occupation, which may be valuable to therapists seeking to strengthen the occupational focus of neonatal intervention. Neonatal therapists may need to advocate for service provision policy change to fully address the observable and nonobservable doing, being, and becoming occupational and co-occupational needs of parents and infants.
In vitro studies of immunological responses of lymphoid cells.

Publisher Summary In vitro studies of antibody synthesis have great attraction because they offer the hope of isolating and examining separately the variables involved in the interaction of antigen with lymphoid cells, which results in an immunological response. The chapter reviews such studies and critically analyzes the different experimental conditions employed, the types of data obtained, and their interpretation. The mechanisms and problems involved in antibody synthesis appear to be similar to those involved in synthesis of other proteins. Of more peculiarly, immunological interest are attempts to induce and demonstrate specific responses in vitro. One of the simplest changes to measure is increased DNA synthesis and that is applicable to stimulation by cell surface antigens. The phenomenon is clear enough, but despite many ingenious experiments, this chapter shows how little is yet understand about its mechanism. The advantages of an in vitro analysis of the immunological response were clear from the earliest times. In the study of a mechanism involving a complex series of events and the possible interaction of cell populations, it is essential to be able to identify the cells under study, regulate the conditions of their exposure to antigen, and to study their subsequent morphological and biochemical response. In spite of these potential advantages, there was a long induction period during which a great deal of effort was expended and relatively little achieved.
Summer Transition Training Project for Professionals Who Work with Adolescents and Young Adults.

In the first three years of the Summer Transition Training Project, 50 professionals received training in transition and rehabilitation teaching and 46 adolescents and young adults enhanced a varie...
A Perfect Ten-Decoy Maps Uncover Polymerase Complexes within Reoviridae Virion.

In this issue of Structure, Kaelber et al. (2020) use cryo-EM and synthetic decoy maps to reveal the patterning of 10 polymerase complexes within FAKV, a Reoviridae family member containing 9 genome segments. Their findings support a model for FAKV assembly that has implications for the entire Reoviridae family.
Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Abstract High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand, which exacerbate misfolded, unfolded and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. In this study, we report that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion through the outer layers of omentum as well as significantly decreased the in vivo metastatic tumor growth in ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed the down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1 silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. Implications This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC. It recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress and as novel alternative therapeutic approaches.
Whiteness, repressive victimhood, and the foil of the intolerant left

This essay argues that recent controversies over conservative speakers on college campuses are an opaque vehicle for White supremacy. Revisiting Herbert Marcuse’s concept of repressive tolerance th...
Photoinactivation of Catalase Sensitizes Wide-Ranging Bacteria to ROS-Producing Agents and Immune Cells

Bacteria have evolved to cope with the detrimental effects of reactive oxygen species (ROS) using their essential molecular components. Catalase, a heme-containing tetramer protein expressed universally in most of the aerobic bacteria, plays an indispensable role in scavenging excess hydrogen peroxide (H2O2). Here, through utilization of wild-type and catalase-deficient mutants, we identified catalase as an endogenous therapeutic target of 400-420 nm blue light. Catalase residing in bacteria could be effectively inactivated by blue light, subsequently rendering the pathogens extremely vulnerable to H2O2 and H2O2-producing agents. As a result, photoinactivation of catalase and H2O2 synergistically eliminate a wide range of catalase-positive planktonic bacteria and P. aeruginosa inside biofilms. In addition, photoinactivation of catalase is shown to facilitate macrophages to defend against intracellular pathogens. The antimicrobial efficacy of catalase photoinactivation is further validated using a Pseudomonas aeruginosa-induced mice abrasion model. Taken together, our findings offer a catalase-targeting phototherapy against multidrug-resistant bacterial infections.
The Statist Neo-Institutionalism of Acemoglu and Robinson

In a long review of Acemoglu and Robinson’s 2019 The Narrow Corridor McCloskey praises their scholarship but criticizes their relentless statism – their enthusiasm for a bigger and bigger Stato, so long as it is somehow «caged». Their case is mechanical, materialist, and structuralist, none of which is a good guide to history or politics. Their theory of social causation mixes up necessary with sufficient conditions, though they are not unusual among political scientists and economists in doing so. They downplay the role of ideas, which after all made the modern world through liberalism. They recognize how dangerous the modern «capable» State can be, what they call The Leviathan, after Hobbes. But their construal of «liberty» is the provision of goodies to children by a beneficent Leviathan. It is not the adultism that in fact made the modern world of massive enrichment and true liberty. Their vision is deeply illiberal, and mistaken as science.
Impact of the COVID-19 Pandemic on Early Child Cognitive Development: Initial Findings in a Longitudinal Observational Study of Child Health

Since the first reports of novel coronavirus in the 2020, public health organizations have advocated preventative policies to limit virus, including stay-at-home orders that closed businesses, daycares, schools, playgrounds, and limited child learning and typical activities. Fear of infection and possible employment loss has placed stress on parents; while parents who could work from home faced challenges in both working and providing full-time attentive childcare. For pregnant individuals, fear of attending prenatal visits also increased maternal stress, anxiety, and depression. Not surprising, there has been concern over how these factors, as well as missed educational opportunities and reduced interaction, stimulation, and creative play with other children might impact child neurodevelopment. Leveraging a large on-going longitudinal study of child neurodevelopment, we examined general childhood cognitive scores in 2020 and 2021 vs. the preceding decade, 2011-2019. We find that children born during the pandemic have significantly reduced verbal, motor, and overall cognitive performance compared to children born pre-pandemic. Moreover, we find that males and children in lower socioeconomic families have been most affected. Results highlight that even in the absence of direct SARS-CoV-2 infection and COVID-19 illness, the environmental changes associated COVID-19 pandemic is significantly and negatively affecting infant and child development.
Improving Mental Health Support, Career Transitions and Access to Health Care for Surgical Residents.

OBJECTIVE To increase access to mental health support, assist with career transitions, and improve access to health care. DESIGN Retrospective survey data. SETTING General surgery residency program. PARTICIPANTS Surgical residents. RESULTS We developed three programs to address the issues above. The “Fifth Tuesday of the Month” program allows residents to take time off during the first Tuesday morning of any month with five Tuesdays. The Physician Wellness Collaborative provides confidential, affordable, and easy-to-access counseling resources for residents. Residents are automatically signed up for a session to establish care. The Peer Resident Mentorship Program matches a fourth-year resident with a first-year resident based on personal and professional interests to help ease the transition and improve career satisfaction. All programs were associated with improvement in related outcome measures on our institution's annual program evaluation survey. CONCLUSIONS At our institution, we introduced three simple and accessible programs aimed at increasing access to mental health support, assisting with career transitions, and improving work-life balance. These programs have improved related outcomes in our residents and can be easily implemented at any program.
Using ethnodrama to support parents in sense-making after prenatal or neonatal diagnosis of a child's disabling condition.

Background/aims This study describes the process of developing video vignettes to meet the parent-expressed need for balanced, meaningful messages about what life may be like for parents who have a child with a disability. Each vignette teaches a general audience salient concepts derived from a grounded theory of the parental process of Rescuing Hope after a child's diagnosis with a developmental disability. Methods Using ethnodrama methodology, we completed a secondary analysis of 21 interviews with parents who learned of their child's diagnosis of Down syndrome. Results Understanding the grounded theory of Rescuing Hope has the potential to help parents construct meaning and purpose as they adapt to parenting a child with a disability. Discussion The short dramatic vignettes may be placed across platforms, settings and partnerships, with relevance for teachers, clinicians, family members, caregivers. Designed for wide distribution, video vignettes may reach the people who most need sense-making support.
Shallow Semantic Analysis of Interactive Learner Sentences

Focusing on applications for analyzing learner language which evaluate semantic appropriateness and accuracy, we collect data from a task which models some aspects of interaction, namely a picture description task (PDT). We parse responses to the PDT into dependency graphs with an an off-the-shelf parser, then use a decision tree to classify sentences into syntactic types and extract the logical subject, verb, and object, finding 92% accuracy in such extraction. The specific goal in this paper is to examine the challenges involved in extracting these simple semantic representations from interactive learner sentences.
Nonlinear flexural-flexural-torsional interactions in beams including the effect of torsional dynamics. II: Combination resonance

In Part I of this work nonlinear coupling between torsional motion and both in-plane and out-of-plane flexural motion was examined for inextensional beams in the presence of a one-to-one internal resonance. Here the nonlinear response of the system considered in Part I is investigated for the case of an internal combination resonance involving modes associated with bending in two directions and torsion. The analysis presented is based on a consistent set of nonlinear differential equations which contain both curvature and inertia nonlinearities and account for torsional dynamics.
Exception-handling Design Patterns

Abstract Achieving dependable behavior from complex software systems requires that the software logic be able to recover from anomalous conditions or exceptional states. Such conditions and states may arise from embedded defects in the code or from erroneous data provided to the software for processing. One technique for enhancing the ability of software to perform such recovery is the insertion of exception detection and handling features into the logic. Such features may depend on specific exception-handling language facilities or on general-purpose language constructs. This chapter provides an overview of design considerations necessary to implement such recovery, and presents a series of commonly used design patterns that have proved to be successful in enhancing dependable behavior.
Self-reported health status of students in-processing into military medical advanced individual training

It is important to be aware of the health and injury status of students in military training settings in order to adequately plan for their progression through required physical training and provision of health care to meet their needs. This paper describes the self-reported health status of students arriving in two medical training Battalions at Ft. Sam Houston. The results revealed that 43% of arriving soldiers had musculoskeletal symptoms and 35% had symptoms that interfered with their ability to accomplish the normal daily activities required as students. The most common sites of symptoms were knee (17 and 18%), foot/toe (16 and 13%), ankle (9 and 10%), and lower leg (9 and 12%) for the 232 nd and 187 th Medical Battalions respectively. Risk factors for those with musculoskeletal injury (MSI) symptoms that interfere with their abilities to do their jobs include gender, past history of injury, and self-reported stress and fitness levels. Other risk factors for medical specialties other than combat medic include being older (over 24 yrs of age), active duty status, being overweight, and use of smokeless tobacco. This information can help identify soldiers considered at risk of incurring a MSI during AIT. With this knowledge, physical training can be designed to help soldiers achieve fitness without additional injury and health care facilities can be designed to provide appropriate staffing of the health care professionals needed for evaluation and treatment.
Autoprocessing of HIV-1 protease is tightly coupled to protein folding.

In the Gag-Pol polyprotein of HIV-1, the 99-amino acid protease is flanked at its N-terminus by a transframe region (TFR) composed of the transframe octapeptide (TFP) and 48 amino acids of the p6pol, separated by a protease cleavage site. The intact precursor (TFP-p6pol-PR) has very low dimer stability relative to that of the mature enzyme and exhibits negligible levels of stable tertiary structure. Thus, the TFR functions by destabilizing the native structure, unlike proregions found in zymogen forms of monomeric aspartic proteases. Cleavage at the p6pol-PR site to release a free N-terminus of protease is concomitant with the appearance of enzymatic activity and formation of a stable tertiary structure that is characteristic of the mature protease as demonstrated by nuclear magnetic resonance. The release of the mature protease from the precursor can either occur in two steps at pH values of 4 to 6 or in a single step above pH 6. The mature protease forms a dimer through a four-stranded β-sheet at the interface. Residues 1–4 of the mature protease from each subunit constitute the outer strands of the β-sheet, and are essential for maintaining the stability of the free protease but are not a prerequisite for the formation of tertiary structure and catalytic activity. Our experimental results provide the basis for the model proposed here for the regulation of the HIV-1 protease in the viral replication cycle.
AND/OR graph representation of assembly plans

This paper presents a compact representation of all possible assembly plans of a given product using AND/OR graphs. Such a representation forms the basis for efficient planning algorithms which enable an increase in assembly system flexibility by allowing an intelligent robot to pick a course of action according to instantaneous conditions. Two applications are discussed: the selection of the best assembly plan (off-line planning), and opportunistic scheduling (online planning). An example of an assembly with four parts illustrates the use of the AND/OR graph representation to find the best assembly plan based on weighing of operations according to complexity of manipulation and stability of subassemblies. In practice, a generic search algorithm, such as the AO* may be used to find this plan. The scheduling efficiency using this representation is compared to fixed sequence and precedence graph representations. The AND/OR graph consistently reduces the average number of operations.
Quenching of Fluorescence

Fluorescence quenching refers to any process which decreases the fluorescence intensity of a given substance. A variety of processes can result in quenching. These include excited state reactions, energy transfer, complex formation, and collisional quenching. In this chapter we will be concerned primarily with quenching resulting from collisional encounters between the fluorophore and quencher, which is called collisional or dynamic quenching. We will also consider static quenching, which is due to complex formation. Static quenching is a frequent complicating factor in the analysis of dynamic quenching. In addition to the processes described above, apparent quenching can occur due to the optical properties of the sample. For example, high optical densities or turbidity can result in decreased fluorescence intensities. This is a trivial type of quenching which contains little molecular information. Throughout this chapter we will assume such trivial effects are not the cause of the observed decreases in fluorescence intensity.
Banking crises in transition economies : fiscal costs and related issues

The authors look at strategies for dealing with banking crises in 12 transition economies -- five from Central and Eastern Europe (CEE): Bulgaria, the Czech Republic, Hungary, Macedonia, and Poland; the three Baltic states: Estonia, Latvia, and Lithuania; and four countries from the Commonwealth of Independent States (CIS): Georgia, Kazakhstan, the Kyrgyz Republic, and Ukraine. Three types of strategies were used to deal with the crises. The CEE countries generally pursued extensive restructuring and recapitalizing of banks; most CIS countries pursued large-scale liquidation; and the Baltic states generally pursued a combination of liquidation and restructuring. The strategy pursued reflected macroeconomic conditions and the level of development in a country's banking sector. There were more new banks in the former Soviet Union (FSU-the CIS and Baltic states), but they tended to be small, undercapitalized, and not deeply engaged in financial intermediation. The CEE countries generally incurred higher fiscal costs than the FSU countries but ended up with sounder, more efficient banking systems, with many of the recapitalized banks being privatized to strategic foreign investors. The CIS countries pursued a less fiscally costly approach but have been left with weak banking systems and low levels of intermediation. The Baltic states appear to have struck a good balance, incurring modest fiscal costs while making their systems sounder and more efficient. The findings suggest the following: a) Operational, financial, and institutional restructuring should be undertaken in parallel. b) Financial restructuring should involve adequate recapitalization to deter moral hazard and repeated recapitalization. c) Operational restructuring should entail privatization to core investors (particularly to reputable foreign banks). d) The enterprise problems underlying banking problems must also be addressed. e) Fiscal costs were reduced when governments dealt only with bad debt inherited from the socialist period; when small banks that held few deposits were allowed to fail, where the social costs of such failure were low; and when only banks that got into trouble because of external shocks were rescued while those suffering from poor management were liquidated. f) The government, not the central bank, should undertake bank restructuring. Central bank refinancing is not transparent and could lead to hyperinflation.
Lateral electromagnetic pulses generated on a plane boundary between dielectrics by vertical and horizontal dipole sources with Gaussian pulse excitation

The exact lateral electromagnetic pulse generated by a vertical dipole excited by a Gaussian pulse is derived. A comparison with the previously derived approximate formula shows that the latter gives the correct field at all radial distances except for the nonappearance of the relatively small second pulse. Corresponding approximate formulas are derived for the electric field of a horizontal dipole. These should give the correct field except for the nonappearance of the small second pulse in some components.
A Pediatric Screening Examination for Psychosocial Problems

In an effort to avert the cumulative effects of unresolved emotional problems on children9s social and school adjustment, a psychosocial phase was added to a pediatric multiphasic examination. Based upon a cumulative stress concept, the screening procedures included child behavior and family stress questionnaires for parents, and abbreviated standard psychological tests for children, administered by specially trained aides. Computerized results were reported to the child9s pediatrician. Follow-up by mental health counselors attached to the pediatric clinic was provided for patients identified as being at high risk of serious psychosocial problems. Evidence of validity of the screen, factors affecting the scores, and effectiveness of clinical follow-up of high-risk patients are discussed. Valid semicomputerized screening of school-age children for serious psychosocial problems can be carried out routinely and at relatively low cost by paraprofessional personnel in a pediatric setting. Impediments to effective use of the screening results on the part of both health care provider and patient are discussed.
Managing multi-chamber tool productivity

Multi-chamber tools have enabled significant technical breakthroughs in wafer processing in the last decade. Expenditures for these tools are increasing as a percentage of the total capital base. Fully one-third of the capital dollars invested in 0.4 /spl mu/m technology processing equipment will be spent on multi-chamber tools. These tools also present some special productivity problems, as a significant portion of the tool can fail to produce wafers while the remaining portions of the tool still are able to do so at a reduced run rate. Classical measures of tool availability and run rates are insufficient to account for reduced output when part of the tool is down. This paper presents measurements, operating scenarios and operating guidelines to maximize multi-chamber tool productivity in a volume manufacturing environment.
Legal Regulation of Environmental Risk

I wish to address a question that has divided the two cultures of law and science: What should be the role of courts, lawyers, and litigation in the administrative regulation of environmental hazards?
Changes in the thermosphere and ionosphere of Mars from Viking to MAVEN

We compare Viking and Mars Atmosphere and Volatile EvolutioN mission (MAVEN) Neutral Gas and Ion Mass Spectrometer (NGIMS) observations of the thermosphere and ionosphere of Mars in order to test predictions of large variations in conditions over the solar cycle and with season. Substantial differences exist between the Viking observations at solar minimum and near aphelion and the MAVEN NGIMS observations at moderate solar activity and near perihelion. Differences in the O/CO2 ratio, the O + ionospheric peak, ion densities at high altitude, and neutral and ion scale heights can be attributed to differences in solar activity and season, but the relative importance of solar activity and season for these differences was not established. Current models do not explain the observed differences in the mixing ratios of N, NO, and O2. These results place new constraints on models of how the thermosphere and ionosphere of Mars vary over the solar cycle and with season.
Novel Technology to Study Chemokine Receptor Signaling Complexes

C-C chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) involved in immune responses and it is the primary co-receptor required for HIV-1 cellular entry. To obtain functional heterologous over-expression of engineered GPCRs is one of the major hurdles in GPCR research aimed at elucidating structure-activity relationships. It can be especially difficult to obtain structural information about GPCRs in signaling complexes with other cellular proteins that form a so-called “signalosome.” We have developed two new technologies for investigating the structure and function of GPCRs, which we have now applied to CCR5. First, we have established a membrane nanoparticle system called NABBs (nanoscale apolipoprotein bound bilayers), which are self-assembling discs that maintain receptors in a native-like membrane environment outside of the cell. We have incorporated functional CCR5 into NABBs and plan to use this platform to reconstitute the ternary complex with chemokine ligand and G protein from purified components. In addition, we have adapted unnatural amino acid mutagenesis for use with GPCRs. This is a method to incorporate amino acids with unique side chains at specific sites in the receptor. We introduced p-benzoyl-L-phenylalanine, into CCR5 at various positions on both the extracellular and intracellular surface of the protein using the amber suppression technology. Since the benzoyl moiety is a photo-activatable crosslinker, these mutants can now be used to map the specific sites of interaction between ligand, receptor, and G protein as predicted from molecular modeling and molecular dynamics simulations. Our methods will form the basis of a new experimental paradigm in the structural biology of signaling complexes on a mesoscopic level. Ultimately, these methods will be useful for developing a chemically-precise model for how an extracellular ligand stimulates a GPCR to activate a cytosolic G protein.
Financial innovation and investor wealth: A study of the poison put in convertible bonds

Abstract The takeover boom of the 1980s was accompanied by a series of innovations in debt contracts, including the poison put that allows bonds to be redeemed in the event of a corporate control change. The poison put was included in a large majority of convertible debt offerings, shortly after the first issues with such provisions. We attempt to understand the factors that contributed to the widespread adoption of this innovation in convertible bonds and the consequences for shareholder wealth. Our findings suggest that by reducing the potential for bondholder-shareholder conflicts and by conveying positive information about future takeover prospects, poison puts result in significant benefits to issuing firm shareholders, particularly if the firm is under takeover speculation. There are, however, no benefits when a firm has adopted antitakeover measures prior to the offering. There is weaker evidence that existing bondholders do worse when poison puts are present.
Architecture of solid state transformer-based energy router and models of energy traffic

Recently, a large number of renewable energy resources and DC loads spur the research spotlight of the future power grid, which is also referred to as Energy Internet. In order to achieve such a fundamental innovation to the novel energy paradigm, many devices are to be designed, manufactured, and evaluated. In this paper, we describe the solid state transformer-based energy router in which incoming energy traffic can be converted and routed to an outgoing energy traffic. In particular, we focus on the architecture design of such a router and models of energy storage devices, generators, and loads, for Energy Local Area Network (ELAN). The proposed energy router features plug-and-play Multiple-Input Multiple-Output (MIMO), and customized operating system, that providing a system level modeling for the optimal design and performance analysis of energy routers.
Food and Culture in Appalachian Kentucky: An Ethnography

Using interviews with 21 Appalachian Kentucky residents and out-migrants, this paper examines the ways in which food plays a central role in constructing, maintaining, and transforming a sense of regional identity. In contrast to much work on Appalachia, the participants in this study suggest that, while their regionality is important, they participate in larger cultural productions and find ways to incorporate both the familiar ways and mass food culture into understandings of what it means to be Appalachian.
Computed and observed ocean topography: A comparison

The Goddard Space Flight Center's latest Gravity Earth Model, GEM-8, was used to construct a static sea surface. Such a surface corresponds to the surface of an ocean without the time-varying effects of atmospheric pressure, surface wind friction, tides, and currents. It conforms to a surface dictated by the earth's gravitational and rotational forces. The sea surface model is the result of analyzing more than 500,000 satellite observations together with about 1600 5 deg x 5 deg and about 38,000 1 deg x 1 deg surface gravity anomalies. Preliminary comparisons between the computed and measured sea surface topography indicate that they agree quite well and differ by less than 1 m in many places including the Atlantic test area. Sea-surface features such as undulations caused by trenches and ridges are clearly and accurately detectable. The use of altimeter data for orbit computation reduces the uncertainty of the spacecraft height and thus the errors of the sea-surface topography.
Rotor design for high pressure magic angle spinning nuclear magnetic resonance.

Abstract High pressure magic angle spinning (MAS) nuclear magnetic resonance (NMR) with a sample spinning rate exceeding 2.1 kHz and pressure greater than 165 bar has never been realized. In this work, a new sample cell design is reported, suitable for constructing cells of different sizes. Using a 7.5 mm high pressure MAS rotor as an example, internal pressure as high as 200 bar at a sample spinning rate of 6 kHz is achieved. The new high pressure MAS rotor is re-usable and compatible with most commercial NMR set-ups, exhibiting low 1 H and 13 C NMR background and offering maximal NMR sensitivity. As an example of its many possible applications, this new capability is applied to determine reaction products associated with the carbonation reaction of a natural mineral, antigorite ((Mg,Fe 2+ ) 3 Si 2 O 5 (OH) 4 ), in contact with liquid water in water-saturated supercritical CO 2 (scCO 2 ) at 150 bar and 50 °C. This mineral is relevant to the deep geologic disposal of CO 2 , but its iron content results in too many sample spinning sidebands at low spinning rate. Hence, this chemical system is a good case study to demonstrate the utility of the higher sample spinning rates that can be achieved by our new rotor design. We expect this new capability will be useful for exploring solid-state, including interfacial, chemistry at new levels of high-pressure in a wide variety of fields.
Deacetylase Inhibitors Dissociate the Histone-Targeting ING2 Subunit from the Sin3 Complex

Histone deacetylase (HDAC) inhibitors are in clinical development for several diseases, including cancers and neurodegenerative disorders. HDACs 1 and 2 are among the targets of these inhibitors and are part of multisubunit protein complexes. HDAC inhibitors (HDACis) block the activity of HDACs by chelating a zinc molecule in their catalytic sites. It is not known if the inhibitors have any additional functional effects on the multisubunit HDAC complexes. Here, we find that suberoylanilide hydroxamic acid (SAHA), the first FDA-approved HDACi for cancer, causes the dissociation of the PHD-finger-containing ING2 subunit from the Sin3 deacetylase complex. Loss of ING2 disrupts the in vivo binding of the Sin3 complex to the p21 promoter, an important target gene for cell growth inhibition by SAHA. Our findings reveal a molecular mechanism by which HDAC inhibitors disrupt deacetylase function.
Post embolectomy thrombosis treated with intra-arterial streptokinase.

A case is presented which demonstrates the occasional need for selective intra- arterial streptokinase when re-thrombosis has occurred following catheter thromboem bolectomy of a peripheral artery. It is recommended that repeat embolectomy be carried out and all mechanical causes for re-thrombosis be excluded before resorting to fi brinolysis.The literature citing other indications for selective arterial use of streptokinase is reviewed.
Nonsense codons trigger an RNA partitioning shift.

T-cell receptor-β (TCRβ) genes naturally acquire premature termination codons (PTCs) as a result of programmed gene rearrangements. PTC-bearing TCRβ transcripts are dramatically down-regulated to protect T-cells from the deleterious effects of the truncated proteins that would otherwise be produced. Here we provide evidence that two responses collaborate to elicit this dramatic down-regulation. One is rapid mRNA decay triggered by the nonsense-mediated decay (NMD) RNA surveillance pathway. We demonstrate that this occurs in highly purified nuclei lacking detectable levels of three different cytoplasmic markers, but containing an outer nuclear membrane marker, suggesting that decay occurs either in the nucleoplasm or at the outer nuclear membrane. The second response is a dramatic partitioning shift in the nuclear fraction-to-cytoplasmic fraction mRNA ratio that results in few TCRβ transcripts escaping to the cytoplasmic fraction of cells. Analysis of TCRβ mRNA kinetics after either transcriptional repression or induction suggested that this nonsense codon-induced partitioning shift (NIPS) response is not the result of cytoplasmic NMD but instead reflects retention of PTC+ TCRβ mRNA in the nuclear fraction of cells. We identified TCRβ sequences crucial for NIPS but found that NIPS is not exclusively a property of TCRβ transcripts, and we identified non-TCRβ sequences that elicit NIPS. RNA interference experiments indicated that NIPS depends on the NMD factors UPF1 and eIF4AIII but not the NMD factor UPF3B. We propose that NIPS collaborates with NMD to retain and degrade a subset of PTC+ transcripts at the outer nuclear membrane and/or within the nucleoplasm.
Cyclic GMP diffusion coefficient in rod photoreceptor outer segments.

Cyclic GMP (cGMP) is the intracellular messenger that mediates phototransduction in retinal rods. As photoisomerizations of rhodopsin molecules are local events, the longitudinal diffusion of cGMP in the rod outer segment should be a contributing factor to the response of the cell to light. We have employed the truncated rod outer segment preparation from bullfrog (Rana catesbeiana) and tiger salamander (Ambystoma tigrinum) to measure the cGMP diffusion coefficient. In this preparation, the distal portion of a rod outer segment was drawn into a suction pipette for measuring membrane current, and the rest of the cell was then sheared off with a glass probe, allowing bath cGMP to diffuse into the outer segment and activate the cGMP-gated channels on the surface membrane. Addition and removal of bath cGMP were fast enough to produce effectively step changes in cGMP concentration at the open end of the outer segment. When cGMP hydrolysis is inhibited by isobutylmethylxanthine (IBMX), the equation for the diffusion of cGMP inside the truncated rod outer segment has a simple analytical solution, which we have used to analyze the rise and decay kinetics of the cGMP-elicited currents. From these measurements we have obtained a cGMP diffusion coefficient of approximately 70 x 10(-8) cm2 s-1 for bullfrog rods and approximately 60 x 10(-8) cm2 s-1 for tiger salamander rods. These values are six to seven times lower than the expected value in aqueous solution. The estimated diffusion coefficient is the same at high (20–1000 microM) and low (5–10 microM) concentrations of cGMP, suggesting no significant effect from buffering over these concentration ranges.
A Nonlinear Model for the Spatial Characteristics of the Human Visual System

Several recent papers have presented data from experimental investigations of the human ivsual system (HVS) which support the general hypothesis that the HVS is composed of spatial frequency channels. It has been pointed out, however, that a linear systems analysis of the entire system is not valid. Furthermore, a nonlinear model consisting of a log-bandpass filter produced some experimental results with deviations at high spatial frequencies. A new structure for a nonlinear mathematical model which is easily quantifiable, produces results which compare with experimental data, and has a physiological correlate is presented. The significance of this model is that the bandwidth of the visual system decreases as contrast increases. Thus the system appears to maximize the signal to noise ratio while attempting to maintain a constant " perceptual" spatial-frequency fidelity.
Tool wear reduction through an externally applied electric current

It was shown in a previous investigation that when an electric current is passed between two sliding surfaces in the presence of engine oils, the wear characteristics of two surfaces could be altered significantly, but not friction. The wear on the cathode surface is decreased while the wear on the anode surface increased. The difference in wear rate of surfaces with and without current is attributed to the modification of the elemental composition of surface films. In this investigation, the concept was extended to a machining operation where it is desirable to reduce wear of the cutting tool while increasing metal removal. Two types of experiments were conducted: (a) ball-on-disk test and (b) face milling test. It was observed in ball-on-disk tests that in the presence of a metalworking fluid, the wear of the anode surface decreased significantly while the wear of the cathode surface increased slightly. Similar observations were made in face milling tests where the milling insert wear was reduced when it was the anode and increased when the insert was the cathode. In addition to wear, vibration during milling was also reduced when the insert was the anode.
The Tissue Distribution and Excretion of Radioactive Digitoxin Studies on Normal Rats and Cats, and Rats with Dietary-Induced Myocardial Lesions

The tissue distribution and excretion of radioactive digitoxin and its metabolites were studied in normal rats and cats and in rats with dietary induced myocardial lesions. The prolonged cardiac and renal retention of digitoxin and its derivatives, associated with the persistence of these substancces in the excreta of sensitive animals, supports the concept of storage as an explanation for the cumulative action of certain of the cardiac glycosides. There is a suggestive increase in digitoxin metabolism in heart failure.
Striated Muscle Regulation of Isometric Tension by Multiple Equilibria

Cooperative activation of striated muscle by calcium is based on the movement of tropomyosin described by the steric blocking theory of muscle contraction. Presently, the Hill model stands alone in reproducing both myosin binding data and a sigmoidal-shaped curve characteristic of calcium activation (Hill TL (1983) Two elementary models for the regulation of skeletal muscle contraction by calcium. Biophys J 44: 383-396.). However, the free myosin is assumed to be fixed by the muscle lattice and the cooperative mechanism is based on calcium-dependent interactions between nearest neighbor tropomyosin subunits, which has yet to be validated. As a result, no comprehensive model has been shown capable of fitting actual tension data from striated muscle. We show how variable free myosin is a selective advantage for activating the muscle and describe a mechanism by which a conformational change in tropomyosin propagates free myosin given constant total myosin. This mechanism requires actin, tropomyosin, and filamentous myosin but is independent of troponin. Hence, it will work equally well with striated, smooth and non-muscle contractile systems. Results of simulations with and without data are consistent with a strand of tropomyosin composed of approximately 20 subunits being moved by the concerted action of 3-5 myosin heads, which compares favorably with the predicted length of tropomyosin in the overlap region of thick and thin filaments. We demonstrate that our model fits both equilibrium myosin binding data and steady-state calcium-dependent tension data and show how both the steepness of the response and the sensitivity to calcium can be regulated by the actin-troponin interaction. The model simulates non-cooperative calcium binding both in the presence and absence of strong binding myosin as has been observed. Thus, a comprehensive model based on three well-described interactions with actin, namely, actin-troponin, actin-tropomyosin, and actin-myosin can explain the cooperative calcium activation of striated muscle.
Antinociceptive effects of alcohol and nicotine: Involvement of the opioid system

Both alcohol and nicotine have been shown to possess antinociceptive or analgesic effects. An additive or synergistic antinociceptive effect induced by simultaneous administration of alcohol and nicotine could further contribute to their co-abuse. In this study, we sought to evaluate the antinociceptive effects of various combinations of ethanol and nicotine and to determine whether these effects could be blocked by an opioid antagonist. Adult male Wistar rats were treated with various doses of alcohol (0.1-2 g/kg), nicotine (0.01-2 mg/kg) or their combination and their behavior in tail flick test, reflective of spinal antinociception and hotplate test, mainly reflective of supraspinal antinociception were evaluated. Alcohol at the highest dose of 2 g/kg resulted in significant antinociceptive effects in both assays. Nicotine at 1 mg/kg resulted in significant antinociception in the hotplate; however, in the tail flick test a dose of 2 mg/kg was required for an antinociceptive effect. Combination of doses of alcohol and nicotine that were ineffective by themselves resulted in antinociceptive responses in both paradigms. These effects were attenuated by pretreatment with the non-selective opioid receptor antagonist naloxone. The data indicate that a combination of alcohol and nicotine can result in a synergistic antinociceptive response that is at least partially mediated by the opioid system. The analgesic effects induced by combination of alcohol and nicotine may be a contributory factor in their co-abuse.