Miracle-dz/UniFAR-FTUs huggingface dataset:
Adenylyl Cyclase Subtype–Specific Compartmentalization: Differential Regulation of L-Type Ca2+ Current in Ventricular Myocytes

Rationale: Adenylyl cyclase (AC) represents one of the principal molecules in the &bgr;-adrenergic receptor signaling pathway, responsible for the conversion of ATP to the second messenger, cAMP. AC types 5 (ACV) and 6 (ACVI) are the 2 main isoforms in the heart. Although highly homologous in sequence, these 2 proteins play different roles during the development of heart failure. Caveolin-3 is a scaffolding protein, integrating many intracellular signaling molecules in specialized areas called caveolae. In cardiomyocytes, caveolin is located predominantly along invaginations of the cell membrane known as t-tubules. Objective: We take advantage of ACV and ACVI knockout mouse models to test the hypothesis that there is distinct compartmentalization of these isoforms in ventricular myocytes. Methods and Results: We demonstrate that ACV and ACVI isoforms exhibit distinct subcellular localization. The ACVI isoform is localized in the plasma membrane outside the t-tubular region and is responsible for &bgr;1-adrenergic receptor signaling–mediated enhancement of the L-type Ca2+ current (ICa,L) in ventricular myocytes. In contrast, the ACV isoform is localized mainly in the t-tubular region where its influence on ICa,L is restricted by phosphodiesterase. We further demonstrate that the interaction between caveolin-3 with ACV and phosphodiesterase is responsible for the compartmentalization of ACV signaling. Conclusions: Our results provide new insights into the compartmentalization of the 2 AC isoforms in the regulation of ICa,L in ventricular myocytes. Because caveolae are found in most mammalian cells, the mechanism of &bgr;- adrenergic receptor and AC compartmentalization may also be important for &bgr;-adrenergic receptor signaling in other cell types.
Cautious Expected Utility and the Certainty Effect

Many violations of the Independence axiom of Expected Utility can be traced to subjects’ attraction to risk-free prospects. The key axiom in this paper, Negative Certainty Independence (Dillenberger, 2010), formalizes this tendency. Our main result is a utility representation of all preferences over monetary lotteries that satisfy Negative Certainty Independence together with basic rationality postulates. Such preferences can be represented as if the agent were unsure of how to evaluate a given lottery p; instead, she has in mind a set of possible utility functions over outcomes and displays a cautious behavior: she computes the certainty equivalent of p with respect to each possible function in the set and picks the smallest one. The set of utilities is unique in a well-dened sense. We show that our representation can also be derived from a ‘cautious’ completion of an incomplete preference relation.
Insights into Pain: A Review of Qualitative Research

• Qualitative research exposes and explores important aspects of the pain experience that are inaccessible to other approaches. • Qualitative work adopts a different epistemological and ontological perspective to quantitative work. • Qualitative research is not well established in the field of pain, but is growing. • More interpretative engagement with qualitative data is required.
How Does the Preparation of Rye Porridge Affect Molecular Weight Distribution of Extractable Dietary Fibers?

Extractable dietary fiber (DF) plays an important role in nutrition. This study on porridge making with whole grain rye investigated the effect of rest time of flour slurries at room temperature before cooking and amount of flour and salt in the recipe on the content of DF components and molecular weight distribution of extractable fructan, mixed linkage (1→3)(1→4)-β-d-glucan (β-glucan) and arabinoxylan (AX) in the porridge. The content of total DF was increased (from about 20% to 23% of dry matter) during porridge making due to formation of insoluble resistant starch. A small but significant increase in the extractability of β-glucan (P = 0.016) and AX (P = 0.002) due to rest time was also noted. The molecular weight of extractable fructan and AX remained stable during porridge making. However, incubation of the rye flour slurries at increased temperature resulted in a significant decrease in extractable AX molecular weight. The molecular weight of extractable β-glucan decreased greatly during a rest time before cooking, most likely by the action of endogenous enzymes. The amount of salt and flour used in the recipe had small but significant effects on the molecular weight of β-glucan. These results show that whole grain rye porridge made without a rest time before cooking contains extractable DF components maintaining high molecular weights. High molecular weight is most likely of nutritional importance.
Waiting to Choose

We study the role of heuristic versus deliberative processing in intertemporal choice. Using studies in the Democratic Republic of Congo and an online labor market, we show that waiting periods –designed to prompt deliberation by temporally separating news about choice sets from choices themselves– can shift individuals away from decisions consistent with heuristic thinking and lead to substantially more patient choices. These findings are not captured by exponential or hyperbolic discounting. Additionally, waiting periods have larger effects on those shown to be particularly prone to myopia as a result of prior trauma, highlighting their potential as targeted interventions.
Exome sequencing allows for rapid gene identification in a Charcot‐Marie‐Tooth family

Charcot‐Marie‐Tooth (CMT) disease comprises a large number of genetically distinct forms of inherited peripheral neuropathies. The relative uniform phenotypes in many patients with CMT make it difficult to decide which of the over 35 known CMT genes are affected in a given patient. Genetic testing decision trees are therefore broadly based on a small number of major subtypes (eg, CMT1, CMT2) and the observed mutation frequency for CMT genes. Since conventional genetic testing is expensive many rare genes are not being tested for at all.
Increased Frequency of a Unique Spleen Tyrosine Kinase Bright Memory B Cell Population in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and autoantibody production. As spleen tyrosine kinase (Syk) is pivotal in B cell activation, these experiments aimed to examine the extent to which Syk was abnormally expressed in SLE B cells and the nature of the B cell subset that differently expressed Syk.
The Complete Genome Sequence of Escherichia coli DH10B: Insights into the Biology of a Laboratory Workhorse

ABSTRACT Escherichia coli DH10B was designed for the propagation of large insert DNA library clones. It is used extensively, taking advantage of properties such as high DNA transformation efficiency and maintenance of large plasmids. The strain was constructed by serial genetic recombination steps, but the underlying sequence changes remained unverified. We report the complete genomic sequence of DH10B by using reads accumulated from the bovine sequencing project at Baylor College of Medicine and assembled with DNAStar's SeqMan genome assembler. The DH10B genome is largely colinear with that of the wild-type K-12 strain MG1655, although it is substantially more complex than previously appreciated, allowing DH10B biology to be further explored. The 226 mutated genes in DH10B relative to MG1655 are mostly attributable to the extensive genetic manipulations the strain has undergone. However, we demonstrate that DH10B has a 13.5-fold higher mutation rate than MG1655, resulting from a dramatic increase in insertion sequence (IS) transposition, especially IS150. IS elements appear to have remodeled genome architecture, providing homologous recombination sites for a 113,260-bp tandem duplication and an inversion. DH10B requires leucine for growth on minimal medium due to the deletion of leuLABCD and harbors both the relA1 and spoT1 alleles causing both sensitivity to nutritional downshifts and slightly lower growth rates relative to the wild type. Finally, while the sequence confirms most of the reported alleles, the sequence of deoR is wild type, necessitating reexamination of the assumed basis for the high transformability of DH10B.
Asymptotic Estimates for r-Whitney Numbers of the Second Kind

The r-Whitney numbers of the second kind are a generalization of all the Stirling-type numbers of the second kind which are in line with the unified generalization of Hsu and Shuie. In this paper, asymptotic formulas for r-Whitney numbers of the second kind with integer and real parameters are obtained and the range of validity of each formula is established.
Environmental Determinants of Asthma among School Children Aged 13–14 in and around Polokwane, Limpopo Province, South Africa

Asthma has become a public health issue since the 1960’s. Factors associated with asthma are environmental and genetic. This study is based on a random sample of 742 students aged 13–14 attending various schools at Polokwane, in the Province of Limpopo in South Africa. Survey logistic regression and multi-level analyses were used for data analysis. The study identifies three key determinants of asthma at the district, school and individual levels. The study shows that persistent cough (OR = 4.01), exposure to smoke at the household level (OR = 2.39) and lack of access to flush toileta at the household level (OR = 1.89) are key predictors of asthma in children. Variability at the level of districts accounts for 46% of total variance. Variability at the level of schools accounts for 33% of total variance.
Comparative Involvement of Cyclic Nucleotide Phosphodiesterases and Adenylyl Cyclase on Adrenocorticotropin-Induced Increase of Cyclic Adenosine Monophosphate in Rat and Human Glomerulosa Cells.

The present study investigated the role and identity of cyclic nucleotide phosphodiesterases (PDEs) in the regulation of basal and ACTH-stimulated levels of intracellular cAMP in human and rat adrenal glomerulosa cells. Comparative dose-response curves indicated that maximal hormone-stimulated cAMP accumulation was 11- and 24-fold higher in human and rat cells, compared with cAMP production obtained in corresponding membranes, respectively. Similarly to 3-isobutyl-1-methyl-xanthine, 25 microM erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA, a specific PDE2 inhibitor), caused a large increase in ACTH-stimulated cAMP accumulation; by contrast, it did not change cAMP production in membranes. Moreover, in membrane fractions, addition of 10 microM cGMP inhibited ACTH-induced cAMP production, an effect completely reversed by addition of 25 microM EHNA. These results indicate that PDE2 activity is involved in the regulation of cAMP accumulation induced by ACTH, and suggest that ACTH inhibits this activity. Indeed, time-course studies indicated that ACTH induced a rapid decrease in cGMP production, resulting in PDE2 inhibition, which in turn, contributed [with adenylyl cyclase (AC) activation] to an accumulation in cAMP for 15 min. Thereafter, cAMP content decreased, because of cAMP-stimulated PDE2, as confirmed by measurement of PDE activity that was activated by ACTH, but only after a 10-min incubation. Hence, we demonstrate that the ACTH-induced increase in intracellular cAMP is the result of a balance between activation of AC and direct modulation of PDE2 activity, an effect mediated by cGMP content. Although similar results were observed in both models, PDE2 involvement is more important in rat than in human adrenal glomerulosa cells, whereas AC is more stimulated in human than in rat glomerulosa cells.
The Relationship Between Slowing EEGs and the Progression of Parkinson’s Disease

The previous association study confirmed that diffuse slowing of EEGs was present in Parkinson’s disease (PD), demonstrated with the use of the quantitative EEG technique. This study was the first to assess the relationship between progression of PD and quantitative EEG. A total of 106 patients with PD with a mean Hoehn-Yahr stage of 2.73 were serially enrolled. Lack of ischemic lesions was confirmed in all patients by magnetic resonance imaging. Absolute power values were measured for four frequency bands from delta to beta. The electrodes were divided among six locations: frontal pole, frontal, central, parietal, temporal, and occipital locations. Spectral ratio was calculated as the sum of power values for the alpha and beta waves divided by the sum values for the slow waves. The relationship between the progression of PD and spectral ratio was assessed by the Jonckheere-Terpstra trend test. At all electrode locations, spectral ratio significantly decreased with progression of Hoehn-Yahr stage (frontal pole, P = 0.007; frontal, P = 0.005; central, P = 0.031; parietal, P = 0.017; temporal, P = 0.005; occipital, P = 0.010). This shows that the slowing of EEGs became more obvious with PD progression.
Increases in transient receptor potential vanilloid‐1 mRNA and protein in primary afferent neurons stimulated by protein kinase C and their possible role in neurogenic inflammation

A recent study by our group demonstrates pharmacologically that the transient receptor potential vanilloid‐1 (TRPV1) is activated by intradermal injection of capsaicin to initiate neurogenic inflammation by the release of neuropeptides in the periphery. In this study, expression of TRPV1, phosphorylated protein kinase C (p‐PKC), and calcitonin gene‐related peptide (CGRP) in dorsal root ganglion (DRG) neurons was visualized by using immunofluorescence, real‐time PCR, and Western blots to examine whether increases in TRPV1 mRNA and protein levels evoked by capsaicin injection are subject to modulation by the activation of PKC and to analyze the role of this process in the pathogenesis of neurogenic inflammation. Capsaicin injection into the hindpaw skin of anesthetized rats evoked increases in the expression of TRPV1, CGRP and p‐PKC in mRNA and/or protein levels and in the number of single labeled TRPV1, p‐PKC, and CGRP neurons in ipsilateral L4‐5 DRGs. Coexpressions of TRPV1 with p‐PKC and/or CGRP in DRG neurons were also significantly increased after CAP injection. These evoked expressions at both molecular and cellular levels were significantly inhibited after TRPV1 receptors were blocked by 5′‐iodoresiniferatoxin (5 μg) or PKC was inhibited by chelerythrine chloride (5 μg). Taken together, these results provide evidence that up‐regulation of TRPV1 mRNA and protein levels under inflammatory conditions evoked by capsaicin injection is subject to modulation by the PKC cascade in which increased CGRP level in DRG neurons may be related to the initiation of neurogenic inflammation. Thus, up‐regulation of TRPV1 receptors in DRG neurons seems critical for initiating acute neurogenic inflammation. © 2008 Wiley‐Liss, Inc.
Evidence based medicine in clinical practice: how to advise patients on the influence of age on the outcome of surgical anterior cruciate ligament reconstruction: a review of the literature

Objective: To determine, using a literature search, whether patient age influences the outcome of surgical reconstruction of a torn anterior cruciate ligament. Methods: Medline (1966 to present) was searched using the PubMed interface, Embase (1974 to present) using the Datastar system, and the Cochrane Library at the Update Software web site. Papers retrieved from the three databases were independently assessed by two reviewers using preliminary inclusion criteria. Reference lists of papers satisfying the preliminary criteria were then scanned and appropriate papers reviewed. Any new papers in turn had their reference lists scanned, this process continuing until no new papers were identified. Final inclusion criteria were then applied to all papers satisfying the preliminary inclusion criteria. Results: The initial search identified 661 papers. Exclusion of duplicates produced 536 unique papers. Medline contained 445, Embase 185, and the Cochrane Library 31. Of the 536, 523 were assessed by abstract and 12 by full text; one paper was not retrieved. Application of the preliminary inclusion criteria produced 33 papers. Their reference lists contained 950 references. Scanning of these added six new papers to the dataset. These six had their reference lists assessed; no new papers were identified. Four of the 39 papers in the completed dataset satisfied the final inclusion criteria. There was wide variation in the total number of subjects in the four studies, ranging from 22 to 203 patients. The total number of different outcome measures was 17; only one measure was used by all four studies. None of the objective outcome measures showed any significant difference between age groups, and the subjective measures, which did show differences, were contradictory. A total of 108 interlibrary loans were requested, by a full time researcher, at a total cost of IR£432.00 over a 10 week period. Conclusions: When advising patients on the outcome of anterior cruciate ligament reconstruction, age should not be considered in isolation. In the absence of relevant guidelines, meta-analyses, or systematic reviews, the application of evidence based medicine to clinical practice has significant resource implications.
Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach

Recent statistics describe breast cancer as the leading cause of death among women across the world with varied causes and reasons. Lifestyle, diet, genetic and environmental factors introduce their generous contributions towards breast cancer, among which genetic factors have lately become one of the most important aspects in understanding the mechanism. Although various genes have already been reported in causing breast cancer, PIK3CA stands second on the list. Mutations observed in this gene have the ability to trigger the different activities of the cell, thereby bypassing the regular cellular cycle. Among the mutations in PIK3CA, three hotspot mutations were commonly reported, one in the catalytic domain (position HIS1047) and other two in the helical domain (position GLU542 and GLU545). In the helical domain of PIK3CA, the lysine substitution at 542–545 positions was significantly studied in causing breast cancer. To compare the deleterious effect of these mutations, in silico prediction tools along with molecular dynamics simulations and molecular docking approach was initiated to analyse the change in binding landscape upon mutation. In this comparative analysis, we report that the mere existence of mutant E545K can trigger the function of the protein but may not be as harmful as H1047R. Among the two mutations E542K and E545K, the latter shows the most deleterious effect that correlates with the previous reported experimental studies. We assume the results observed in this combinatorial computational study might further pave a better way for providing better treatment procedures.
5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression

Genes that regulate the serotonin signalling system are potential targets for research in the aetiology of mood disorders and also in the treatment response of serotonin reuptake inhibitors. In this study, we evaluated the association of seven serotonin signal transduction-linked single nucleotide polymorphisms [HTR1A (rs6295), HTR2A (rs6313, rs6311 and rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) and TPH2 (rs1386494)] with major depressive disorder and/or treatment outcome with serotonin reuptake inhibitors. Patients who met the criteria for major depressive disorder were treated for 6 weeks with fluoxetine, paroxetine or citalopram. The treatment response was evaluated with the Montgomery–Asberg Depression Rating Scale, and according to predefined response criteria, the patients were divided into responders, nonresponders, remitters and nonremitters. Altogether, 86 patients completed the entire study according to the study protocol. We had also a control population (N = 395) of healthy blood donors. None of the seven single nucleotide polymorphisms was associated with major depressive disorder or with treatment response in our study population of Finnish individuals.
Psychiatric symptoms and alcohol use in community violence by persons with a psychotic disorder or depression.

OBJECTIVE Prior studies have shown a significant but modest association between mental disorders and violence and an increased risk in the presence of co-occurring substance use disorders. Categorical diagnoses, however, have limited utility when assessing dynamic risk state over time. This study used data from the MacArthur Violence Risk Assessment Study to examine the relationship of symptom levels and alcohol use to violence in repeated observations within two diagnostic groups. METHODS Participants with a primary categorical diagnosis of depression (N=386) or a psychotic disorder (N=201) were identified. Subscale scores for affective or positive symptoms from the Brief Psychiatric Rating Scale and self-reported alcohol consumption were tested in panel logistic models over five ten-week intervals for their concurrent and lagged relationship to violence. An interaction term between each type of symptom and alcohol use was also tested. RESULTS In models including the amount of alcohol consumed and symptom levels, a high level of affective symptoms was associated with violence during the next follow-up period only for participants with depression. There was a significant interaction between alcohol use and affective symptoms for participants with depression. CONCLUSIONS The relationship of symptoms and alcohol use to community violence should be considered in the context of the individual's primary diagnosis. Further characterization of interactions between symptoms and substance use in relation to violent behavior may allow for more effective assessment of risk state and interventions for violence prevention.
A generalization of Apollonian packing of circles

Three circles touching one another at distinct points form two curvilinear triangles. Into one of these we can pack three new circles, touching each other, with each new circle touching two of the original circles. In such a sextuple of circles there are three pairs of circles, with each of the circles in a pair touching all four circles in the other two pairs. Repeating the construction in each curvilinear triangle that is formed results in a generalized Apollonian packing. We can invert the whole packing in every circle in it, getting a “generalized Apollonian super-packing”. Many of the properties of the Descartes configuration and the standard Apollonian packing carry over to this case. In particular, there is an equation of degree 2 connecting the bends (curvatures) of a sextuple; all the bends can be integers; and if they are, the packing can be placed in the plane so that for each circle with bend b and center (x, y), the quantities bx/ √ 2 and by are integers. The construction provides a generalization of the Farey series and the associated Ford circles.