A general and efficient method for estimating continuous IBD functions for use in genome scans for QTL

<p>Abstract</p> <p>Background</p> <p>Identity by descent (IBD) matrix estimation is a central component in mapping of Quantitative Trait Loci (QTL) using variance component models. A large number of algorithms have been developed for estimation of IBD between individuals in populations at discrete locations in the genome for use in genome scans to detect QTL affecting various traits of interest in experimental animal, human and agricultural pedigrees. Here, we propose a new approach to estimate IBD as continuous functions rather than as discrete values.</p> <p>Results</p> <p>Estimation of IBD functions improved the computational efficiency and memory usage in genome scanning for QTL. We have explored two approaches to obtain continuous marker-bracket IBD-functions. By re-implementing an existing and fast deterministic IBD-estimation method, we show that this approach results in IBD functions that produces the exact same IBD as the original algorithm, but with a greater than 2-fold improvement of the computational efficiency and a considerably lower memory requirement for storing the resulting genome-wide IBD. By developing a general IBD function approximation algorithm, we show that it is possible to estimate marker-bracket IBD functions from IBD matrices estimated at marker locations by any existing IBD estimation algorithm. The general algorithm provides approximations that lead to QTL variance component estimates that even in worst-case scenarios are very similar to the true values. The approach of storing IBD as polynomial IBD-function was also shown to reduce the amount of memory required in genome scans for QTL.</p> <p>Conclusion</p> <p>In addition to direct improvements in computational and memory efficiency, estimation of IBD-functions is a fundamental step needed to develop and implement new efficient optimization algorithms for high precision localization of QTL. Here, we discuss and test two approaches for estimating IBD functions based on existing IBD estimation algorithms. Our approaches provide immediately useful techniques for use in single QTL analyses in the variance component QTL mapping framework. They will, however, be particularly useful in genome scans for multiple interacting QTL, where the improvements in both computational and memory efficiency are the key for successful development of efficient optimization algorithms to allow widespread use of this methodology.</p

Парсическая роль интеллигенции в истории

In 1661, Borelli and Ecchellensis published a Latin translation of a text which they called the Ltmmas of Archimedes. The first fifteen propositions of this translation correspond to the contents of the Arabic Book of Assumptions, which the Arabic tradition attributes to Archimedes. The work is not found in Greek and the attribution is uncertain at best. Nevertheless, the Latin translation of the fifteen propositions was adopted as a work of Archimedes in the standard editions and translations by Heiberg, Heath, Ver Eecke and others. Our paper concerns the remaining two propositions, 16 and 17, in the Latin translation by Borelli and Ecchellensis, which are not found in the Arabic Book of Assumptions. Borelli and Ecchellensis believed that the Arabic Book of Assumptions is a mutilated version of a lost "old book" by Archimedes which is mentioned by Eutodus (ca. A.D. 500) in his commentary to Proposition 4 of Book 2 of Archimedes' On the Sphere and Cylinder. This proposition is about cutting a sphere by a plane in such a way that the volumes of the segments have a given ratio. Because the fifteen propositions in the Arabic Book of Assumptions have no connection whatsoever to this problem, Borelli and Ecchellensis "restored" two more propositions, their 16 and 17. Propositions 16 and 17 concern the problem of cutting a given line segment AG at a point X in such a way that the product AX· XG2 is equal to a given volume K. This problem is mentioned by Archimedes, and although he promised a solution, the solution is not found in On the Sphere and Cylinder. In his commentary, Eutodus presents a solution which he adapted from the "old book" of Archimedes which he had found. Proposition 17 is the synthesis of the problem by means of two conic sections, as adapted by Eutodus. Proposition 16 presents the diorismos: the problem can be solved only if K::::;;; AB · BG2, where point B is defined on AG such that AB = 1/zBG. We will show that Borelli and Ecchellensis adapted their Proposition 16 not from the commentary by Eutocius but from the Arabic text On Filling the Gaps in Archimedes' Sphere and Cylinder which was written by Abu Sahl al-Kuru in the tenth century, and which was published by Len Berggren. Borelli preferred al-Kiihi's diorismos (by elementary means) to the diorismos by means of conic sections in the commentary of Eutocius, even though Eutocius says that he had adapted it from the "old book." Just as some geometers in later Greek antiquity, Borelli and Ecchellensis bdieved that it is a "sin" to use conic sections in the solution of geometrical problems if elementary Euclidean means are possible. They (incorrectly) assumed that Archimedes also subscribed to this opinion, and thus they included their adaptation of al-Kuru's proposition in their restoration of the "old book" of Archimedes. Our paper includes the Latin text and an English translation of Propositions 16 and 17 of Borelli and Ecchellensis

Agency, qualia and life: connecting mind and body biologically

Many believe that a suitably programmed computer could act for its own goals and experience feelings. I challenge this view and argue that agency, mental causation and qualia are all founded in the unique, homeostatic nature of living matter. The theory was formulated for coherence with the concept of an agent, neuroscientific data and laws of physics. By this method, I infer that a successful action is homeostatic for its agent and can be caused by a feeling - which does not motivate as a force, but as a control signal. From brain research and the locality principle of physics, I surmise that qualia are a fundamental, biological form of energy generated in specialized neurons. Subjectivity is explained as thermodynamically necessary on the supposition that, by converting action potentials to feelings, the neural cells avert damage from the electrochemical pulses. In exchange for this entropic benefit, phenomenal energy is spent as and where it is produced - which precludes the objective observation of qualia

Genetic and Other Contributions to Alcohol Intake in Rhesus Macaques ( Macaca mulatta )

The etiology of alcoholism and alcohol abuse, like many other complex diseases, is heterogeneous and multifactorial. Numerous studies demonstrate a genetic contribution to variation in the expression of alcohol-related disorders in humans. Over the past decade, nonhuman primates have emerged as a valuable model for some aspects of human alcohol abuse because of their phylogenetic proximity to humans. Long-term, longitudinal studies of rhesus macaques ( Macaca mulatta ) have provided much insight into environmental influences, especially early life experiences, on alcohol consumption and behavior patterns that characterize alcohol intake later in life. It is not known, however, whether there is a genetic component as well to the variation seen in alcohol consumption in rhesus macaques. A significant genetic component to variation in alcohol consumption in rhesus macaques would show for the first time that like humans, for nonhuman primates additive genetic influences are important. Moreover, their use as a model for alcohol-related disorders in humans would have even greater relevance and utility for designing experiments incorporating the expanding molecular genetics field, and allow researchers to investigate the interaction among the known environmental influences and various genotypes. Methods : In this study, we investigate factors contributing to variation in alcohol consumption of 156 rhesus macaques collected over 10 years when subjects were adolescent in age, belonging to a single extended pedigree, with each cohort receiving identical early rearing backgrounds and subsequent treatments. To measure alcohol consumption each animal was provided unfettered simultaneous access both to an aspartame-sweetened 8.4% (v/v) alcohol-water solution, the aspartame-sweetened vehicle, and to water for 1 hour each day during the early afternoon between 13:00 and 15:00 in their home cages for a period of 5 to 7 weeks. We use multiple regression to identify factors that significantly affect alcohol consumption among these animals and a maximum likelihood program (ASReml) that, controlling for the significant factors, estimates the genetic contribution to the variance in alcohol consumption. Results : Multiple regression analysis identified test cohort and rearing environment as contributing to 57 and 2%, respectively, of the total variance in alcohol consumption. Of the remaining 41% of the variance about half (19.8%) was attributable to additive genetic effects using a maximum likelihood program. Conclusion : This study demonstrates that, as in humans, there are additive genetic factors that contribute to variation in alcohol consumption in rhesus macaques, with other nongenetic factors accounting for substantial portions of the variance in alcohol consumption, Our findings show the presence of an additive genetic component and suggest the potential utility of the nonhuman primate as a molecular genetics tool for understanding alcohol abuse and alcoholism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66182/1/j.1530-0277.2006.00044.x.pd

Group B streptococcal carriage, serotype distribution and antibiotic susceptibilities in pregnant women at the time of delivery in a refugee population on the Thai-Myanmar border

<p>Abstract</p> <p>Background</p> <p>Group B Streptococcus (GBS) is the leading cause of neonatal sepsis in the developed world. Little is known about its epidemiology in the developing world, where the majority of deaths from neonatal infections occur. Maternal carriage of GBS is a prerequisite for the development of early onset GBS neonatal sepsis but there is a paucity of carriage data published from the developing world, in particular South East Asia.</p> <p>Methods</p> <p>We undertook a cross sectional study over a 13 month period in a remote South East Asian setting on the Thai-Myanmar border. During labour, 549 mothers had a combined vaginal rectal swab taken for GBS culture. All swabs underwent both conventional culture as well as PCR for GBS detection. Cultured GBS isolates were serotyped by latex agglutination, those that were negative or had a weak positive reaction and those that were PCR positive but culture negative were additionally tested using multiplex PCR based on the detection of GBS capsular polysaccharide genes.</p> <p>Results</p> <p>The GBS carriage rate was 12.0% (95% CI: 9.4-15.0), with 8.6% positive by both culture and PCR and an additional 3.5% positive by PCR alone. Serotypes, Ia, Ib, II, III, IV, V, VI and VII were identified, with II the predominant serotype. All GBS isolates were susceptible to penicillin, ceftriaxone and vancomycin and 43/47 (91.5%) were susceptible to erythromycin and clindamycin.</p> <p>Conclusions</p> <p>GBS carriage is not uncommon in pregnant women living on the Thai-Myanmar border with a large range of serotypes represented.</p

Patient-Perceived Changes in the System of Values After Cancer Diagnosis

A cross-sectional study investigated changes in patients’ value systems following a diagnosis of cancer. Fifty patients at 1 to 6 months following cancer diagnosis, were asked to compare their current values with their recollection of past values. Using the Rokeach Value Survey we obtained statistically significant results showing that twenty-seven out of thirty-six values changed their importance from the patients’ perspective: 16 values significantly increased, while 11 values significantly decreased in importance. Changes with respect to nine values were insignificant. We indentified clusters of values increasing in importance the most: Religious morality (Salvation, Forgiving, Helpful, Clean), Personal orientation (Self-Respect, True Friendship, Happiness), Self-constriction (Self-Controlled, Obedient, Honest), Family security (Family Security, Responsible), and Delayed gratification (Wisdom, Inner Harmony). We also observed that the following value clusters decreased in importance: Immediate gratification (An Exciting Life, Pleasure, A Comfortable Life); Self-expansion (Capable, Ambitious, Broadminded), Competence (A Sense of Accomplishment, Imaginative, Intellectual). The remaining values belonged to clusters that as a group changed slightly or not at all. Practical implications of the study are discussed

Persistence of SARS-CoV-2 N-Antibody Response in Healthcare Workers, London, UK.

Prospective serosurveillance of severe acute respiratory syndrome coronavirus 2 in 1,069 healthcare workers in London, UK, demonstrated that nucleocapsid antibody titers were stable and sustained for <12 weeks in 312 seropositive participants. This finding was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c