cssi/SciSciGPT-SciSciNet huggingface dataset:
Regulation of protein synthesis and the role of eIF3 in cancer

Maintenance of cell homeostasis and regulation of cell proliferation depend importantly on regulating the process of protein synthesis. Many disease states arise when disregulation of protein synthesis occurs. This review focuses on mechanisms of translational control and how disregulation results in cell malignancy. Most translational controls occur during the initiation phase of protein synthesis, with the initiation factors being the major target of regulation through their phosphorylation. In particular, the recruitment of mRNAs through the m⁷G-cap structure and the binding of the initiator methionyl-tRNA(i) are frequent targets. However, translation, especially of specific mRNAs, may also be regulated by sequestration into processing bodies or stress granules, by trans-acting proteins or by microRNAs. When the process of protein synthesis is hyper-activated, weak mRNAs are translated relatively more efficiently, leading to an imbalance of cellular proteins that promotes cell proliferation and malignant transformation. This occurs, for example, when the cap-binding protein, eIF4E, is overexpressed, or when the methionyl-tRNA(i)-binding factor, eIF2, is too active. In addition, enhanced activity of eIF3 contributes to oncogenesis. The importance of the translation initiation factors as regulators of protein synthesis and cell proliferation makes them potential therapeutic targets for the treatment of cancer.
EGLN3 Inhibition of NF-κB Is Mediated by Prolyl Hydroxylase-Independent Inhibition of IκB Kinase γ Ubiquitination

NF-κB transcription factors are crucial regulators of inflammation, immunity, stress responses, and cell differentiation. Many studies have demonstrated that ubiquitination of IκB kinase γ (IKKγ), a regulatory subunit of IKK, is instrumental in the activation of IKK and NF-κB. We and others previously identified EGLN3, a member of a family of prolyl hydroxylases, as a negative regulator of the NF-κB pathway. Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK-NF-κB signaling. EGLN3 competes with cIAP1 for IKKγ binding, leading to inhibition of cIAP1-IKKγ interaction, IKKγ ubiquitination, and IKK-NF-κB signaling. This study provides novel insights into EGLN3 function and sheds new light on the regulation of IKKγ ubiquitination and NF-κB.
Abstracts of the fall 2009 meeting of the Microcirculatory Society, Inc. “Frontiers in microcirculation: control processes and clinical applications”

AcknowledgmentsThe following companies are gratefully acknowledged for their generous support of this scientific conference: Danish Myo Technology (www.dmt.dk/); Hitschfel Instruments, Inc. (www.hitschfel.com/); IonOptix LLC (www.ionoptix.com/); Living Systems Instrumentation, Inc. (www.livingsys.com/); Siskiyou Corporation (www.siskiyou.com/); Solamere Technology Group (www.solameretech.com/); Stanford Photonics, Inc. (www.stanfordphotonics.com/); Sutter Instrument Company (www. sutter.com/); Warner Instruments, LLC (www.warneronline.com/); and World Precision Instruments (www.wpiinc.com/).
Speculative execution exception recovery using write-back suppression

Compiler-controlled speculative execution has been shown to be effective in increasing the available instruction level parallelism (ILP) found in non-numeric programs. An important problem associated with compiler-controlled speculative execution is to accurately report and handle exceptions caused by speculatively executed instructions. Previous solutions to this problem incur either excessive hardware overhead or significant register pressure. The paper introduces a new architectural scheme referred to as write-back suppression. This scheme systematically suppresses register file updates for subsequent speculative instructions after an exception condition is detected for a speculatively executed instruction. The authors show that with a modest amount of hardware, write-back suppression supports accurate reporting and handling of exceptions for compiler-controlled speculative execution with minimal additional register pressure. Experiments based on a prototype compiler implementation and hardware simulation indicate that ensuring accurate handling of exceptions with write-back suppression incurs little run-time performance overhead. >
A Dynamic Reconfigurable Fabric for Platform SoCs

A dynamic coarse-grained reconfigurable architecture which targets computationally intensive applications like multimedia and wireless applications is presented. Fundamental features of the architecture are an interconnection matrix, switch buffers, functional units, and a controller. Important aspects of the architecture is dynamic datapath reconfiguration over each control step of the application. Simulations of several classes of applications with results are also presented. Results of Xilinx Virtex 4 Implementations are provided.
Prehospital emergency care training practices regarding lesbian, gay, bisexual, and transgender patients in Maryland (USA).

Introduction Prehospital Emergency Medical Services (EMS) providers are expected to treat all patients the same, regardless of race, gender identity, sexual orientation, or religion. Some EMS personnel who are poorly trained in working with lesbian, gay, bisexual, and transgender (LGBT) patients are at risk for managing such patients incompletely and possibly incorrectly. During emergency situations, such mistreatment has meant the difference between life and death. Methods An anonymous survey was electronically distributed to EMS educational program directors in Maryland (USA). The survey asked participants if their program included training cultural sensitivity, and if so, by what modalities. Specific questions then focused on information about LGBT education, as well as related topics, that they, as program directors, would want included in an online training module. Results A total of 20 programs met inclusion criteria for the study, and 16 (80%) of these programs completed the survey. All but one program (15, 94%) included cultural sensitivity training. One-third (6, 38%) of the programs reported already teaching LGBT-related issues specifically. Three-quarters of the programs that responded (12, 75%) were willing to include LGBT-related material into their curriculum. All programs (16, 100%) identified specific aspects of LGBT-related emergency health issues they would be interested in having included in an educational module. Conclusion Most EMS educational program directors in Maryland are receptive to including LGBT-specific education into their curricula. The information gathered in this survey may help guide the development of a short, self-contained, open-access module for EMS educational programs. Further research, on a broader scale and with greater geographic sampling, is needed to assess the practices of EMS educators on a national level. Jalali S , Levy MJ , Tang N . Prehospital Emergency Care Training Practices Regarding Lesbian, Gay, Bisexual, and Transgender Patients in Maryland (USA). Prehosp Disaster Med. 2015;30(2):1-4 .
Walking Patterns of Healthy Subjects Wearing Rocker Shoes

We compared walking in rocker shoes with walking in athletic shoes at free and fast velocities in 15 healthy women who were between the ages of 21 and 30 years. Footswitches, electrogoniometers, surface electromyograms, and a force plate were used for data collection. No significant differences were found in velocity, cadence, gait-cycle duration, single-limb support, or swing-stance ratios in free and fast walking. Double-limb support was decreased by 9% in the rocker shoes in free walking. The ankle range of motion showed accommodation of the foot to the 8.5 degrees of plantar flexion built into the rocker shoes. Electromyographic responses appeared to be similar regardless of shoes or cadence.
Mating in Saccharomyces cerevisiae: The Role of the Pheromone Signal Transduction Pathway in the Chemotropic Response to Pheromone

The mating process in yeast has two distinct aspects. One is the induction and activation of proteins required for cell fusion in response to a pheromone signal; the other is chemotropism, i.e., detection of a pheromone gradient and construction of a fusion site available to the signaling cell. To determine whether components of the signal transduction pathway necessary for transcriptional activation also play a role in chemotropism, we examined strains with null mutations in components of the signal transduction pathway for diploid formation, prezygote formation and the chemotropic process of mating partner discrimination when transcription was induced downstream of the mutation. Cells mutant for components of the mitogen-activated protein (MAP) kinase cascade (ste5, ste20, ste11, ste7 or fus3 kss1) formed diploids at a frequency 1% that of the wild-type control, but formed prezygotes as efficiently as the wild-type control and showed good mating partner discrimination, suggesting that the MAP kinase cascade is not essential for chemotropism. In contrast, cells mutant for the receptor (ste2) or the beta or gamma subunit (ste4 and ste18) of the G protein were extremely defective in both diploid and prezygote formation and discriminated poorly between signaling and nonsignaling mating partners, implying that these components are important for chemotropism.
Adhesion, Invasion, and Translocation Characteristics of Listeria monocytogenes Serotypes in Caco-2 Cell and Mouse Models

Adhesion is a crucial first step in Listeria monocytogenes pathogenesis. In this study, we examined how the adhesion properties of serotypes correlate with their invasion efficiencies in a cell culture model (Caco-2) and in a mouse model. Adhesion characteristics of all 13 serotypes of L. monocytogenes (25 strains) were analyzed, which yielded three distinct groups (P < 0.05) with high-, medium-, and low-level-adhesion profiles. The efficiency of these strains in invading the Caco-2 cell line was analyzed, which produced two groups; however, the overall correlation (R2) was only 0.1236. In the mouse bioassay, all selected strains, irrespective of their adhesion profiles, translocated to the liver and the spleen with almost equal frequencies that did not show any clear relationship with adhesion profiles. However, the serotypes with increased adhesion showed a slightly increased translocation to the brain (R2 = 0.3371). Collectively, these results indicate that an in vitro adhesion profile might not be an accurate assessment of a strain's ability to invade a cultured cell line or organs or tissues in a mouse model.
Agreement between a partial coherence interferometer and 2 manual keratometers

Purpose To establish repeatability and validity of a partial coherence interferometry (PCI) device in patients with astigmatism. Setting Industry and university. Design Observational studies. Methods A prospective study determined the agreement between the IOLMaster 500 PCI device and the Marco 1-position manual keratometer for measurement of mean corneal power, astigmatic power, and axis. Interinstrument and interoperator reproducibility was also assessed. A retrospective study determined the agreement between the PCI device and the Javal 2-position manual keratometer. Repeatability was also assessed. The 95% limits of agreement (LoA) were determined for all comparisons. Results Comparing the PCI device and the 1-position manual keratometer, the axis was within 5 degrees in 72.1% of eyes; the cylinder power differed by 0.18 diopter (D) (95% LoA, ±0.45 D) and the mean power by 0.33 D (95% LoA, ±0.25 D). Comparing the PCI device and the 2-position manual keratometer, the axis was within 5 degrees in 77.1% of eyes. The mean difference in cylinder power between the 2 instruments was close to zero (95% LoA, ±0.37 D); however, the mean power differed by 0.34 D (95% LoA, ±0.25 D). The repeatability of the PCI device was better than that of both manual keratometers. Conclusions Agreement between the PCI device and the 2-position manual keratometer for measures of corneal astigmatism and axis was excellent. The 1-position manual keratometer gave slightly lower estimates of corneal astigmatism, although the agreement for axis was excellent. Thus, the PCI device is an appropriate choice for the calculation of toric intraocular lenses. Financial Disclosure Dr. Bullimore is a consultant to Carl Zeiss Meditec AG and Alcon Surgical, Inc. Drs. Buehren and Bissmann are employees of Carl Zeiss Meditec AG.
The Dynamic Structure of Congressional Elections

We address three questions. First we ask to what degree elections to the U.S. House of Representatives may be understood to reflect the influence of current public opinion? This requires us to entertain models of House elections with incumbency effects as a dynamic system. We ask, second, how do the effects of exogenous influences of all sorts work their way into ultimate House composition? Third, we ask if some portion of the effects attributed to incumbency might not be simply these dynamics, reasserted effects of previous elections, in addition to the well-known advantages individual incumbents accrue? We estimate pooled models of state-level aggregate voting for the House. We add Policy Mood to the usual set of explanations as a means to specify the central focus of democratic theories of elections. We focus on how incumbency translates contemporaneous effects of the explanatory variables into dynamic effects and on how this translation differentially affects the various inputs to the system.
Surrogate-channel design of universal LDPC codes

A universal code is a code that may be used across a number of different channel types or conditions with little degradation relative to a good single-channel code. The explicit design of universal codes, which simultaneously seeks to solve a multitude of optimization problems, is a daunting task. This letter shows that a single channel may be used as a surrogate for an entire set of channels to produce good universal LDPC codes. This result suggests that sometimes a channel for which LDPC code design is simple may be used as a surrogate for a channel for which LDPC code design is complex. We explore here the universality of LDPC codes over the BEC, AWGN, and flat Rayleigh fading channels in terms of decoding threshold performance. Using excess mutual information as a performance metric, we present design results which support the contention that an LDPC code designed for a single channel can be universally good across the three channels
Rule-Consequentialism and Irrelevant Others

In this article, I argue that Brad Hooker's rule-consequentialism implausibly implies that what earthlings are morally required to sacrifice for the sake of helping their less fortunate brethren depends on whether or not other people exist on some distant planet even when these others would be too far away for earthlings to affect.
Detection of sex-region Y (SRY) transcripts in human prostate adenocarcinoma and benign prostatic hypertrophy.

The human sex-region Y (SRY) gene maps to Yp 11.3 and encodes a protein that shares significant sequence homology with a conserved DNA binding motif found in the nonhistone high-mobility group (HMG) proteins. In the mouse, Sry is required for normal testicular development and is expressed in the developing male gonadal ridge as well as in the adult testis. In man, SRY expression has been observed in the adult testis, but not in other adult male tissues. We have analyzed samples from human prostate adenocarcinoma and benign prostatic hypertrophy (BPH) for the expression of the SRY gene. We found expression of SRY in 60% of malignant prostate tumors and in three of six samples of BPH. We did not find expression in male or female colon mucosa, or in tissue from a cystic ovary. Malignant and atrophic testicular tissue both contained SRY transcript and served as positive controls in these experiments. We also found SRY transcript in the DU-145 prostate adenocarcinoma cell line. Interestingly, SRY expression is absent in the Tera-2 teratocarcinoma cell line. The potential for the SRY gene product to bind HMG core response elements in vitro suggests that SRY could participate in the cascade of gene regulatory events that result in aberrant cell growth or malignancy. © 1993 Wiley-Liss, Inc.
Bilateral spontaneous hyphema, vitreous hemorrhage, and choroidal detachment with concurrent dabigatran etexilate therapy

A 79-year-old woman was referred for rapid onset of painless bilateral vision loss. Anterior segment exams revealed bilateral spontaneous hyphema and fibrin accumulation. Observation of the posterior chamber by B-scan ultrasound showed vitreous hemorrhage and choroidal detachment bilaterally. No evidence of additional intraocular inflammation was present. Laboratory work-up for hematologic abnormalities was unremarkable. These hemorrhagic events were suspected to be a complication from taking the novel anticoagulant, dabigatran etexilate (Pradaxa; Boehringer, Ingelheim, Germany). She initially underwent non-surgical therapy, which included immediate cessation of dabigatran, and administration of topical and systemic steroids. The lack of response to medical therapy in the left eye led to surgical treatment of vitreous and persistent subcapsular hemorrhage via pars planar vitrectomy with capsulectomy.
MYC, FAS, Apoptosis, and Immune Tolerance

The problem of immunological tolerance, the apparent ability of the immune system to discriminate between self and “nonself” is almost as old as the field of immunology. Arguably, Ehrlich’s description of the phenomenon and the ensuing belief that it is a fundamental attribute of the immune system delayed the recognition of the existence of autoimmune disease until the 1950’s (1). However, once it was realized that the immune system could respond to self molecules, the idea that self/nonself discrimination was “learned” (and therefore potentially fallible) came into vogue. It is therefore likely that this recognition prompted the appearance of models of immune tolerance, and served as the impetus for the development of the clonal selection theory (2,3). The application of this theory to explain tolerance through the deletion of potentially autoreactive cells as proposed by Burnet (3,4) persist in almost unchanged form today.
Neurobiological Relationships between Aging and Alcohol Abuse

Both biological aging and chronic exposure to alcohol may cause impaired learning and memory in man and animals. The chains of processes beginning with molecular changes that in turn alter electrophysiology and morphology and finally culminate in changes of behavior (individual and social) are largely unknown. While these chains originating with molecular events leading to the same behavioral end result may be totally different, they may also overlap at any one of these levels of biological organization, accentuate, attenuate each other, to branch again and to develop parallel to each other. There is currently some evidence from observations in humans and animals that both aging and chronic alcohol toxicity induce the following changes: brain atrophy measured in vivo by computerized tomography, histological loss of the dendritic tree of neurons in various brain regions including hippocampus and cerebellum, and a variety of chemical changes of brain synaptic function, such as loss of benzodiazepine receptors.
Effects of Question Order on Estimates of the Prevalence of Attempted Weight Loss

Although numerous surveys have been conducted to estimate the prevalence of attempted weight loss, little information is available on the possible effects of question order on the prevalence estimates. The authors examined data collected from 231,852 respondents to surveys conducted in the District of Columbia and 20 states that participated in the Behavioral Risk Factor Surveillance System between 1985 and 1992. In surveys conducted from 1985 to 1988, respondents (n = 117,827) were first asked their body weight and then were asked if they were trying to lose weight; 48% of the women and 29% of the men reported that they were trying to lose weight. In 1989, 1991, and 1992 (no questions about weight control were asked in 1990), the order of the questions was reversed so that respondents (n = 114,025) were asked whether they were trying to lose weight before they were asked to report their weight; 41% of the women and 26% of the men reported that they were trying to lose weight. The authors conclude that survey respondents, especially women, may be more likely to report that they are trying to lose weight when questions about weight control practices immediately follow questions on current weight. This apparent effect of question order points to the need for caution in comparing prevalence estimates across surveys in which the questions are not asked in a similar order, even when the questions are worded identically.
A record of sustained prehistoric and historic land use from the Cahokia region, Illinois, USA

In eastern North America, large prehistoric settlements were concentrated in and along the floodplains of the midcontinent, but few sedimentary records have been examined adjacent to these sites to evaluate the impacts of Native American land use on terrestrial ecosystems. Here we report a high-resolution and multiproxy paleoecological record from Horseshoe Lake, an oxbow lake in the central Mississippi River valley that is adjacent to the Cahokia site (Illinois, USA), the largest prehistoric settlement north of Mexico. Palynological and carbon isotope data document pronounced vegetation changes over the past 1700 yr driven primarily by land use, including 900 yr (450–1350 CE) of sustained prehistoric human impacts. Rapid forest clearance was followed closely by the proliferation of indigenous seed crops of the Eastern Agricultural Complex beginning ca. 450 CE, centuries before the emergence of Cahokia at 1050 CE. Agricultural intensification that included the use of maize ( Zea mays subsp. mays ) followed this initial clearance, with peak land use intensity between 900 and 1200 CE. A large flood event ca. 1200 CE marks the onset of agricultural contraction and Cahokia’s decline. Reforestation follows the abandonment of the Cahokia region at ca. 1350 CE. The Horseshoe Lake record thus indicates that regional agricultural activity began abruptly at 450 CE and intensified over the following centuries, well before the formation of Cahokia and other large prehistoric settlements. The evidence that a major flood coincided with the onset of Cahokia’s decline is noteworthy, but will require corroboration from additional records.
REINFORCEMENT: A NEW PERSPECTIVE ON AN OLD CONTROVERSY.

A critical component of the reinforcement model, incomplete postzygotic reproductive isolation, has been overlooked in the many selection experiments designed to test this model. Many field observations are consistent with the reinforcement model, but theoretical work predicts that reinforcement should only work when nearly complete postzygotic reproductive isolation has developed. The experiments described here used four levels of postzygotic reproductive isolation: complete, strong, moderate, and none. A significant decrease in heterotypic matings occurred over 25 generations in the complete postzygotic reproductive isolation treatment. No evidence for reinforcement was found in any of the other treatments using incomplete postzygotic reproductive isolation.
Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice

Inbred immunocompetent C57BL/6 mice have been a favored strain to study transgene expression of human blood coagulation factor IX (hF.IX) from viral vectors because systemic expression of the secreted protein is not limited by antibody responses following intravenous (i.v.) injection of vector. For example, i.v. injection of an adenoviral (Ad) vector results in sustained expression of hF.IX in normal or hemophilic C57BL/6 mice, while anti-hF.IX antibodies rapidly emerge in other strains (Gene Therapy 4: 473; Blood 91: 784). To investigate these observations further, we injected naive C57BL/6 mice and C57BL/6 mice with pre-existing anti-hF.IX with Ad-hF.IX vector via peripheral vein. All mice expressed hF.IX antigen without detectable anti-hF.IX, even when challenged with hF.IX in different immunogenic settings at later time points. Moreover, in mice with pre-existing immunity, anti-hF.IX titers diminished to undetectable levels after i.v. administration of Ad-hF.IX. Lymphocytes from mice that had received Ad-hF.IX i.v. failed to proliferate when stimulated with hF.IX in vitro after the animals had been repeatedly challenged with hF.IX protein formulated in complete Freund's adjuvant. Thus, absence of anti-hF.IX in C57BL/6 mice after i.v. injection of Ad vector is not due to ignorance to the foreign transgene product. Similar experiments in other strains showed that immune tolerance to hF.IX does not correlate with the strain haplotype or expression of IL-10 cytokine. Given the well-documented immunogenicity of the first-generation adenoviral vector, data from C57BL/6 mice may therefore grossly underestimate immunological consequences in certain gene therapy protocols.
Pro-oxidant and anti-oxidant mechanism(s) of BHT and beta-carotene in photocarcinogenesis.

An hypothesis for the role of free radicals in cancer was elaborated by D. Harman in 1962 who suggested that it might be possible to reduce the extent of damage caused by free radicals through three dietary changes: (i) caloric reduction, i.e., lowering the level of free radical reactions arising in the course of normal metabolism; (ii) minimize dietary components that tend to increase the level of free radical reactions (e.g., polyunsaturated fats); and (iii) supplement the diet with one or more free radical reaction inhibitors (anti-oxidants). With respect to (ii) and (iii), lipid peroxidation exemplifies the type of chain reaction initiated by free radicals, with unsaturated fatty acids being the primary center of free radical attack. Anti-oxidants act as free radical scavengers and are able to terminate these reactions. Indeed, the phenolic anti-oxidant butylated hydroxytoluene (BHT), and the carotenoid beta-carotene, have both been shown to influence photocarcinogenesis, although the lack of correlation between physicochemical parameters and pathophysiological responses is apparent in both instances. The bimolecular rate constant for reaction of BHT with model peroxyl radicals is low while beta-carotene is highly reactive. However, both are able to efficiently inhibit lipid peroxidation reactions in biological membranes. Indeed, the influence of photocarcinogenesis by both BHT and beta-carotene is diminished as the level of dietary fat decreases, pointing to the involvement of lipid peroxidative reactions. Nevertheless, the mode of action of BHT in inhibiting photocarcinogenesis appears to be related to dose-diminution resulting from an increased spectral absorbance of the stratum corneum. On the other hand, beta-carotene has no such effect and may actually exacerbate photocarcinogenesis under certain dietary conditions. This paradox points to the complex relationship between chemical mechanisms and biological mode of action of anti-oxidants in photocarcinogenesis. Recent clinical and experimental data also suggest that supplementation of the complex and intricately balanced natural antioxidant defense system with one or more anti-oxidants as a cancer prevention strategy will demand extreme caution.
Prognostic Factors in Carcinoma of the Ureter

AbstractThe records and pathological slides of 60 patients with ureteral cancer were reviewed with particular attention being paid to the tumor-adjacent mucosa. Mucosal abnormalities increased as grade and stage increased but their presence did not correlate with survival nor with the presence of urothelial tumors elsewhere, that is previous, concomitant and subsequent tumors.Patients with papillary and solid tumors survived equally well. Survival among patients with stage B tumors was better than that reported previously (82 per cent survived 5 years).
Age-dependent vitreous separation from the macula in a clinic population.

BACKGROUND Vitreous degeneration begins soon after birth and accelerates throughout life. Vitreous liquefaction with a slowly progressive separation of the posterior hyaloid from the peripheral macula usually leads to complete posterior vitreous detachment. The purpose of this study is to measure the age-related prevalence of partial vitreous separation and the length of residual vitreous adhesion in an ophthalmology clinic population. METHODS Patients examined by the senior author (MWS) during a 6-month period were included in a retrospective chart review. Demographic data and spectral domain optical coherence tomography scan results were gathered. Data analysis with descriptive statistics focused on the prevalence and extent of partial vitreous separation. RESULTS The mean age of the study patients was 69.9 years, and 62% were phakic. The highest prevalence of partial posterior hyaloid separation from the internal limiting membrane (71.2%) was seen in the 50- to 54-year age group. This prevalence rate steadily decreased to 5.6% in the 95- to 99-year age group. The prevalence of complete vitreous detachment as determined by slit-lamp biomicroscopy increased from 1.7% in the <50-year age group to a maximum of 29.2% in the 75- to 79-year group. The length of vitreomacular adhesion averaged 4.6 mm in the 50- to 54-year age group and steadily decreased to 2.1 mm in the 90- to 95-year group. CONCLUSION Vitreomacular separation affects the majority of eyes in the sixth decade of life. The prevalence of partial vitreous separation decreases with advancing age, probably because an increasing number of these patients progress to complete posterior vitreous detachment.
What’s New in Pharmacokinetics and Pharmacodynamics?

Summary The optimum administration of drugs during the course of an anesthetic requires a precise knowledge of pharmacokinetics and pharmacodynamics. Some recent work has demonstrated that clearer and more accurate information about these relations can be obtained with greater facility with the use of the latest advances in clinical pharmacology study design and data analysis. The influences of age, anesthetic drugs, and genetics may account for some of the important interindividual variability in kinetics and dynamics. Delineation of the qualitative and quantitative influence of these and other factors should improve clinical anesthetic care. This may occur by the avoidance of dose-related side effects and the application of creative and new methods of administering already existant drugs (for example, exponentially tapering drug infusions). Much of what is new in anesthetic drugs is intimately tied to the principles of pharmacokinetics and pharmacodynamics. Therefore, anesthesiologists should be conversant with the terminology and concepts used by investigators in this field so that new information can be assessed and, if appropriate, incorporated into anesthesia practice.
Association Between Intensity of Statin Therapy and Mortality in Patients With Atherosclerotic Cardiovascular Disease.

Importance High-intensity statin therapy is recommended for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Nevertheless, statin therapy in general, and high-intensity statin therapy in particular, is underused in patients with established ASCVD. Objective To determine the association between all-cause mortality and intensity of statin therapy in the Veterans Affairs health care system. Design, Setting, and Participants A retrospective cohort analysis was conducted of patients aged 21 to 84 years with ASCVD treated in the Veterans Affairs health care system from April 1, 2013, to April 1, 2014. Patients who were included had 1 or more International Classification of Diseases, Ninth Revision codes for ASCVD on 2 or more different dates in the prior 2 years. Exposures Intensity of statin therapy was defined by the 2013 American College of Cardiology/American Heart Association guidelines, and use was defined as a filled prescription in the prior 6 months. Patients were excluded if they were taking a higher statin dose in the prior 5 years. Main Outcomes and Measures The primary outcome was death from all causes adjusted for the propensity to receive high-intensity statins. Results The study sample included 509 766 eligible adults with ASCVD at baseline (mean [SD] age, 68.5 [8.8] years; 499 598 men and 10 168 women), including 150 928 (29.6%) receiving high-intensity statin therapy, 232 293 (45.6%) receiving moderate-intensity statin therapy, 33 920 (6.7%) receiving low-intensity statin therapy, and 92 625 (18.2%) receiving no statins. During a mean follow-up of 492 days, there was a graded association between intensity of statin therapy and mortality, with 1-year mortality rates of 4.0% (5103 of 126 139) for those receiving high-intensity statin therapy, 4.8% (9703 of 200 709) for those receiving moderate-intensity statin therapy, 5.7% (1632 of 28 765) for those receiving low-intensity statin therapy, and 6.6% (4868 of 73 728) for those receiving no statin ( P Conclusions and Relevance We found a graded association between intensity of statin therapy and mortality in a national sample of patients with ASCVD. High-intensity statins were associated with a small but significant survival advantage compared with moderate-intensity statins, even among older adults. Maximal doses of high-intensity statins were associated with a further survival benefit.
Measuring Signaling and RNA-Seq in the Same Cell Links Gene Expression to Dynamic Patterns of NF-κB Activation

Signaling proteins display remarkable cell-to-cell heterogeneity in their dynamic responses to stimuli, but the consequences of this heterogeneity remain largely unknown. For instance, the contribution of the dynamics of the innate immune transcription factor nuclear factor κB (NF-κB) to gene expression output is disputed. Here we explore these questions by integrating live-cell imaging approaches with single-cell sequencing technologies. We used this approach to measure both the dynamics of lipopolysaccharide-induced NF-κB activation and the global transcriptional response in the same individual cell. Our results identify multiple, distinct cytokine expression patterns that are correlated with NF-κB activation dynamics, establishing a functional role for NF-κB dynamics in determining cellular phenotypes. Applications of this approach to other model systems and single-cell sequencing technologies have significant potential for discovery, as it is now possible to trace cellular behavior from the initial stimulus, through the signaling pathways, down to genome-wide changes in gene expression, all inside of a single cell.
Optimized static and video EEG rapid serial visual presentation (RSVP) paradigm based on motion surprise computation

In this paper, we describe an algorithm and system for optimizing search and detection performance for “items of interest” (IOI) in large-sized images and videos that employ the Rapid Serial Visual Presentation (RSVP) based EEG paradigm and surprise algorithms that incorporate motion processing to determine whether static or video RSVP is used. The system works by first computing a motion surprise map on image sub-regions (chips) of incoming sensor video data and then uses those surprise maps to label the chips as either “static” or “moving”. This information tells the system whether to use a static or video RSVP presentation and decoding algorithm in order to optimize EEG based detection of IOI in each chip. Using this method, we are able to demonstrate classification of a series of image regions from video with an azimuth value of 1, indicating perfect classification, over a range of display frequencies and video speeds.
An analog phase prediction based fractional-N PLL

A synthesizer design for achieving high frequency resolution and stability is described. Fractional-N resolution is achieved, without using the classical dual-modulus divider, by exploiting the predictable phase evolution. The predicted phase is added in the feed-forward path within an integer-N analog PLL. A digital pulse generator (DPG) cancels the expected phase difference between the reference and feedback signal. A high-speed current-steering DAC increases the effective pulse width resolution overcoming the limit imposed by the VCO frequency. A novel ping-pong swallow counter topology masks the pipeline delay of a synchronous frequency divider used in the DPG. The architecture has been designed and simulated in a CMOS 0.13 μm technology. For a 5 GHz VCO and 100 MHz reference, the synthesizer exhibits 1.5 Hz frequency steps with the wide-band performance of a conventional charge pump PLL.
Systemic and unconventional antigen presentation generates insulin autoantibodies targeting the islet of Langerhans

The presence of class-switched insulin autoantibodies (IAAs) is a prominent feature of patients with type 1 diabetes (T1D) and the non-obese diabetic (NOD) mice. Although IAAs are commonly used as a biomarker for T1D prognosis, their genesis and whether they play a pathogenic role is largely unknown. In this study, we developed a novel anti-insulin T cell and B cell receptor transgenic mouse model to investigate cognate interactions between insulin-reactive T and B lymphocytes, a process necessary for IAA production. Strikingly, dynamic anti-insulin T-B cell interactions, spontaneous germinal center formation, and active class-switch recombination occurred in multiple lymphoid organs, leading to remarkable IAA production. Naive anti-insulin T cells differentiated into competent T follicular helper cells that produced critical factors for reversing B cell tolerance, promoting GC selection, and broadening the repertoire of insulin epitope presentation. Furthermore, the IAAs produced in the peripheral sites relocated into the islets of Langerhans, formed deposits on β-cells, and enhanced presentation of diabetogenic antigens by the resident islet macrophages. Overall, these results indicate that insulin presentation is disseminated throughout secondary lymphoid tissues, and is sufficient for generation of autoantibodies that precipitate previously unrecognized pathogenic outcomes in the target organ.
Chapter 7 – The Vitamin D Receptor: Biochemical, Molecular, Biological, and Genomic Era Investigations

Publisher Summary This chapter presents a historical overview as well as a contemporary summary of the vitamin D receptor's (VDR's) central role in mediating the actions of the vitamin D hormone. It also describes the discovery of the receptor and summarizes its biochemical characteristics and comment on several of the biological processes with which the receptor is involved. The now available crystal structure of the VDR LBD has placed much of the biochemical and molecular biologic investigation into perspective. The structure of the VDR/RXR heterodimer bound to its cognate response element is yet to be determined, however. Following this discussion, the chapter describes the VDR's structural domains and describes how these components of the receptor integrate various processes through which gene expression is regulated. The results of recent analyses which demonstrate new principles of transcriptional control at both genome-wide and epigenomic levels are also considered in the chapter. Finally, the chapter explains the structural organization of the human VDR chromosomal gene and, using new genomic approaches, provides new insight into how the VDR gene is regulated at the molecular level.
Open Access, African Scholarly Publishing, and Cultural Rights: An Exploratory Usage and Accessibility Study

The Open Access (OA) Movement has been praised by proponents as a way to reverse the unsustainability of traditional scholarly publishing economic models and to aid in the equalization of the flow of information between industrialized and less industrialized nations. The OA Movement is thus also seen as a means of helping achieve both Articles 19 and 27 of the Universal Declaration of Human Rights (UDHR) which jointly articulate the basic human rights to seek, receive and impart information, to participate in the cultural life of the community, to enjoy the arts, and to share in scientific advancement. Historically however, library and information development in much of colonial Sub-Saharan Africa was influenced by hegemonic structures that did not promote these ideals. This exploratory study uses data gathered during a forty day period to compare the OA journal usage of researchers in African countries with that of researchers in Latin American and Caribbean countries. Indexing and abstracting of African scholarly journals is also a key necessity if a more even flow of information from Southern to Northern countries is to be achieved and if the journals themselves are to be truly accessible to other scholars. Therefore, the study also examines the accessibility of indexing and abstracting coverage of African scholarly OA journals and compares the data with that of non-OA journals from the continent. I examine the relationship between current African OA usage and content production and the cultural rights expressed in Article 27 of the UDHR. The study data suggests that, in contrast to Latin American and Caribbean countries, African researchers are being less active consumers and more passive contributors to the OA model. OA is thus not yet contributing significantly to the reversal of North to South information flows in the African context nor is it yet making a significant impact on achieving the rights guaranteed in Articles 19 and 27 of the UDHR. The results also indicate that African OA publications are more accessible in the abstracting and indexing services than non-OA African publications, so an increased shift from non-OA to OA publications in African scholarly publishing may contribute to improving information flow reversal in the future.
Position of the American Dietetic Association: Functional foods.

All foods are functional at some physiological level, but it is the position of the American Dietetic Association (ADA) that functional foods that include whole foods and fortified, enriched, or enhanced foods have a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis, at effective levels. ADA supports research to further define the health benefits and risks of individual functional foods and their physiologically active components. Health claims on food products, including functional foods, should be based on the significant scientific agreement standard of evidence and ADA supports label claims based on such strong scientific substantiation. Food and nutrition professionals will continue to work with the food industry, allied health professionals, the government, the scientific community, and the media to ensure that the public has accurate information regarding functional foods and thus should continue to educate themselves on this emerging area of food and nutrition science. Knowledge of the role of physiologically active food components, from plant, animal, and microbial food sources, has changed the role of diet in health. Functional foods have evolved as food and nutrition science has advanced beyond the treatment of deficiency syndromes to reduction of disease risk and health promotion. This position paper reviews the definition of functional foods, their regulation, and the scientific evidence supporting this evolving area of food and nutrition. Foods can no longer be evaluated only in terms of macronutrient and micronutrient content alone. Analyzing the content of other physiologically active components and evaluating their role in health promotion will be necessary. The availability of health-promoting functional foods in the US diet has the potential to help ensure a healthier population. However, each functional food should be evaluated on the basis of scientific evidence to ensure appropriate integration into a varied diet.
Genetic Algorithms as a Computational Theory of Conceptual Design

The essentially inductive processes of conceptual design have received scant attention in those portions of the design literature concerned with effective computation or mathematical rigor. This paper draws a connection between the discriminative and recombinative processes of conceptual design and genetic algorithms (GAs)—search procedures based on the mechanics of natural genetics and natural selection. Recent empirical and theoretical results with a type of GA called a messy genetic algorithm support the conjecture that GAs can solve all problems no harder than the functions of bounded deception in time that grows no more quickly than a polynomial function of the number of decision variables. These results suggest that inductive designers—far from wasting their efforts when they bet on some combination of past designs—are engaging in a computationally effective means of solving very difficult, even misleading, design problems. Although more theoretical and computational work is needed, the paper shows one path to a more rigorous theory of conceptual design, a path that should help put design on the same mathematical foundations as analysis without detracting from the joy, or the necessity, of human invention.
Nietzsche’s Conception of Health: The Idealization of Struggle

With Darwin, a materialistic basis was established for explaining the emergence and transformation of species, shaking to its very foundation the preceding conception of natural order. By the end of the last century, it was generally recognized that the crucial role played by Darwin was the introduction of historical analysis to the center of biological thinking. Both the species and the organism became less entities than processes, dynamically evolving and ever-different. Being was fully realized as a Heraclitean flux, a becoming. This metaphysical revolution of how we would henceforth regard time, the biological world, and most fundamentally, ourselves, was the challenge to which Friedrich Nietzsche responded; and in that response he challenged the pre-Darwinian notions of health. Specifically, what Bernard had championed as the “normal,” a stable interior milieu (or what Walter Cannon would later call “homeostasis”), Nietzsche would endeavor to replace with inner turmoil as the essence of biological function. While evolutionary biologists would refer to “fitness,” Nietzsche would pervade his entire philosophy with the elusive maximal adaptation of the striving organism. This struggle was directed towards some unspecified and unknowable ideal, and Nietzsche invoked this struggle as the essence of health.
Deep Venous Thrombosis and Pulmonary Embolism

10% of hospital deaths are attributed to pulmonary embolism (PE) In-hospital case-fatality rate of venous thromboembolism (VTE) is ∼12% Pulmonary embolism (PE) 79% of patients who present with PE have evidence of DVT in lower extremities Overall 3-month mortality is ∼15% Most common cause of early death is right ventricular failure Mortality after 30 days is usually caused by underlying disease 18% of patients with PE and right ventricular (RV) failure or pulmonary hypertension present in cardiac arrest Mortality of untreated PE is ∼30% Mortality can be reduced to 2–8% with anticoagulant therapy Independent comorbid predictors of 3-month mortality: age, congestive heart failure, cancer, chronic lung disease Rate of recurrent VTE on anticoagulation is <5% (30% after 10 years) PE occurs in ∼15% of patients with central venous catheter-related upper-extremity deep venous thrombosis (DVT) Intracranial VTE can be a cause of new-onset seizure activity