KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.

Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.

Influence of "historic" photoperiod during stem elongation on the number of fertile florets in wheat

Extending the duration of the late reproductive phase in wheat has been proposed as a possible avenue to improve spike fertility. There is a positive correlation between the number of fertile florets and the duration of the stem elongation phase when this phase is varied by extended photoperiod. Photoperiod treatments imposed during the vegetative period also influence the duration of stem elongation. The present study analysed the effect of long photoperiod (19 h) of different duration (10, 12, 14, 18 or 22 d) imposed before the onset of stem elongation on floret fertility in wheat. It was found that the length of the stem elongation phase was modified by earlier ‘historic ’ photoperiod treatments imposed during previous phases. However, neither the number of fertile florets per spike nor the spikelet fertility was affected significantly by these historic treatments. The results of the study therefore showed that an increased duration of the late reproductive phase was ineffective in increasing the number of fertile florets, unless the length of that phase was directly altered by current photoperiod.

Copy number variation in the porcine genome inferred from a 60 k SNP BeadChip

Background: Recent studies in pigs have detected copy number variants (CNVs) using the Comparative Genomic Hybridization technique in arrays designed to cover specific porcine chromosomes. The goal of this study was to identify CNV regions (CNVRs) in swine species based on whole genome SNP genotyping chips. Results: We used predictions from three different programs (cnvPartition, PennCNV and GADA) to analyze data from the Porcine SNP60 BeadChip. A total of 49 CNVRs were identified in 55 animals from an Iberian x Landrace cross (IBMAP) according to three criteria: detected in at least two animals, contained three or more consecutive SNPs and recalled by at least two programs. Mendelian inheritance of CNVRs was confirmed in animals belonging to several generations of the IBMAP cross. Subsequently, a segregation analysis of these CNVRs was performed in 372 additional animals from the IBMAP cross and its distribution was studied in 133 unrelated pig samples from different geographical origins. Five out of seven analyzed CNVRs were validated by real time quantitative PCR, some of which coincide with well known examples of CNVs conserved across mammalian species. Conclusions: Our results illustrate the usefulness of Porcine SNP60 BeadChip to detect CNVRs and show that structural variants can not be neglected when studying the genetic variability in this species.

Complexation to macromolecules with a large number of sites

This paper presents an approach based on the saddle-point approximation to study the equilibrium interactions between small molecules and macromolecules with a large number of sites. For this case, the application of the Darwin–Fowler method results in very simple expressions for the stoichiometric equilibrium constants and their corresponding free energies in terms of integrals of the binding curve plus a correction term which depends on the first derivatives of the binding curve in the points corresponding to an integer value of the mean occupation number. These expressions are simplified when the number of sites tends to infinity, providing an interpretation of the binding curve in terms of the stoichiometric stability constants. The formalism presented is applied to some simple complexation models, obtaining good values for the free energies involved. When heterogeneous complexation is assumed, simple expressions are obtained to relate the macroscopic description of the binding, given by the stoichiomeric constants, with the microscopic description in terms of the intrinsic stability constants or the affinity spectrum. © 1999 American Institute of Physics.

Female major histocompatibility complex type affects male testosterone levels and sperm number in the horse (Equus caballus).

Odours of vertebrates often contain information about the major histocompatibility complex (MHC), and are used in kin recognition, mate choice or female investment in pregnancy. It is, however, still unclear whether MHC-linked signals can also affect male reproductive strategies. We used horses (Equus caballus) to study this question under experimental conditions. Twelve stallions were individually exposed either to an unfamiliar MHC-similar mare and then to an unfamiliar MHC-dissimilar mare, or vice versa. Each exposure lasted over a period of four weeks. Peripheral blood testosterone levels were determined weekly. Three ejaculates each were collected in the week after exposure to both mares (i.e. in the ninth week) to determine mean sperm number and sperm velocity. We found high testosterone levels when stallions were kept close to MHC-dissimilar mares and significantly lower ones when kept close to MHC-similar mares. Mean sperm number per ejaculate (but not sperm velocity) was positively correlated to mean testosterone levels and also affected by the order of presentation of mares: sperm numbers were higher if MHC-dissimilar mares were presented last than if MHC-similar mares were presented last. We conclude that MHC-linked signals influence testosterone secretion and semen characteristics, two indicators of male reproductive strategies.

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Priming psychic and conjuring abilities of a magic demonstration influences event interpretation and random number generation biases

Magical ideation and belief in the paranormal is considered to represent a trait-like character; people either believe in it or not. Yet, anecdotes indicate that exposure to an anomalous event can turn skeptics into believers. This transformation is likely to be accompanied by altered cognitive functioning such as impaired judgments of event likelihood. Here, we investigated whether the exposure to an anomalous event changes individuals' explicit traditional (religious) and non-traditional (e.g., paranormal) beliefs as well as cognitive biases that have previously been associated with non-traditional beliefs, e.g., repetition avoidance when producing random numbers in a mental dice task. In a classroom, 91 students saw a magic demonstration after their psychology lecture. Before the demonstration, half of the students were told that the performance was done respectively by a conjuror (magician group) or a psychic (psychic group). The instruction influenced participants' explanations of the anomalous event. Participants in the magician, as compared to the psychic group, were more likely to explain the event through conjuring abilities while the reverse was true for psychic abilities. Moreover, these explanations correlated positively with their prior traditional and non-traditional beliefs. Finally, we observed that the psychic group showed more repetition avoidance than the magician group, and this effect remained the same regardless of whether assessed before or after the magic demonstration. We conclude that pre-existing beliefs and contextual suggestions both influence people's interpretations of anomalous events and associated cognitive biases. Beliefs and associated cognitive biases are likely flexible well into adulthood and change with actual life events.

Evaluating the impact of filming on the number of errors committed by nursing students to determine the efficacy of simulated clinical situations

Clinic simulation as a training and knowledge method allows people experiment a real event representation with the aim of acquiring knowledge, abilities and aptitudes. The filming of the staging represents a useful tool to review the decisions taken and the actions they did, with the purpose to highlight the strengths, weaknesses and the areas for improvement. The article describes a study carried out by a group of students in second course of nursing, and it tries to evaluate if there is any influence if somebody is filming you during the clinic simulation, does it make you do more errors or not?

Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder.

BACKGROUND: Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. METHODS: In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. RESULTS: We found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). CONCLUSIONS: After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

Ultrasound-guided fine-needle aspiration of thyroid nodules: assessment of the ideal number of punctures

OBJECTIVE: To determine the number of punctures in fine-needle aspiration biopsies required for a safe cytological analysis of thyroid nodules. MATERIALS AND METHODS: Cross-sectional study with focus on diagnosis. The study population included 94 patients. RESULTS: The mean age of the patients participating in the study was 52 years (standard-deviation = 13.7) and 90.4% of them were women. Considering each puncture as an independent event, the first puncture has showed conclusive results in 78.7% of cases, the second, in 81.6%, and the third, in 71.8% of cases. With a view to the increasing chance of a conclusive diagnosis at each new puncture, two punctures have showed conclusive results in 89.5% of cases, and three punctures, in 90.6% of cases with at least one conclusive result. CONCLUSION: Two punctures in fine-needle aspiration biopsies of thyroid nodules have lead to diagnosis in 89.5% of cases in the study sample, suggesting that there is no need for multiple punctures to safely obtain the diagnosis of thyroid nodules.

DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer.

PURPOSE: Prospective-retrospective assessment of theTOP1gene copy number andTOP1mRNA expression as predictive biomarkers for adjuvant irinotecan in stage II/III colon cancer. EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant colon cancer trial (PETACC3) where patients were randomized to 5-fluorouracil/folinic acid with or without additional irinotecan.TOP1copy number status was analyzed by fluorescencein situhybridization (FISH) using aTOP1/CEN20 dual-probe combination.TOP1mRNA data were available from previous analyses. RESULTS: TOP1FISH and follow-up data were obtained from 534 patients.TOP1gain was identified in 27% using a single-probe enumeration strategy (≥4TOP1signals per cell) and in 31% when defined by aTOP1/CEN20 ratio ≥ 1.5. The effect of additional irinotecan was not dependent onTOP1FISH status.TOP1mRNA data were available from 580 patients with stage III disease. Benefit of irinotecan was restricted to patients characterized byTOP1mRNA expression ≥ third quartile (RFS: HRadjusted, 0.59;P= 0.09; OS: HRadjusted, 0.44;P= 0.03). The treatment byTOP1mRNA interaction was not statistically significant, but in exploratory multivariable fractional polynomial interaction analysis, increasingTOP1mRNA values appeared to be associated with increasing benefit of irinotecan. CONCLUSIONS: In contrast to theTOP1copy number, a trend was demonstrated for a predictive property ofTOP1mRNA expression. On the basis ofTOP1mRNA, it might be possible to identify a subgroup of patients where an irinotecan doublet is a clinically relevant option in the adjuvant setting of colon cancer.Clin Cancer Res; 22(7); 1621-31. ©2015 AACR.

Copy number variations of colorectal cancer by whole exome sequencing data

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death worldwide. About 85% of the cases of CRC are known to have chromosomal instability, an allelic imbalance at several chromosomal loci, and chromosome amplification and translocation. The aim of this study is to determine the recurrent copy number variant (CNV) regions present in stage II of CRC through whole exome sequencing, a rapidly developing targeted next-generation sequencing (NGS) technology that provides an accurate alternative approach for accessing genomic variations. 42 normal-tumor paired samples were sequenced by Illumina Genome Analyzer. Data was analyzed with Varscan2 and segmentation was performed with R package R-GADA. Summary of the segments across all samples was performed and the result was overlapped with DEG data of the same samples from a previous study in the group1. Major and more recurrent segments of CNV were: gain of chromosome 7pq(13%), 13q(31%) and 20q(75%) and loss of 8p(25%), 17p(23%), and 18pq(27%). This results are coincident with the known literature of CNV in CRC or other cancers, but our methodology should be validated by array comparative genomic hybridisation (aCGH) profiling, which is currently the gold standard for genetic diagnosis of CNV.

A Case-based reasoning approach to validate grammatical gender and number agreement in Spanish language

Across Latin America 420 indigenous languages are spoken. Spanish is considered a second language in indigenous communities and is progressively introduced in education. However, most of the tools to support teaching processes of a second language have been developed for the most common languages such as English, French, German, Italian, etc. As a result, only a small amount of learning objects and authoring tools have been developed for indigenous people considering the specific needs of their population. This paper introduces Multilingual–Tiny as a web authoring tool to support the virtual experience of indigenous students and teachers when they are creating learning objects in indigenous languages or in Spanish language, in particular, when they have to deal with the grammatical structures of Spanish. Multilingual–Tiny has a module based on the Case-based Reasoning technique to provide recommendations in real time when teachers and students write texts in Spanish. An experiment was performed in order to compare some local similarity functions to retrieve cases from the case library taking into account the grammatical structures. As a result we found the similarity function with the best performance

Minimum number of assessment times to compare chemical control treatments for papaya fruit anthracnose

The chemical treatment evaluation in the field to control post-harvest fruit anthracnose (Colletotrichum gloeosporioides) requires a suitable disease incidence assessment on harvested papaya (Carica papaya) fruits. The minimum number of papaya fruit harvests was determined for valid treatment comparison in field trials for anthracnose chemical control. Repeatability analysis was done using previously published data. The coefficient determination (R²) estimate range, using four methods, and based on means of 12 assessment times, was 92.58 < R² < 94.45%. The number of assessment times required for R²=90% varied from seven to nine. The R² values of 85.1 < R² < 91.3% estimated by ANOVA suggested that any seven successive assessment times were sufficient for treatment comparison.