Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

UNLABELLED To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation of glucose disposal. IN CONCLUSION (a) decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.
Cumulative Lead Exposure and Age at Menopause in the Nurses’ Health Study Cohort

Background: Early menopause has been associated with many adverse health outcomes, including increased risk of cardiovascular disease morbidity and mortality. Lead has been found to be adversely associated with female reproductive function, but whether exposures experienced by the general population are associated with altered age at menopause has not been explored. Objective: Our goal was to assess the association between cumulative lead exposure and age at natural menopause. Methods: Self-reported menopausal status and bone lead concentration measured with K-shell X-ray fluorescence—a biomarker of cumulative lead exposure—were obtained from 434 women participants in the Nurses’ Health Study. Results: The mean (± SD) age at natural menopause was 50.8 ± 3.6 years. Higher tibia lead level was associated with younger age at menopause. In adjusted analyses, the average age of menopause for women in the highest tertile of tibia lead was 1.21 years younger (95% CI: –2.08, –0.35) than for women in the lowest tertile (p-trend = 0.006). Although the number of cases was small (n = 23), the odds ratio for early menopause (< 45 years of age) was 5.30 (95% CI: 1.42, 19.78) for women in the highest tertile of tibia lead compared with those in the lowest tertile (p-trend = 0.006). There was no association between patella or blood lead and age at menopause. Conclusions: Our results support an association between low-level cumulative lead exposure and an earlier age at menopause. These data suggest that low-level lead exposure may contribute to menopause-related health outcomes in older women through effects on age at menopause. Citation: Eum KD, Weisskopf MG, Nie LH, Hu H, Korrick SA. 2014. Cumulative lead exposure and age at menopause in the Nurses’ Health Study Cohort. Environ Health Perspect 122:229–234; http://dx.doi. org/10.1289/ehp.1206399
Comparative sequence analysis of nitrogen fixation-related genes in six legumes

Legumes play an important role as food and forage crops in international agriculture especially in developing countries. Legumes have a unique biological process called nitrogen fixation (NF) by which they convert atmospheric nitrogen to ammonia. Although legume genomes have undergone polyploidization, duplication and divergence, NF-related genes, because of their essential functional role for legumes, might have remained conserved. To understand the relationship of divergence and evolutionary processes in legumes, this study analyzes orthologs and paralogs for selected 20 NF-related genes by using comparative genomic approaches in six legumes i.e., Medicago truncatula (Mt), Cicer arietinum, Lotus japonicus, Cajanus cajan (Cc), Phaseolus vulgaris (Pv), and Glycine max (Gm). Subsequently, sequence distances, numbers of synonymous substitutions per synonymous site (Ks) and non-synonymous substitutions per non-synonymous site (Ka) between orthologs and paralogs were calculated and compared across legumes. These analyses suggest the closest relationship between Gm and Cc and the highest distance between Mt and Pv in six legumes. Ks proportional plots clearly showed ancient genome duplication in all legumes, whole genome duplication event in Gm and also speciation pattern in different legumes. This study also reports some interesting observations e.g., no peak at Ks 0.4 in Gm-Gm, location of two independent genes next to each other in Mt and low Ks values for outparalogs for three genes as compared to other 12 genes. In summary, this study underlines the importance of NF-related genes and provides important insights in genome organization and evolutionary aspects of six legume species analyzed.
Generalization of the Dempster-Shafer Theory

The Dempster-Shafer theory gives a solid basis for reasoning applications characterized by uncertainty. A key feature of the theory is that propositions are represented as subsets of a set which represents a hypothesis space. This power set along with the set operations is a Boolean algebra. Can we generalize the theory to cover arbitrary Boolean algebras? We show that the answer is yes. The theory then covers, for example, infinite sets. The practical advantages of generalization are that increased flexibility of representation is allowed and that the performance of evidence accumulation can be enhanced. In a previous paper we generalized the Dempster-Shafer orthogonal sum operation to support practical evidence pooling. In the present paper we provide the theoretical underpinning of that procedure, by systematically considering familiar evidential functions in turn. For each we present a "weaker form" and we look at the relationships between these variations of the functions. The relationships are not so strong as for the conventional functions. However, when we specialize to the familiar case of subsets, we do indeed get the wellknown relationships.
Democracy, deliberation and design: the case of online discussion forums

Within democratic theory, the deliberative variant has assumed pre-eminence. It represents for many the ideal of democracy, and in pursuit of this ideal, online discussion forums have been proposed as solutions to the practical limits to mass deliberation. Critics have pointed to evidence which suggests that online discussion has tended to undermine deliberation. This article argues that this claim, which generates a stand-off between the two camps, misses a key issue: the role played by design in facilitating or thwarting deliberation. It argues that political choices are made both about the format and operation of the online discussion, and that this affects the possibility of deliberation. Evidence for the impact of design (and the choices behind it) is drawn from analysis of European Union and UK discussion forums. This evidence suggests that we should view deliberation as dependent on design and choice, rather than a predetermined product of the technology.
Escherichia coli cytolethal distending toxin blocks the HeLa cell cycle at the G2/M transition by preventing cdc2 protein kinase dephosphorylation and activation

Cytolethal distending toxins (CDT) constitute an emerging heterogeneous family of bacterial toxins whose common biological property is to inhibit the proliferation of cells in culture by blocking their cycle at G2/M phase. In this study, we investigated the molecular mechanisms underlying the block caused by CDT from Escherichia coli on synchronized HeLa cell cultures. To this end, we studied specifically the behavior of the two subunits of the complex that determines entry into mitosis, i.e., cyclin B1, the regulatory unit, and cdc2 protein kinase, the catalytic unit. We thus demonstrate that CDT causes cell accumulation in G2 and not in M, that it does not slow the progression of cells through S phase, and that it does not affect the normal increase of cyclin B1 from late S to G2. On the other hand, we show that CDT inhibits the kinase activity of cdc2 by preventing its dephosphorylation, an event which, in normal cells, triggers mitosis. This inhibitory activity was demonstrated for the three partially related CDTs so far described for E. coli. Moreover, we provide evidence that cells exposed to CDT during G2 and M phases are blocked only at the subsequent G2 phase. This observation means that the toxin triggers a mechanism of cell arrest that is initiated in S phase and therefore possibly related to the DNA damage checkpoint system.
Correlation of CD4 counts with the FNAC patterns of tubercular lymphadenitis in patients with HIV: A cross sectional pilot study

Fine needle aspiration cytology (FNAC) of TB lymphadenitis (TBL) in HIV shows four different patterns, which may be reflective of immune status. We hypothesize that the CD4 counts, a marker of immunologic status, correlates with FNAC morphology of TBL. This study was undertaken to compare the mean CD4 counts across the different cytology patterns and to correlate the CD4 counts with FNAC patterns in these patients.
Algebraic designs for coherent and differentially coherent space-time codes

The authors previously presented a new space-time architecture combining generalized layered transmission, advanced iterative multi-user detection techniques, and space-time code design that provides superior performance compared to the layered architectures proposed by Foschini (1996) and Tarokh et al. (see IEEE Trans. on Information Theory, vol.IT-44, p.744-65, 1998). We discuss the design of algebraic space-time codes for layered and non-layered architectures. We present new constructions for the quasi-static and block fading channels that extend to the diagonal transmission architecture proposed for differentially coherent space-time coding.
Neural representation of action sequences: how far can a simple snippet-matching model take us?

The macaque Superior Temporal Sulcus (STS) is a brain area that receives and integrates inputs from both the ventral and dorsal visual processing streams (thought to specialize in form and motion processing respectively). For the processing of articulated actions, prior work has shown that even a small population of STS neurons contains sufficient information for the decoding of actor invariant to action, action invariant to actor, as well as the specific conjunction of actor and action. This paper addresses two questions. First, what are the invariance properties of individual neural representations (rather than the population representation) in STS? Second, what are the neural encoding mechanisms that can produce such individual neural representations from streams of pixel images? We find that a simple model, one that simply computes a linear weighted sum of ventral and dorsal responses to short action "snippets", produces surprisingly good fits to the neural data. Interestingly, even using inputs from a single stream, both actor-invariance and action-invariance can be accounted for, by having different linear weights.
Overexpression of the Insulin Receptor Isoform A Promotes Endometrial Carcinoma Cell Growth

Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR–B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P<0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway.
Position Effects in Choice From Simultaneous Displays

From drop-down computer menus to department-store aisles, people in everyday life often choose from simultaneous displays of products or options. Studies of position effects in such choices show seemingly inconsistent results. For example, in restaurant choice, items enjoy an advantage when placed at the beginning or end of the menu listings, but in multiple-choice tests, answers are more popular when placed in the middle of the offered list. When reaching for a bottle on a supermarket shelf, bottles in the middle of the display are more popular. But on voting ballots, first is the most advantageous position. Some of the effects are quite sensible, whereas others are harder to justify and can aptly be regarded as biases. This article attempts to put position effects into a unified and coherent framework and to account for them simply by using a small number of familiar psychological principles.
The secreted and surface proteomes of the adult stage of the carcinogenic human liver fluke Opisthorchis viverrini

Infection with the human liver fluke, Opisthorchis viverrini, is a serious public health problem in Thailand, Laos and nearby locations in Southeast Asia. Both experimental and epidemiological evidence strongly implicate liver fluke infection in the etiology of one of the liver cancer subtypes, cholangiocarcinoma (CCA). To identify parasite proteins critical for liver fluke survival and the etiology of CCA, OFFGEL electrophoresis and multiple reaction monitoring were employed to characterize 300 parasite proteins from the O. viverrini excretory/secretory products and, utilizing selective labeling and sequential solubilization, from the host‐exposed tegument. The excretory/secretory included a complex mixture of proteins that have been associated with cancers, including proteases of different mechanistic classes and orthologues of mammalian growth factors and anti‐apoptotic proteins. Also identified was a cysteine protease inhibitor which, in other helminth pathogens, induces nitric oxide production by macrophages, and, hence may contribute to malignant transformation of inflamed cells. More than 160 tegumental proteins were identified using sequential solubilization of isolated teguments, and a subset of these was localized to the surface membrane of the tegument by labeling living flukes with biotin and confirming surface localization with fluorescence microscopy. These included annexins, which are potential immuno‐modulators, and orthologues of the schistosomiasis vaccine antigens Sm29 and tetraspanin‐2. Novel roles in pathogenesis were suggested for the tegument–host interface since more than ten surface proteins had no homologues in the public databases. The O. viverrini proteins identified here provide an extensive catalogue of novel leads for research on the pathogenesis of opisthorchiasis and the development of novel interventions for this disease and CCA, as well as providing a scaffold for sequencing the genome of this fluke.
Psychological Reactance And User Workarounds. A Study In The Context Of Electronic Medical Records Implementations

User workarounds are a growing problem in many complex system implementations including healthcare settings. Anecdotal evidence from the healthcare informatics as well as the information systems (IS) fields suggest that many system users are employing workarounds in order to bypass the system’s functionality. Yet, little theory exists on the topic. This study proposes a theoretical model to investigate why user workarounds occur based on psychological reactance, protection motivation and technology threat avoidance theories. We view user workarounds as a response to situational reactance and coping appraisals with respect to electronic medical record systems (EMR). Situational reactance is based on EMR system appraisals, perceived EMR threat to freedom, threat appraisal, trait reactance and job time constraints. Together, these elements form the nomological net surrounding the important phenomenon of user workarounds. We propose to test our model using a multi-method approach. Implications for theory and practice are discussed.
Reciprocal Transcriptional Regulation of Metabolic and Signaling Pathways Correlates With Disease Severity in Heart Failure

Background— Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and gene mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate. Methods and Results— Using a meta-analysis of 28 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, whereas cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern that recapitulates a fetal gene expression program in experimental animal models of HF, human HF microarray studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in end-stage human hearts. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in nonfailing human samples, which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS), thus mimicking gene expression patterns observed in failing samples. Additionally, &bgr;-blockers and ACE inhibitor use in end-stage human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity. Conclusions— Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are a consistent feature in the heterogeneous transcriptional response observed in phenotypically similar models of HF.
Guided interaction

Many decades of research, coupled with continuous increases in computing power, have enabled highly efficient execution of queries on large databases. In consequence, for many databases, far more time is spent by users formulating queries than by the system evaluating them. It stands to reason that, looking at the overall query experience we provide users, we should pay attention to how we can assist users in the holistic process of obtaining the information they desire from the database, and not just the constituent activity of efficiently generating a result given a complete precise query. In this paper, we examine the conventional query-result paradigm employed by databases and demonstrate challenges encountered when following this paradigm for an information seeking task. We recognize that the process of query specification itself is a major stumbling block. With current computational abilities, we are at a point where we can make use of the data in the database to aid in this process. To this end, we propose a new paradigm, guided interaction, to solve the noted challenges, by using interaction to guide the user through the query formulation, query execution and result examination processes. The user can be given advance information during query specification that can not only assist in query formulation, but may also lead to abandonment of an unproductive query direction or the satisfaction of information need even before the query specification is complete. There are significant engineering challenges to constructing the system we envision, and the technological building blocks to address these challenges exist today.