Miracle-dz/UniFAR-FTUs huggingface dataset:
Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2

ABSTRACT Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.
The incidence and costs of hypoglycemia in type 2 diabetes.

OBJECTIVES To estimate the rate and costs of hypoglycemia in patients with type 2 diabetes. STUDY DESIGN We used a retrospective cohort design to assess the rate and costs of hypoglycemia among working-age patients with type 2 diabetes in the 2004 to 2008 MarketScan database. METHODS We followed patients from cohort entry to the first instance of hypoglycemia requiring medical intervention (inpatient, emergency department [ED], or outpatient) and calculated incidence rates (IRs), stratifying these estimates by age (18-34, 35-49, 50-64, and 65+ years) and gender. We calculated inflation-adjusted total and mean direct costs of medical visits for hypoglycemia, other diabetes-related visits, and all other medical visits. RESULTS The cohort was composed of 536,581 members with approximately 1.21 million person years (p-yrs) of follow-up. The IR of hypoglycemic events leading to an inpatient admission, ED, or outpatient visit was 153.8/10,000 p-yrs. The IRs of hypoglycemic events were highest in adults aged 18 to 34 years (218.8/10,000 p-yrs). Regardless of age group, rates of hypoglycemia were greater in women than in men (P < .001). Total hypoglycemia costs were $52,223,675 over the study period and accounted for 1.0% of all inpatient costs, 2.7% of ED costs, and 0.3% of outpatient costs. The mean costs for hypoglycemia visits were $17,564 for an inpatient admission, $1387 for an ED visit, and $394 for an outpatient visit. CONCLUSIONS The overall incidence of visits for hypoglycemia was considerable in this large database, and was associated with high per-episode costs. Continued vigilance and the development of strategies to decrease potentially avoidable hypoglycemic episodes requiring medical intervention are needed.
Falls in patients with vestibular deficits.

OBJECTIVE To determine to what extent patients with vestibular hypofunction experience falls. STUDY DESIGN Prospective clinical study. SETTING Outpatient tertiary care facility in a university. PATIENTS Patients with unilateral (n = 70) and bilateral (n = 45) vestibular hypofunction, confirmed on vestibular function testing, aged 24 to 89 years. INTERVENTION None. MAIN OUTCOME MEASURE Incidence of falls. RESULTS There was a significant difference in the incidence of falls reported since the onset of the vestibular deficit by patients with unilateral (UVL) and bilateral (BVL) vestibular hypofunction. The incidence of falls for BVL was significantly greater than that for UVL. The incidence of falls for UVL was not different from that expected in a community-based population when age was considered. The incidence of falls for BVL was significantly greater than that reported for the general population aged 65 through 74 years (51.1% for BVL, 25% for community-dwelling individuals) but was significantly less than expected for persons aged > or =75 years (18.2% for BVL, 49% for community-dwelling individuals). The lower incidence of falls in patients with BVL aged > or =75 years may be related to the use of assistive devices and to a decrease in risky behavior. All patients with serious injury were from the UVL group, and all were >65 years old. The incidence of fall-related injuries requiring medical attention among patients with UVL was similar to that in community-dwelling individuals. CONCLUSIONS Falls are an important consequence of bilateral vestibular hypofunction, and patients should be counseled about the increased risk of falling. Assistive devices should be considered, especially for persons aged >65 years with BVL.
Analysis of blast furnace cross thermometric based on spatial data mining

Current clustering algorithms are limited in insufficient use of spatial information of cross thermometric temperature data. To address this problem, this paper presents a new similarity and distance measurement approach with which the spatial distance can be effectively computed. On the basis of new measurement, the clustering result of Jinan Iron and Steel 1# blast furnace cross thermometric temperature data show that the method can fully extract useful information of the temperature data and in practical applications with higher accuracy and reliability.
Toward an Understanding of How Threads Die in Asynchronous Computer Conferences

Previous computer conferencing research has been concerned with the organizational, technical, social, and motivational factors that support and sustain online interaction. This article studies online interaction from a different perspective. Rather than analyze the processes that sustain discourse, the following research examines how and why discussions shut down. A computer simulation of asynchronous threaded interaction suggests that certain common online habits, when practiced by many people, can adversely affect the lifespan of some threads. Specifically, the widespread practice of focusing attention on unread notes during computer conferencing sessions can produce a starvation condition that hastens the death of some threads and reduces the likelihood that inactive threads will become active again. The longevity of a thread, therefore, is partially affected by the kinds of routines that online participants follow when they use a computer conferencing interface. The educational implications of this finding are discussed, and strategies are presented for limiting adverse educational effects.
Barriers to concordance with antidiabetic drugs—cultural differences or human nature?

British Indian and British Pakistani patients think that the products of the pharmaceutical industry are potent and may do harm. They do not want to take any more tablets than they absolutely have to. They discontinue their tablets if they have major side effects. They distrust doctors who stand to gain financially from prescribing particular drugs. They use creative strategies to titrate the dose of their drugs to the lowest that they consider works.1 In all these respects, the sample reported here has more similarities to than differences from the indigenous British population, and indeed most other groups studied in relation to medicine taking.2 3 That said, this study is no less …
The SK3 Subunit of Small Conductance Ca2+-activated K+ Channels Interacts with Both SK1 and SK2 Subunits in a Heterologous Expression System*

The aim of this study was to determine whether functional heteromeric channels can be formed by co-assembly of rat SK3 (rSK3) potassium channel subunits with either SK1 or SK2 subunits. First, to determine whether rSK3 could co-assemble with rSK2 we created rSK3VK (an SK3 mutant insensitive to block by UCL 1848). When rSK3VK was co-expressed with rSK2 the resulting currents had an intermediate sensitivity to UCL 1848 (IC50 of ∼5nm compared with 120 pm for rSK2 and >300 nm for rSK3VK), suggesting that rSK3 and rSK2 can form functional heteromeric channels. To detect co-assembly of SK3 with SK1, we initially used a dominant negative construct of the human SK1 subunit (hSK1YP). hSK1YP dramatically reduced the SK3 current, supporting the idea that SK3 and SK1 subunits also interact. To determine whether these assemblies were functional we created rSK3VF, an rSK3 mutant with an enhanced affinity for tetraethylammonium chloride (TEA) (IC50 of 0.3 mm). Co-transfection of rSK3VF and hSK1 produced currents with a sensitivity to TEA not different from that of hSK1 alone (IC50 ∼15 mm). These results suggest that hSK1 does not produce functional cell-surface assemblies with SK3. Antibody-staining experiments suggested that hSK1 may reduce the number of functional SK3 subunits reaching the cell surface. Additional experiments showed that co-expression of the rat SK1 gene with SK3 also dramatically suppressed SK current. The pharmacology of the residual current was consistent with that of homomeric SK3 assemblies. These results demonstrate interactions that cause changes in protein trafficking, cell surface expression, and channel pharmacology and strongly suggest heteromeric assembly of SK3 with the other SK channel subunits.
A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer.

BACKGROUND & AIMS Helicobacter pylori is the main cause of peptic ulceration and gastric adenocarcinoma. The vacuolating cytotoxin gene, vacA, is a major determinant of virulence. Two naturally polymorphic sites in vacA, the signal region and midregion, are well-characterized determinants of toxicity and markers of pathogenesis. The aim of this study was to characterize a new vacA polymorphic site, the intermediate (i) region. METHODS The vacA i-region was identified and characterized by constructing isogenic vacA exchange mutants and determining their vacuolating activity on HeLa, AGS, and RK13 cell lines. The vacA i-region types of H pylori isolates from patients undergoing routine endoscopy were determined by nucleotide sequencing and allele-specific polymerase chain reaction. RESULTS Two i-region types were identified, i1 and i2, and both were common among 42 Western clinical isolates. Interestingly, only naturally occurring s1/m2 strains varied in i-type; s1/m1 and s2/m2 strains were exclusively i1 and i2, respectively. Vacuolation assays showed that i-type determined vacuolating activity among these s1/m2 strains, and exchange mutagenesis confirmed that the i-region itself was directly responsible. Using a simple i-region polymerase chain reaction-based typing system, it was shown for 73 Iranian patients that i1-type strains were strongly associated with gastric adenocarcinoma (P < 10(-3)). Finally, logistic regression analysis showed this association to be independent of, and larger than, associations of vacA s- or m-type or cag status with gastric adenocarcinoma. CONCLUSIONS Together these data show that the vacA i-region is an important determinant of H pylori toxicity and the best independent marker of VacA-associated pathogenicity.
Hyperreactivity to nitrovasodilators in forearm vasculature is related to autonomic dysfunction in insulin-dependent diabetes mellitus.

BACKGROUND The link between diabetes and vascular disease is poorly understood. Data regarding endothelial function in vivo in patients with insulin-dependent diabetes mellitus (IDDM) have been inconsistent with in vitro studies demonstrating hyperglycemia-induced impairments in endothelium-dependent vasodilation. METHODS AND RESULTS We determined whether alterations in neural control of the vascular tone might contribute to blood flow responses to intrabrachial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), and L-N-monomethyl-arginine (L-NMMA) in 22 men with IDDM (12 with normoalbuminuria. HbA1c = 8.6 +/- 0.3%; 10 with macroalbuminuria, HbA1c = 8.6 +/- 0.3%) and 11 matched normal men. Autonomic function was assessed from reflex vasoconstriction to cold, the blood pressure response to standing and hand grip, and heart rate variation, including spectral analysis, during controlled breathing, and the Valsalva maneuver. IDDM with macroalbuminuria exhibited hyperresponsiveness to both ACh and SNP compared with the patients with normoalbuminuria or normal subjects. Reflex sympathetic vasoconstriction to cold was severely impaired in the IDDM patients with macroalbuminuria (-19 +/- 6%) compared with normoalbuminuric patients (-39 +/- 5%, P < .05) and normal subjects (-54 +/- 7%, P < .001). The macroalbuminuric patients also had evidence of autonomic dysfunction during controlled and deep breathing tests and during the Valsalva maneuver. Within the group of IDDM patients, neither the urinary albumin excretion rate nor other parameters such as HbA1c or serum cholesterol correlated with forearm blood flow during the vasoactive drug infusions. There were, however, significant inverse correlations between several measures of both sympathetic and parasympathetic autonomic functions and vascular hyperresponsiveness to SNP and ACh. For example, the Valsalva ratio was inversely correlated with the increase in blood flow in response to infusion of 3 (r = -.74, P < .001) and 10 (r = -.73, P < .001) micrograms/min SNP and 7.5 (r = -.73, P < .001) and 15 (r = -.75, P < .001) micrograms/min ACh. CONCLUSIONS These data are consistent with idea that altered neurotransmission is an important determinant of vascular reactivity of diabetic blood vessels to nitrovasodilators in vivo.
Epigenetic disruption of the WNT/ß-catenin signaling pathway in human cancers

Aberrant activation of the WNT/ß-catenin signaling pathway is frequently involved in a broad spectrum of human malignancies. Alternative to genetic deletions and point mutations, epigenetic inactivation of negative WNT regulators, through DNA methylation of promoter CpG islands and/or histone modification, leads to the activation or amplification of aberrant WNT/ß-catenin signaling. In this review, we summarized the contribution of epigenetic dysregulation of WNT/ß-catenin signaling to tumorigenesis and highlighted the importance of epigenetic identification of negative regulators of this pathway as putative tumor suppressors. The reversal of these silenced regulators may be developed as potential cancer therapeutics.
A Two-Step Global Alignment Method for Feature-Based Image Mosaicing

Image mosaicing sits at the core of many optical mapping applications with mobile robotic platforms. As these platforms have been evolving rapidly and increasing their capabilities, the amount of data they are able to collect is increasing drastically. For this reason, the necessity for efficient methods to handle and process such big data has been rising from different scientific fields, where the optical data provides valuable information. One of the challenging steps of image mosaicing is finding the best image-to-map (or mosaic) motion (represented as a planar transformation) for each image while considering the constraints imposed by inter-image motions. This problem is referred to as Global Alignment (GA) or Global Registration, which usually requires a non-linear minimization. In this paper, following the aforementioned motivations, we propose a two-step global alignment method to obtain globally coherent mosaics with less computational cost and time. It firstly tries to estimate the scale and rotation parameters and then the translation parameters. Although it requires a non-linear minimization, Jacobians are simple to compute and do not contain the positions of correspondences. This allows for saving computational cost and time. It can be also used as a fast way to obtain an initial estimate for further usage in the Symmetric Transfer Error Minimization (STEMin) approach. We presented experimental and comparative results on different datasets obtained by robotic platforms for mapping purposes.
Une Charpente De Semi-Unification

This paper is mainly the development of a pattern-matching algorithm by stepwise transformations starting from a définition of pattern-matching as an inverse of substitution. This pattern-matching algorithm is able to recognize sublists of arbitrary length in tree-structured lists, mainly Lisp-like S-expressions. The early définitions and the intermediate results are expressed by means of recursive équations with separate cases, following J. Darlington's way. The main transformations are inversion and then making the continuation explicit and catching it under the form of auxiliary parameters. The structure of the resulting algorithm may be seen as a framework to develop similar algorithms, adapted to n-ary tree structures or to functional expressions like combinatory logic, or to add other elementary patterns like those occuring in rules based Systems.
Modeling of multiconductor systems for packaging and interconnecting high-speed digital IC's

In the design of high-speed circuits, it is important to consider the adverse effects of packaging and interconnections on signal integrity. A review of quasi-TEM capacitance and inductance analysis of multiconductor transmission line systems is presented. The development of three general modeling techniques is discussed, namely, the boundary element method, the finite element method, and the partial element equivalent circuit technique. The application of each method to practical systems is outlined, with particular reference to the literature. A complete formulation for the boundary element, which is applicable to multiconductor systems of arbitrary geometry in nonhomogeneous media, is provided. The analysis of a seven-line buried microstrip structure illustrates the main differences between the finite element and boundary element approaches. >
Modeling subjective tests of quality of experience with a Generalized Linear Model

Subjective tests of telecommunication services engaging a panel of subjects aim to analyze how service users experience their quality (QoE) with varying parameters of both a network and/or application itself. Subjects express their opinion on a few-grade categorical scale during tests performed in a controlled environment. The proposed Generalized Linear Model (GLZ)1 relates probabilities of particular QoE levels to independent network and application explanatory variables in a statistically credible way. The GLZ model is executed in several steps including maximum likelihood estimation of model parameters, selection of the most effective model with the Bayesian information criterion, model validation with a chi-squared test, and last but not least confidence interval estimation. Monitoring a QoE level with a GLZ model provides to operators an effective tool towards a mid- and long-term adaptation of both network and/or application parameters in order to follow users' experience and expectations.
Characterization of New Monoclonal Antibodies Directed Against Normal Human Exocrine Pancreas and Pancreatic Adenocarcinomas

A series of 12 cell fusions of BALB/c mice spleen cells with the SP210-Ag14 mouse myeloma cell line were performed after immunizations with normal human pancreas to generate monoclonal antibodies (mAbs) with high affinity against antigens of the exocrine pancreas. The immunohistologic tissue screening resulted in the selection of 14 clones that were further characterized on frozen tissues, tumor cell lines, and lectin binding assays. Four mAbs reacting with pancreatic acini detected granular antigens and three mAbs reacted with acinar cell membrane antigens. Six other clones reacted with pancreatic ducts; among these were three clones positive with antigens in both acini and ducts. Among the clones reactive with secretory products, there was one pair of mAbs identified as pancreas specific (P78C9/P79D4); the other secretory antigens (identified by P97F3 and P109H1) were also detectable in other exocrine organs, but were absent from the gastrointestinal rnucosa. Two clones reactive with acinar cell membranes (P96H2 and P100H1) were also positive with hepatocytes. All but four antigens were detectable in pancreatic cancer cell lines Capan-1, Capan-2, and DAN-G. On the whole, immunizations were more effective using whole pancreatic tissues (eight clones selected) compared with single-cell suspensions as immunogen (four clones) or cell membrane preparations (two clones). Therefore, the immunization and screening strategies used in this study resulted in the generation of new mAbs against specific substructures of the exocrine pancreas. The shared expression of some of these antigens with other exocrine organs and pancreatic adenocarcinoma cell lines suggests that these mAbs detect antigens that are characteristic for the exocrine system and could therefore be useful for the study of the exocrine pancreas and pancreatic adenocarcinomas.
Isolation and characterization of simple and complex lipoproteins containing apolipoprotein F from human plasma.

Apolipoprotein F (ApoF), one of the minor apolipoproteins in human plasma, has been recently isolated and partially characterized [Olofsson, S.O. , McConathy, W.J., & Alaupovic, P. (1978) Biochemistry 17, 1032-1036]. In the present work, the interaction of ApoF with other apolipoproteins and lipids in human plasma was studied. By the successive use of immunosorbers specific for ApoF, apolipoprotein A-II (ApoA-II) and apolipoprotein A-I (ApoA-I), three different ApoF-containing lipoproteins were isolated from normolipidemic fasting human plasma. Their apolipoprotein content was determined by double immunodiffusion against monospecific antisera to all known serum apolipoproteins, electroimmunoassay, crossed immunoelectrophoresis, and polyacrylamide gel electrophoresis. Their lipid composition was determined by thin-layer chromatography. The three ApoF-containing lipoproteins were identified as LpF:A-I:A-II (lipoprotein containing ApoF, ApoA-I, and ApoA:II), LpF:A-I (lipoprotein containing ApoF and ApoA-I), and LpF (lipoprotein containing only ApoF). LpF:A-I:A-II was found to contain ApoF, ApoA-I, and ApoA-II in an apparent 2:1:1 molar ratio. Its lipid moiety was characterized by cholesterol ester (45%) and free cholesterol (28%) as the predominant lipids. LpF contained only ApoF, and in its major lipid components were also cholesterol esters (63%) and free cholesterol (21%). It is suggested that ApoF-containing lipoproteins may be involved in transport and/or esterification of cholesterol.