What Evidence Is There for the Homology of Protein-Protein Interactions?

The notion that sequence homology implies functional similarity underlies much of computational biology. In the case of protein-protein interactions, an interaction can be inferred between two proteins on the basis that sequence-similar proteins have been observed to interact. The use of transferred interactions is common, but the legitimacy of such inferred interactions is not clear. Here we investigate transferred interactions and whether data incompleteness explains the lack of evidence found for them. Using definitions of homology associated with functional annotation transfer, we estimate that conservation rates of interactions are low even after taking interactome incompleteness into account. For example, at a blastp -value threshold of , we estimate the conservation rate to be about between S. cerevisiae and H. sapiens. Our method also produces estimates of interactome sizes (which are similar to those previously proposed). Using our estimates of interaction conservation we estimate the rate at which protein-protein interactions are lost across species. To our knowledge, this is the first such study based on large-scale data. Previous work has suggested that interactions transferred within species are more reliable than interactions transferred across species. By controlling for factors that are specific to within-species interaction prediction, we propose that the transfer of interactions within species might be less reliable than transfers between species. Protein-protein interactions appear to be very rarely conserved unless very high sequence similarity is observed. Consequently, inferred interactions should be used with care.     

Statistical Use in Clinical Studies: Is There Evidence of a Methodological Shift?

Background

Several studies indicate that the statistical education model and level in medical training fails to meet the demands of clinicians, especially when they want to understand published clinical research. We investigated how study designs and statistical methods in clinical studies have changed in the last twenty years, and we identified the current trends in study designs and statistical methods in clinical studies.

Methods

We reviewed 838 eligible clinical study articles that were published in 1990, 2000, and 2010 in four journals New England Journal of Medicine, Lancet, Journal of the American Medical Association and Nature Medicine. The study types, study designs, sample designs, data quality controls, statistical methods and statistical software were examined.

Results

Substantial changes occurred in the past twenty years. The majority of the studies focused on drug trials (61.6%, n = 516). In 1990, 2000, and 2010, there was an incremental increase in RCT studies (74.4%, 82.8%, and 84.0%, respectively, p = 0.013). Over time, there was increased attention on the details of selecting a sample and controlling bias, and there was a higher frequency of utilizing complex statistical methods. In 2010, the most common statistical methods were confidence interval for superiority and non-inferiority comparison (41.6%), survival analysis (28.5%), correction analysis for covariates (18.8%) and Logistic regression (15.3%).

Conclusions

These findings indicate that statistical measures in clinical studies are continuously developing and that the credibility of clinical study results is increasing. These findings provide information for future changes in statistical training in medical education.     

Is Socioeconomic Status of the Rearing Environment Causally Related to Obesity in the Offspring?

We attempt to elucidate whether there might be a causal connection between the socioeconomic status (SES) of the rearing environment and obesity in the offspring using data from two large-scale adoption studies: (1) The Copenhagen Adoption Study of Obesity (CASO), and (2) The Survey of Holt Adoptees and Their Families (HOLT). In CASO, the SES of both biological and adoptive parents was known, but all children were adopted. In HOLT, only the SES of the rearing parents was known, but the children could be either biological or adopted. After controlling for relevant covariates (e.g., adoptee age at measurement, adoptee age at transfer, adoptee sex) the raw (unstandardized) regression coefficients for adoptive and biological paternal SES on adoptee body mass index (BMI: kg/m²) in CASO were -.22 and -.23, respectively, both statistically significant (p = 0.01). Controlling for parental BMI (both adoptive and biological) reduced the coefficient for biological paternal SES by 44% (p = .034) and the coefficient for adoptive paternal SES by 1%. For HOLT, the regression coefficients for rearing parent SES were -.42 and -.25 for biological and adoptive children, respectively. Controlling for the average BMI of the rearing father and mother (i.e., mid-parental BMI) reduced the SES coefficient by 47% in their biological offspring (p≤.0001), and by 12% in their adoptive offspring (p = .09). Thus, despite the differing structures of the two adoption studies, both suggest that shared genetic diathesis and direct environmental transmission contribute about equally to the association between rearing SES and offspring BMI.     

Is There a Twelfth Protein-Coding Gene in the Genome of Influenza A? A Selection-Based Approach to the Detection of Overlapping Genes in Closely Related Sequences

Protein-coding genes often contain long overlapping open-reading frames (ORFs), which may or may not be functional. Current methods that utilize the signature of purifying selection to detect functional overlapping genes are limited to the analysis of sequences from divergent species, thus rendering them inapplicable to genes found only in closely related sequences. Here, we present a method for the detection of selection signatures on overlapping reading frames by using closely related sequences, and apply the method to several known overlapping genes, and to an overlapping ORF on the negative strand of segment 8 of influenza A virus (NEG8), for which the suggestion has been made that it is functional. We find no evidence that NEG8 is under selection, suggesting that the intact reading frame might be non-functional, although we cannot fully exclude the possibility that the method is not sensitive enough to detect the signature of selection acting on this gene. We present the limitations of the method using known overlapping genes and suggest several approaches to improve it in future studies. Finally, we examine alternative explanations for the sequence conservation of NEG8 in the absence of selection. We show that overlap type and genomic context affect the conservation of intact overlapping ORFs and should therefore be considered in any attempt of estimating the signature of selection in overlapping genes.     

Mitotic Instability in Cancer: Is There Method in the Madness?

It has been known for more than a century that neoplastic cells often exhibit disturbances of the mitotic process, but the causes have only recently been thoroughly explored. In many cancers, a combination of cell cycle checkpoint deficiency and abnormal shortening of telomeres predisposes to unbalanced chromosome segregation at cell division and the development of complex genomic rearrangements. Shortening of telomeric repeats beyond normal limits leads to fusion of chromosome ends and the formation of chromatin bridges at anaphase. In turn, these bridges may trigger at least three types of chromosomes mutation: (1) structural rearrangements of chromosomes through extensive chromatin fragmentation beyond the centromeric sequences, typically leading to the formation of isochromosomes and whole-arm translocations, (2) loss of whole chromosomes through mechanical detachment from the mitotic spindle machinery, and (3) failure of cytokinesis, leading to polyploidisation and supernumerary centrosomes, which may in turn orchestrate multipolar spindle configurations at a subsequent mitosis. Anaphase bridging rarely hinders further survival of tumour daughter cells. In contrast, multipolar mitoses may lead to extensive reshuffling of chromosome copies that compromise further clonal expansion. The telomere-dependent instability can be partly counteracted by expression of telomerase during tumour progression, but genomic stabilisation is rarely, if ever, complete.     

Animal Welfare Issues in the Poultry Industry: Is There a Lesson to Be Learned?

Many of the conditions in which poultry live and the procedures to which they are subjected compromise their welfare. This article describes these welfare problems in the hope that they may serve as warnings to the rest of animal agriculture, which then might take steps to avoid the same pitfalls. The article discusses poultry welfare problems under the headings of battery cages for laying hens, forced molting, disposal of spent laying hens, fast growth problems in meat poultry, catching and transportation, food restriction of broiler breeders, hyperaggressiveness in broiler breeder males, elective surgeries, and water-bath stunning.     

Current Status in Diagnosis of Scedosporium Infections: What Is the Impact of New Molecular Methods?

Scedosporium species are increasingly encountered as fungal pathogens. Species identification is important due to species-specific differences in epidemiology, antifungal susceptibility and virulence. Histology and culture-based identification are hampered by their low sensitivity and specificity. The use of new selective media has improved the recovery rate from clinical samples. Molecular methods, including multiplex PCR, PCR-RFLP analysis, DNA sequencing, oligonucleotide arrays, real-time PCR, rolling circle amplification, are increasingly used for species identification. Most recently, Matrix-Assisted Laser Desorption-Time of Flight Mass Spectrometry has been successfully applied as a tool for rapid identification of clinically relevant Scedosporium species. This review aims to summarize the methods currently used to guide the clinical microbiology laboratory in the selection of the most appropriate identification techniques. This will aid the laboratory in making a fast and reliable diagnosis that enables the clinician to make correct treatment choices.     

Is There Selection for the Pace of Successive Inactivation of the arpAT Gene in Primates?

Pseudogenes have classically been considered inactive sequences evolving under neutrality. In recent years, however, a growing body of evidence is favoring the appearance of hypotheses attributing a functional role to pseudogenes. One of these hypotheses is that the silencing of a gene could produce a loss of function that could have been favored by natural selection. Here, we analyzed the pace of pseudogenization of arpAT, an L-DOPA transporter related to the neurotransmitter function of this amino acid in the brain. While active in rodent, dog, and chicken, arpAT has been silenced during primate evolution. Given the high number of inactivating mutations described in humans, it is possible that there have been selective pressures favoring this silencing. Through analysis of orthologous sequences in several primate species, we show that the silencing of arpAT occurred approximately 77 million to 90 million years ago, and that the observed mutation pattern is likely a consequence of its antiquity.     

Metacognition for Spelling in Higher Education Students with Dyslexia: Is There Evidence for the Dual Burden Hypothesis?

We examined whether academic and professional bachelor students with dyslexia are able to compensate for their spelling deficits with metacognitive experience. Previous research suggested that students with dyslexia may suffer from a dual burden. Not only do they perform worse on spelling but in addition they are not as fully aware of their difficulties as their peers without dyslexia. According to some authors, this is the result of a worse feeling of confidence, which can be considered as a form of metacognition (metacognitive experience). We tried to isolate this metacognitive experience by asking 100 students with dyslexia and 100 matched control students to rate their feeling of confidence in a word spelling task and a proofreading task. Next, we used Signal Detection Analysis to disentangle the effects of proficiency and criterion setting. We found that students with dyslexia showed lower proficiencies but not suboptimal response biases. They were as good at deciding when they could be confident or not as their peers without dyslexia. They just had more cases in which their spelling was wrong. We conclude that the feeling of confidence in our students with dyslexia is as good as in their peers without dyslexia. These findings go against the Dual Burden theory (Krüger & Dunning, 1999), which assumes that people with a skills problem suffer twice as a result of insufficiently developed metacognitive competence. As a result, there is no gain to be expected from extra training of this metacognitive experience in higher education students with dyslexia.     

Empathy among Medical Students: Is There a Relation with Quality of Life and Burnout?

Background

We aimed to assess medical students'' empathy and its associations with gender, stage of medical school, quality of life and burnout.

Method

A cross-sectional, multi-centric (22 medical schools) study that employed online, validated, self-reported questionnaires on empathy (Interpersonal Reactivity Index), quality of life (The World Health Organization Quality of Life Assessment) and burnout (the Maslach Burnout Inventory) in a random sample of medical students.

Results

Out of a total of 1,650 randomly selected students, 1,350 (81.8%) completed all of the questionnaires. Female students exhibited higher dispositional empathic concern and experienced more personal distress than their male counterparts (p<0.05; d≥0.5). There were minor differences in the empathic dispositions of students in different stages of their medical training (p<0.05; f<0.25). Female students had slightly lower scores for physical and psychological quality of life than male students (p<0.05; d<0.5). Female students scored higher on emotional exhaustion and lower on depersonalization than male students (p<0.001; d<0.5). Students in their final stage of medical school had slightly higher scores for emotional exhaustion, depersonalization and personal accomplishment (p<0.05; f<0.25). Gender (β = 0.27; p<0.001) and perspective taking (β = 0.30; p<0.001) were significant predictors of empathic concern scores. Depersonalization was associated with lower empathic concern (β = −0.18) and perspective taking (β = −0.14) (p<0.001). Personal accomplishment was associated with higher perspective taking (β = 0.21; p<0.001) and lower personal distress (β = −0.26; p<0.001) scores.

Conclusions

Female students had higher empathic concern and personal distress dispositions. The differences in the empathy scores of students in different stages of medical school were small. Among all of the studied variables, personal accomplishment held the most important association with decreasing personal distress and was also a predicting variable for perspective taking.     

Spatiotemporal Pattern of Bacillary Dysentery in China from 1990 to 2009: What Is the Driver Behind?

Background

Little is known about the spatiotemporal pattern of bacillary dysentery (BD) in China. This study assessed the geographic distribution and seasonality of BD in China over the past two decades.

Methods

Data on monthly BD cases in 31 provinces of China from January 1990 to December 2009 obtained from Chinese Center for Disease Control and Prevention, and data on demographic and geographic factors, as well as climatic factors, were compiled. The spatial distributions of BD in the four periods across different provinces were mapped, and heat maps were created to present the seasonality of BD by geography. A cosinor function combined with Poisson regression was used to quantify the seasonal parameters of BD, and a regression analysis was conducted to identify the potential drivers of morbidity and seasonality of BD.

Results

Although most regions of China have experienced considerable declines in BD morbidity over the past two decades, Beijing and Ningxia still had high BD morbidity in 2009. BD morbidity decreased more slowly in North-west China than other regions. BD in China mainly peaked from July to September, with heterogeneity in peak time between regions. Relative humidity was associated with BD morbidity and peak time, and latitude was the major predictor of BD amplitude.

Conclusions

The transmission of BD was heterogeneous in China. Improved sanitation and hygiene in North-west China, and better access to clean water and food in the big floating population in some metropolises could be the focus of future preventive interventions against BD. BD control efforts should put more emphasis on those dry areas in summer.     

Is There a Third Photoreceptor Involved in the Control of Chloroplast Movements in Mougeotia?

The photometric method was used to test a possibility proposed recently that a new photoreceptor with maximum activity at 620 nm is involved in mediating chloroplast rotation in Mougeotia (Z Lechowski, J Bialczyk [1988] Plant Physiol 88: 189-193). The hypothesis was tested under conditions of continuous dichromatic unilateral or mutually perpendicular irradiation with red light of wavelengths 620 or 660 (680) nanometers and far-red. When the red light was polarized parallel to the long cell axis, chloroplast response could be monitored by changing the direction of far-red irradiation. The level of the response obtained with red and far-red applied from the same direction depended on far-red intensity: at higher fluence rates the maximum response was shifted to longer wavelengths of red light. A high fluence rate of far-red inhibited the response. The absorption coefficients of Mougeotia chloroplasts were measured for the studied wave-lengths using the microphotometric method. Possible impact of absorption by the chloroplast on photoreception has been discussed. Current and previous results can be interpreted in terms of phytochrome action and do not support the involvement of the hypothetical 620 nanometer photoreceptor.     

Is the Oxidant/Antioxidant Status Altered in CADASIL Patients?

The altered aggregation of proteins in non-native conformation is associated with endoplasmic reticulum derangements, mitochondrial dysfunction and excessive production of reactive oxygen species. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary systemic vasculopathy, caused by NOTCH3 mutations within the receptor extracellular domain, that lead to abnormal accumulation of the mutated protein in the vascular wall. NOTCH3 misfolding could cause free radicals increase also in CADASIL. Aim of the study was to verify whether CADASIL patients have increased oxidative stress compared to unrelated healthy controls. We enrolled 15 CADASIL patients and 16 gender- and age-matched healthy controls with comparable cardiovascular risk factor. Blood and plasma reduced and total aminothiols (homocysteine, cysteine, glutathione, cysteinylglycine) were measured by HPLC and plasma 3-nitrotyrosine by ELISA. Only plasma reduced cysteine (Pr-Cys) and blood reduced glutathione (Br-GSH) concentrations differed between groups: in CADASIL patients Br-GSH levels were higher (p = 0.019) and Pr-Cys lower (p = 0.010) than in controls. No correlation was found between Br-GSH and Pr-Cys either in CADASIL patients (rho 0.25, P=0.36) or in controls (rho -0.15, P=0.44). Conversely, 3-nitrotyrosine values were similar in CADASIL and healthy subjects (p = 0.82). The high levels of antioxidant molecules and low levels of oxidant mediators found in our CADASIL population might either be expression of an effective protective action against free radical formation at an early stage of clinical symptoms or they could suggest that oxidative stress is not directly involved in the pathogenesis of CADASIL.