Miracle-dz/UniFAR-FTUs huggingface dataset:
Poliovirus cre(2C)-Dependent Synthesis of VPgpUpU Is Required for Positive- but Not Negative-Strand RNA Synthesis

ABSTRACT The cre(2C) hairpin is a cis-acting replication element in poliovirus RNA and serves as a template for the synthesis of VPgpUpU. We investigated the role of the cre(2C) hairpin on VPgpUpU synthesis and viral RNA replication in preinitiation RNA replication complexes isolated from HeLa S10 translation-RNA replication reactions. cre(2C) hairpin mutations that block VPgpUpU synthesis in reconstituted assays with purified VPg and poliovirus polymerase were also found to completely inhibit VPgpUpU synthesis in preinitiation replication complexes. Surprisingly, blocking VPgpUpU synthesis by mutating the cre(2C) hairpin had no significant effect on negative-strand synthesis but completely inhibited positive-strand synthesis. Negative-strand RNA synthesized in these reactions immunoprecipitated with anti-VPg antibody and demonstrated that it was covalently linked to VPg. This indicated that VPg was used to initiate negative-strand RNA synthesis, although the cre(2C)-dependent synthesis of VPgpUpU was inhibited. Based on these results, we concluded that the cre(2C)-dependent synthesis of VPgpUpU was required for positive- but not negative-strand RNA synthesis. These findings suggest a replication model in which negative-strand synthesis initiates with VPg uridylylated in the 3′ poly(A) tail in virion RNA and positive-strand synthesis initiates with VPgpUpU synthesized on the cre(2C) hairpin. The pool of excess VPgpUpU synthesized on the cre(2C) hairpin should support high levels of positive-strand synthesis and thereby promote the asymmetric replication of poliovirus RNA.
Experiments in Character-Level Neural Network Models for Punctuation

We explore character-level neural network models for inferring punctuation from text-only input. Punctuation inference is treated as a sequence tagging problem where the input is a sequence of un-punctuated characters, and the output is a corresponding sequence of punctuation tags. We experiment with six architectures, all of which use a long short-term memory (LSTM) network for sequence modeling. They differ in the way the context and lookahead for a given character is derived: from simple character embedding and delayed output to enable lookahead, to complex convolutional neural networks (CNN) to capture context. We demonstrate that the accuracy of proposed character-level models are competitive with the accuracy of a state-of-the-art word-level Conditional Random Field (CRF) baseline with carefully crafted features.
Imaging correlates of successful endoscopic third ventriculostomy.

OBJECT The goal of this study was to determine and compare imaging correlates in pediatric patients who underwent successful or failed endoscopic third ventriculostomies (ETVs). To this end, the authors measured ventricular size changes and the presence of cerebrospinal fluid (CSF) flow void in both groups of children following ETV. METHODS Images obtained in children with hydrocephalus immediately before and at least 30 days after having undergone ETV were reviewed by four independent observers (two blinded and two nonblinded). Each observer independently measured the frontal and occipital horn ratio ([FOR], a reliable and valid measure of ventricular size) and provided a subjective assessment of the presence of a flow void at the ETV site, the degree of periventricular edema, and the amount of CSF over the cerebral hemispheres. There were 29 children whose mean age was 6.6 years at the time of ETV and who had a mean postoperative follow-up period lasting 1.6 years. Postoperatively, the mean reduction in ventricular size (as measured using the FOR) was 7% (95% confidence interval [CI] 3-11%) in cases that were deemed failures (eight patients) and 16% (95% CI 12-20%) in clinically successful cases (21 patients). This reduction was significantly greater in cases of clinical success compared with those that were deemed failures (p = 0.03, t-test). There were no substantial differences between blinded and nonblinded assessments. Flow void was present in 94% of successes and absent in 75% of failures (p = 0.01, Fisher's exact test). The other subjective assessments were not significantly different between the groups of successes and failures. CONCLUSIONS Ventricular size appears to be somewhat reduced in both groups of patients who underwent clinically successful and failed ETV; however, the reduction is significantly greater among clinically successful cases. The presence of a flow void also appears to correlate with clinical success and its absence with clinical failure.
Health insurance coverage in survivors of childhood cancer: the Childhood Cancer Survivor Study.

PURPOSE To examine the prevalence and predictors of health insurance coverage and the difficulties obtaining coverage in a large cohort of childhood cancer survivors. PATIENTS AND METHODS This study included 12,358 5-year survivors of childhood cancer and 3,553 sibling controls participating in the Childhood Cancer Survivor Study. Data were collected by surveys distributed in 1994 (baseline) and 2000 (follow-up). RESULTS At baseline, 83.9% of adult survivors, compared with 88.3% of siblings, had health insurance coverage (P < .01); 6 years later, small but significant survivor-sibling differences remained (88% v 91%; P < .01). Twenty-nine percent of survivors reported having had difficulties obtaining coverage, compared with only 3% of siblings (P < .01). In multivariate analysis of survivors 18 years of age or older, factors associated with being uninsured included younger age at diagnosis (diagnosis age of 0 to 4 years; odds ratio [OR] = 1.7; 95% CI, 1.3 to 2.2), male sex (OR = 1.3; 95% CI, 1.2 to 1.5), age at baseline survey (age 22 to 24 years; OR = 1.6; 95% CI, 1.2 to 2.1), lower level of attained education (less than high school, OR = 2.6, 95% CI, 2.1 to 3.3; high school graduate, OR = 2.1, 95% CI, 1.8 to 2.5), income less than 20,000 dollars (OR = 5.6, 95% CI, 4.5 to 7.1), marital status (widowed/divorced/separated; OR = 1.3; 95% CI, 1.1 to 1.6), smoking status (current smoker, OR = 2.0, 95% CI, 1.7 to 2.3; former smoker, OR = 1.4, 95% CI, 1.2 to 1.8), and treatment that included cranial radiation (OR = 1.3, 95% CI, 1.0 to 1.6). CONCLUSION Compared with siblings, adult survivors of childhood cancer had significantly lower rates of health insurance coverage and more difficulties obtaining coverage. Since lack of coverage likely has serious health and financial implications for this at-risk population, any disparity in availability and quality of coverage is of great concern.
Vascular-Targeting Antioxidant Therapy in a Model of Hypertension and Stroke

Oxidative stress is implicated in the pathogenesis of hypertension and stroke. Superoxide is produced by NAD(P)H oxidase in the vasculature and reduces nitric oxide bioavailability, which leads to increased blood pressure. The objective of this study was to determine whether targeting an antioxidant peptide to the vasculature would increase the antioxidant effect and reduce systolic blood pressure (SBP) in a model of genetic hypertension, the stroke-prone spontaneously hypertensive rat. Vascular-targeting peptides CRPPR and CSGMARTKC were identified by phage display in mice. These peptides retain their selectivity across species and target the aorta (CRPPR) and cardiac vasculature (CSGMARTKC) in the stroke-prone spontaneously hypertensive rat. These vascular-targeting peptides were linked to the antioxidant peptide gp91ds, which selectively inhibits assembly of NAD(P)H oxidase, thereby reducing superoxide production. SBP was determined for 1 week before treatment followed by 3 weeks of study duration before euthanasia. SBP in the control animals increased from 178.1 ± 4.1 mmHg to 201.6 ± 9.0 mmHg. The SBP of the animals treated with gp91ds alone, HIV-tat-gp91ds, and CSGMARTKC-gp91ds increased from 177.8 ± 3.5 mmHg, 179.8 ± 4.7 mmHg, and 177.9 ± 5.2 mmHg, respectively, to 201.6 ± 10.8 mmHg, 200.3 ± 11.7 mmHg and 205.7 ± 10.9 mmHg, respectively. This increase in SBP was significantly attenuated in animals receiving CRPPR-gp91ds (maximum SBP 187.5 mmHg ± 5.2, *P < 0.001 versus other treatment groups and control group). Additionally, animals treated with CRPPR-gp91ds, CSGMARTKC-gp91ds, and gp91ds alone showed significantly improved nitric oxide bioavailability determined by large vessel myography. Therefore, targeting an antioxidant to the aortic vasculature in vivo using peptides can significantly improve nitric oxide bioavailability and attenuate the time-dependent and progressive increase in SBP in the stroke-prone spontaneously hypertensive rat. This study has demonstrated the importance and potential benefit of targeting a biologically active peptide in the context of a preclinical model of endothelial dysfunction and hypertension.
Akt 1 kinase and dynamics of insulin resistance in denervated muscles in vivo

Turinsky, Jiri, and Alice Damrau-Abney. Akt1 kinase and dynamics of insulin resistance in denervated muscles in vivo. Am. J. Physiol. 275 (Regulatory Integrative Comp. Physiol. 44): R1425–R1430, 1998. —Basal and insulinstimulated activity of Akt1 kinase and uptake of 2-deoxy-Dglucose (2-DG) were measured in soleus (slow-twitch) and plantaris (fast-twitch) muscles of rats at 1 and 3 days after sectioning the sciatic nerve in one hindlimb of the animals. At 1 day after surgery, the insulin-stimulated activity of Akt1 kinase in denervated soleus and plantaris muscles remained unchanged, but the insulin-stimulated 2-DG uptake by these muscles was reduced by 71 and 61%, respectively, compared with the corresponding muscles of the contralateral sham (control) hindlimb. At 3 days, the insulin-stimulated activity of Akt1 kinase in the denervated soleus and plantaris muscles was 86 and 71% lower, respectively, than in their sham counterparts.At this time point, the denervated soleus muscles showed no increase in 2-DG uptake in response to insulin. In contrast, the denervated plantaris muscle exhibited the same absolute level of insulin-stimulated 2-DG uptake as the sham plantaris muscle; however, the insulin-induced increment in 2-DG uptake was reduced by 60%, whereas basal 2-DG uptake was increased by 251% compared with the sham plantaris muscle. None of the denervated muscles showed a decrease in the abundance of Akt1 kinase. The results demonstrate that the causes of insulin resistance in denervated muscles are dependent on time after surgery. Initially, they involve only mechanisms downstream of Akt1 kinase (day 1), whereas at day 3 they also involve mechanisms upstream of, and including, Akt1 kinase.
Epiplakin Is Dispensable for Skin Barrier Function and for Integrity of Keratin Network Cytoarchitecture in Simple and Stratified Epithelia

ABSTRACT Epiplakin, a giant epithelial protein of >700 kDa, belongs to the plakin family of cytolinker proteins. It represents an atypical family member, however, as it consists entirely of plakin repeat domains but lacks any of the other domains commonly shared by plakins. Hence, its putative function as a cytolinker protein remains to be shown. To investigate epiplakin's biological role, we generated epiplakin-deficient mice by gene targeting in embryonic stem cells. Epiplakin-deficient mice were viable and fertile, without developing any discernible phenotype. Ultrastructurally, their epidermis revealed no differences compared to wild-type littermates, and cornified envelopes isolated from skin showed no alterations in shape or stability. Furthermore, neither embryonal formation nor later function of the epithelial barrier was affected. In primary cultures of epiplakin-deficient keratinocytes, the organization of actin filaments, microtubules, and keratin networks was found to be normal. Similarly, no alterations in keratin network organization were observed in simple epithelia of small intestine and liver or in primary hepatocytes. We conclude that, despite epiplakin's abundant and highly specific expression in stratified and simple epithelia, its absence in mice does not lead to severe skin dysfunctions, nor has it detectable consequences for keratin filament organization and cytoarchitecture of cells.
A Multivariate Sign EWMA Control Chart

Nonparametric control charts are useful in statistical process control (SPC) when there is a lack of or limited knowledge about the underlying process distribution, especially when the process measurement is multivariate. This article develops a new multivariate SPC methodology for monitoring location parameters. It is based on adapting a powerful multivariate sign test to online sequential monitoring. The weighted version of the sign test is used to formulate the charting statistic by incorporating the exponentially weighted moving average control (EWMA) scheme, which results in a nonparametric counterpart of the classical multivariate EWMA (MEWMA). It is affine-invariant and has a strictly distribution-free property over a broad class of population models. That is, the in-control (IC) run length distribution can attain (or is always very close to) the nominal one when using the same control limit designed for a multivariate normal distribution. Moreover, when the process distribution comes from the elliptical direction class, the IC average run length can be calculated via a one-dimensional Markov chain model. This control chart possesses some other favorable features: it is fast to compute with a similar computational effort to the MEWMA chart; it is easy to implement because only the multivariate median and the associated transformation matrix need to be specified (estimated) from the historical data before monitoring; it is also very efficient in detecting process shifts, particularly small or moderate shifts when the process distribution is heavy tailed or skewed. Two real-data examples from manufacturing show that it performs quite well in applications. This article has supplementary material online.
Knowledge-based classification of polarimetric SAR images

In preparation for the flight of the Shuttle Imaging Radar-C (SIR-C) on board the Space Shuttle in the spring of 1994, a level-1 automatic classifier was developed on the basis of polarimetric SAR images acquired by the JPL AirSAR system. The classifier uses L- and C-Band polarimetric SAR measurements of the imaged scene to classify individual pixels into one of four categories: tall vegetation (trees), short vegetation, urban, or bare surface, with the last category encompassing water surfaces, bare soil surfaces, and concrete or asphalt-covered surfaces. The classifier design uses knowledge of the nature of radar backscattering from surfaces and volumes to construct appropriate discriminators in a sequential format. The classifier, which was developed using training areas in a test site in Northern Michigan, was tested against independent test areas in the same test site and in another site imaged three months earlier. Among all cases and all categories, the classification accuracy ranged between 91% and 100%. >
Streptomyces relC mutants with an altered ribosomal protein ST-L11 and genetic analysis of a Streptomyces griseus relC mutant

Several relaxed (rel) mutants have been obtained from Streptomyces species by selecting colonies resistant to thiopeptin, an analogue of thiostrepton. Using two-dimensional gel electrophoresis, I compared the ribosomal proteins from rel and rel+ pairs of S. antibioticus, S. lavendulae, S. griseoflavus, and S. griseus. It was found that all of the Streptomyces rel mutants thus examined had an altered or missing ribosomal protein, designated tentatively ST-L11. These rel mutants therefore could be classified as relC mutants and were highly sensitive to erythromycin or high temperature. A relC mutant of S. griseus was defective in streptomycin production, but phenotypic reversion of this defect to normal productivity was found at high incidence among progeny of the relC mutant. This phenotypic reversion did not accompany a reappearance of ribosomal protein ST-L11, and furthermore the ability of accumulating ppGpp still remained at a low level, thus suggesting existence of a mutation (named sup) which suppresses the streptomycin deficiency phenotype exhibited by the relC mutant. Genetic analysis revealed that there is a correlation between the rel mutation and the inability to produce streptomycin or aerial mycelia. The sup mutation was found to lie at a chromosomal locus distinct from that of the relC mutation. It was therefore concluded that the dependence of streptomycin production on the normal function of the relC gene could be entirely bypassed by a mutation at the suppressor locus (sup). The suppressing effect of the sup mutation on the relC mutation was blocked when the afs mutation (defective in A-factor synthesis) was introduced into a relC sup double mutant. It is proposed that the sup gene or its product can be direct or indirect target for ppGpp.
Author’s Reply to “Comments on ‘Frequency Response of the Noise Conversion From Relative Intensity Noise to Phase Noise in the Photodetection of an Optical Pulse Train”’

We reply to the comments raised by Phung and Lintz in the above comment to conclude that the results in the letter published in IEEE Photonics Technology Letters might have been misinterpreted due to the underestimiation of the RIN-to-phase-noise conversion in the laser when pump modulation is applied. Care should be taken when one uses pump modulation technique to evaluate the RIN-to-phase-noise conversion in the photodiode.
Spectrum of acute renal failure in the intensive care unit: the PICARD experience.

BACKGROUND Acute renal failure (ARF) in the critically ill is associated with extremely high mortality rates. Understanding the changing spectrum of ARF will be necessary to facilitate quality improvement efforts and to design successful interventional trials. METHODS We conducted an observational cohort study of 618 patients with ARF in intensive care units at five academic medical centers in the United States. Participants were required to sign (or have a proxy sign) informed consent for data collection. A comprehensive data collection instrument captured more than 800 variables, most on a daily basis, throughout the course of ARF. Patient characteristics, dialysis status, and major outcomes were determined and stratified by clinical site. RESULTS The mean age was 59.5 years, 41% were women, and 20% were of minority race or ethnicity. There was extensive comorbidity; 30% had chronic kidney disease, 37% had coronary artery disease, 29% had diabetes mellitus, and 21% had chronic liver disease. Acute renal failure was accompanied by extrarenal organ system failure in most patients, even those who did not require dialysis. Three hundred and ninety-eight (64%) patients required dialysis. The in-hospital mortality rate was 37%, and the rate of mortality or nonrecovery of renal function was 50%. The median hospital length of stay was 25 days (26 days, excluding patients who died). CONCLUSION There is a changing spectrum of ARF in the critically ill, characterized by a large burden of comorbid disease and extensive extrarenal complications, obligating the need for dialysis in the majority of patients. There is wide variation across institutions in patient characteristics and practice patterns. These differences highlight the need for additional multicenter observational and interventional studies in ARF.
Allogeneic reaction induces dendritic cell maturation through proinflammatory cytokine secretion1

Background. A bone marrow transplantation conditioning regimen is known to activate host dendritic cells (DC), which then become able to initiate graft-versus-host disease (GVHD) by presenting alloantigens. In this article, the authors addressed whether the alloreaction could reciprocally maintain DC in an activation state through secretion of proinflammatory cytokines. Methods. Skin biopsy specimens from GVHD patients were analyzed for the presence of DC. Supernatants collected from primary major histocompatibility antigen (allogeneic mixed leukocyte reaction [MLR] supernatant [SN]) or secondary minor histocompatibility antigen-mismatched mixed lymphocyte reactions were used to culture cytokine-promoted immature (im) DC. DC phenotype, function, and migration were analyzed. Results. Immunostaining from GVHD skin biopsy specimens showed a deficit of Langerhans cells (LC) in the epidermis but the presence of mature DC in the dermis. Because LC should have recovered in the epidermis by this time, the authors then addressed whether the allogeneic reaction could maintain DC in an activation and migratory state, through secretion of inflammatory cytokines. With this aim, cytokine-mediated imDC were exposed to alloMLR-SN for 2 days. The authors observed that DC increased their expression of CD80, CD86, CD40, and human leukocyte antigen (HLA)-DR and neoexpressed CD83, DC-LAMP/CD208, and CCR7. At the functional level, alloMLR-SN–treated DC lost their ability to capture dextran, improved their allostimulatory capacity, and migrated in response to macrophage inflammatory protein 3&bgr;. Interestingly, SN collected from secondary HLA-identical but minor histocompatibility antigen-mismatched MLR induced almost equivalent DC phenotypic maturation. Conclusions. The authors’ results show that the allogeneic reaction leads to maturation and migration of DC through proinflammatory cytokine secretion. This might contribute to the impairment of LC reconstitution in the skin of patients with GVHD.
Guidelines for economic analysis of pharmaceutical products: a draft document for Ontario and Canada.

In Canada, provincial formulary review committees consider the effectiveness, safety, and cost of products when they derive advice for each Minister of Health. This article offers a draft set of guidelines for pharmaceutical manufacturers making submissions which include economic information, moving beyond a simple presentation of the unit price of the pharmaceutical product (e.g. price per day or course of therapy) and comparison to similar prices for alternative products. A full economic analysis compares all relevant costs and clinical outcomes of the new product with alternate therapeutic strategies for treating patients with a particular condition. The perspective of the decision maker must be clearly identified. The quality of the evidence supporting estimates of the variables incorporated in the analysis should be evaluated. Sensitivity analyses are used to assess the robustness of the qualitative conclusions. Reviewers will examine the answers to a set of 19 questions. Manufacturers can use these questions as a worksheet for preparation of an economic analysis to be incorporated in a submission. These guidelines are intended to be a starting point for further refinement, and discussion with health economists in industry and academia. Considerable flexibility will be used in reviewing documentation supporting economic analysis. Those preparing submissions should be encouraged to experiment with various approaches as part of the general development of this field and to engage provincial review committees in ongoing discussions.