Determination of Porphyrins in Bile Using High Performance Liquid Chromatography and Some Clinical Applications

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Association testing by haplotype-sharing methods applicable to whole-genome analysis

We propose two new haplotype-sharing methods for identifying disease loci: the haplotype sharing statistic (HSS), which compares length of shared haplotypes between cases and controls, and the CROSS test, which tests whether a case and a control haplotype show less sharing than two random haplotypes. The significance of the HSS is determined using a variance estimate from the theory of U-statistics, whereas the significance of the CROSS test is estimated from a sequential randomization procedure. Both methods are fast and hence practical, even for whole-genome screens with high marker densities. We analyzed data sets of Problems 2 and 3 of Genetic Analysis Workshop 15 and compared HSS and CROSS to conventional association methods. Problem 2 provided a data set of 2300 single-nucleotide polymorphisms (SNPs) in a 10-Mb region of chromosome 18q, which had shown linkage evidence for rheumatoid arthritis. The CROSS test detected a significant association at approximately position 4407 kb. This was supported by single-marker association and HSS. The CROSS test outperformed them both with respect to significance level and signal-to-noise ratio. A 20-kb candidate region could be identified. Problem 3 provided a simulated 10 k SNP data set covering the whole genome. Three known candidate regions for rheumatoid arthritis were detected. Again, the CROSS test gave the most significant results. Furthermore, both the HSS and the CROSS showed better fine-mapping accuracy than straightforward haplotype association. In conclusion, haplotype sharing methods, particularly the CROSS test, show great promise for identifying disease gene loci

Patients with Cluster A Personality Disorders in Psychotherapy: An Effectiveness Study

Abstract BACKGROUND: While psychopharmacological studies are common in patients with cluster A personality disorders, the effects of psychotherapy have received little attention. The aim of this study is to explore whether psychotherapeutic treatment yields health gains for these patients. METHODS: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 57 patients with a DSM-IV-TR axis II cluster A diagnosis. Patients were assigned to 3 settings of psychotherapeutic treatment (outpatient, day hospital, inpatient), and effectiveness was assessed at 18 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45) and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. RESULTS: Patients in the day hospital and inpatient group improved substantially in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life. Patients in the outpatient group showed less improvement. Direct comparison of the improvement of psychiatric symptoms showed significant results in favour of day hospital (p = 0.046) and inpatient (p = 0.01) treatment, as compared to outpatient treatment. However, due to substantial baseline differences, this direct comparison should be judged carefully. CONCLUSIONS: Cluster A psychopathology is not a contraindication to benefit from psychotherapy. This is especially true for more intensive forms like inpatient and day hospital treatment. Future research should focus more on psychotherapeutic treatment to gain further insight into effective treatment options for this patient grou

CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3

Objective: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design. Methods: Eighty-two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length. Results: On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression. Interpretation: Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG-dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2020

Effectiveness of different modalities of psychotherapeutic treatment for patients with cluster C personality disorders: results of a large prospective multicentre study.

Abstract BACKGROUND: No previous studies have compared the effectiveness of different modalities of psychotherapeutic treatment, as defined by different settings and durations, for patients with cluster C personality disorders. The aim of this multicentre study wa

Potential migratory routes of Urania boisduvalii (Lepidoptera: Uraniidae) among host plant populations

This work is licensed under a Creative Commons Attribution 4.0 International License.Aim Migratory species depend on various habitats and resources along their migration routes. Characteristics such as dependence on distinct habitats and the presence of multiple threats along their migratory routes make these species vulnerable, and gaps in knowledge about their ecology and migration processes make them difficult to conserve. Urania boisduvalii is a diurnal moth endemic to Cuba that feeds on plants of Omphalea spp. during its larval phases. These plants produce secondary metabolites as a defence against the moth's larvae, which then are forced to migrate. Although some ecological aspects of Urania boisduvalii are known, its migration routes remain largely unknown. This research proposes potential migratory routes of Urania boisduvalii among populations of its host plant. Location Cuba. Methods We developed ecological niche models of the moth and its hosts based on environmental, anthropic, biotic and biogeographic factors to obtain potential distributional areas that include zones where positive interactions are found but exclude those where negative factors are present. These areas were overlapped to hypothesize potential breeding areas for the moths. Potential migratory corridors were proposed based on environmental connectivity. Results The moth and its hosts have broad potential distributions; however, limiting factors have substantially reduced these areas, especially for plants. The potential migratory routes of Urania boisduvalii are complex and mostly involve the western and eastern regions of Cuba. Most records outside potential breeding areas were close to these migratory corridors. Main conclusions We offer initial hypotheses of the migratory routes of U. boisduvalii, which may be useful to guiding monitoring projects that can provide more definitive views of the seasonal distribution of this species across the Cuban archipelago

Laboratory Evolution of Fast-Folding Green Fluorescent Protein Using Secretory Pathway Quality Control

Green fluorescent protein (GFP) has undergone a long history of optimization to become one of the most popular proteins in all of cell biology. It is thermally and chemically robust and produces a pronounced fluorescent phenotype when expressed in cells of all types. Recently, a superfolder GFP was engineered with increased resistance to denaturation and improved folding kinetics. Here we report that unlike other well-folded variants of GFP (e.g., GFPmut2), superfolder GFP was spared from elimination when targeted for secretion via the SecYEG translocase. This prompted us to hypothesize that the folding quality control inherent to this secretory pathway could be used as a platform for engineering similar ‘superfolded’ proteins. To test this, we targeted a combinatorial library of GFPmut2 variants to the SecYEG translocase and isolated several superfolded variants that accumulated in the cytoplasm due to their enhanced folding properties. Each of these GFP variants exhibited much faster folding kinetics than the parental GFPmut2 protein and one of these, designated superfast GFP, folded at a rate that even exceeded superfolder GFP. Remarkably, these GFP variants exhibited little to no loss in specific fluorescence activity relative to GFPmut2, suggesting that the process of superfolding can be accomplished without altering the proteins' normal function. Overall, we demonstrate that laboratory evolution combined with secretory pathway quality control enables sampling of largely unexplored amino-acid sequences for the discovery of artificial, high-performance proteins with properties that are unparalleled in their naturally occurring analogues