The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.

The sibling familiarity effect: Is within-person facial variability shared across siblings?

Humans are experts at familiar face recognition, but poor at unfamiliar face recognition. Familiarity is created when a face is encountered across varied conditions, but the way in which a person’s appearance varies is identity-specific, so familiarity with one identity does not benefit recognition of other individuals. However, the faces of biological siblings share structural similarities, so we explored whether the benefits of familiarity are shared across siblings. Results show that familiarity with one half of a sibling pair improves kin detection (experiment 1), and that unfamiliar face matching is more accurate when targets are the siblings of familiar vs unfamiliar individuals (experiment 2). PCA applied to facial images of celebrities and their siblings demonstrates that, for shape, faces are generally better reconstructed in the principal components of a same-sex sibling than those of an unrelated individual. When we encounter the unfamiliar sibling of someone we already know, our pre-existing representation of their familiar relation may usefully inform processing of the unfamiliar face. This can benefit both kin detection and identity processing, but the benefits are constrained by the degree to which facial variability is shared.

Entrepreneurial alertness, self-efficacy and social entrepreneurship intentions

PurposeConsidering that many unanswered questions remain regarding the antecedents to entrepreneurial intentions, the purpose of this study is to develop insights from existing theories in entrepreneurship frameworks and apply these in the social entrepreneurship context. Consequently the study examines to what extant beliefs and cognitions shape social entrepreneurial intentions.Design/methodology/approachHypotheses were statistically tested using multiple regression analyses based on survey data (n = 156) from individuals in South Africa.FindingsResults support the hypotheses where entrepreneurial alertness significantly explained social entrepreneurial intentions, while self-efficacy showed a positive mediating effect in this relationship.Practical implicationsPolicymakers encouraging social entrepreneurship should not only focus on external support factors such as financial support but also deliberately develop interventions by focusing on beliefs and cognitions, which the study has identified as important predictors of social entrepreneurship intentions.Originality/valueBy introducing previously unrelated individual-level factors to social entrepreneurship, closer empirical links are created between these factors in this study.

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Our ability to predict the effects of drug combinations is limited, in part by limited understanding of how the transcriptional response of two monotherapies results in that of their combination. We performed the first analysis of matched time course RNAseq profiling of cells treated with both single drugs and their combinations. The transcriptional signature of the synergistic combination we studied had unique gene expression not seen in either constituent monotherapy. This can be explained mechanistically by the sequential activation of transcription factors in time in the gene regulatory network. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.84 in the prediction of synergistic drug combinations in an independent dataset.

Parentage assignment with genotyping-by-sequencing data

In this paper we evaluate using genotype-by-sequencing (GBS) data to perform parentage assignment in lieu of traditional array data. The use of GBS data raises two issues: First, for low-coverage GBS data, it may not be possible to call the genotype at many loci, a critical first step for detecting opposing homozygous markers. Second, the amount of sequencing coverage may vary across individuals, making it challenging to directly compare the likelihood scores between putative parents. To address these issues we extend the probabilistic framework of Huisman (2017) and evaluate putative parents by comparing their (potentially noisy) genotypes to a series of proposal distributions. These distributions describe the expected genotype probabilities for the relatives of an individual. We assign putative parents as a parent if they are classified as a parent (as opposed to e.g., an unrelated individual), and if the assignment score passes a threshold. We evaluated this method on simulated data and found that (1) high-coverage GBS data performs similarly to array data and requires only a small number of markers to correctly assign parents and (2) low-coverage GBS data (as low as 0.1x) can also be used, provided that it is obtained across a large number of markers. When analysing the low-coverage GBS data, we also found a high number of false positives if the true parent is not contained within the list of candidate parents, but that this false positive rate can be greatly reduced by hand tuning the assignment threshold. We provide this parentage assignment method as a standalone program called AlphaAssign.

Effect of Biological Relatedness on Perfume Selection for Others: Preliminary Evidence

People tend to choose perfumes to complement their body odour. As kin share some body odour qualities, their ability to select complementary perfumes for relatives might be higher compared with selection for nonrelatives. We tested this in two studies, comparing selection of a perfume for a target man by himself and by either a familiar but unrelated individual (girlfriend; Study 1) or a relative (sister; Study 2). Target men applied the two perfumes (own or other’s choice) to their axillae and then wore cotton pads for 12 hr. Collected perfume-body odour blends and perfumes alone were assessed by rater panels. In Study 1, the blends were rated as nominally more pleasant when body odours were mixed with the perfumes selected by girlfriends compared with those selected by target men themselves. In Study 2, body odours mixed with perfumes selected by sisters were rated significantly more attractive than those mixed with perfumes selected by target men. No significant differences were found for attractiveness and pleasantness ratings when perfumes were rated alone, suggesting that it was the resulting blends that were uniquely different. Our results indicate that sisters might be particularly tuned to select suitable perfumes for their siblings.

Copy-Number Variations Observed in a Japanese Population by BAC Array CGH: Summary of Relatively Rare CNVs

Copy-number variations (CNVs) may contribute to genetic variation in humans. Reports regarding existence and characteristics of CNVs in a large apparently healthy Japanese cohort are quite limited. We report the data from a screening of 213 unrelated Japanese individuals using comparative genomic hybridization based on a bacterial artificial chromosome microarray (BAC aCGH). In a previous paper, we summarized the data by focusing on highly polymorphic CNVs (in ≥5.0 % of the individuals). However, rare variations have recently received attention from scientists who espouse a hypothesis called “common disease and rare variants.” Here, we report CNVs identified in fewer than 10 individuals in our study population. We found a total of 126 CNVs at 52 different BAC regions in the genome. The CNVs observed at 27 of the 52 BAC-regions were found in only one unrelated individual. The majority of CNVs found in this study were not identified in the Japanese who were examined in the other studies. Family studies were conducted, and the results demonstrated that the CNVs were inherited from one parent in the families.

Forensic Value of Ten Short Tandem Repeat Loci in Turkey Compared to Other Ethnic Groups

Forensic Value of Ten Short Tandem Repeat Loci in Turkey Compared to Other Ethnic GroupsAllele frequencies of the 10 short tandem repeats (STRs) loci (D16S539, D2S1338, D3S1358, vWA, D18S51, D21S11, D8S1179, D19S433, FGA, THO1) included in the AmpFISTR SGM Plus kit, were obtained from biological samples from 100 unrelated individual residing in different part of Turkey. The χ2 test showed that all these loci agreed with Hardy-Weinberg equilibrium, The results were compared with the previously published data from Turkish and other ethnic groups. Suggest that these loci with their high heterozygosity and combined power of discrimination (PD) values are useful for forensic identifications.

Rare Polymorphisms Associated with Neonatal Alloimmune Thrombocytopenia (NATP) and New Mutations Identified in Platelet Glycoproteins (GP)

Neonatal Alloimmune Thrombocytopenia (NATP) is caused by maternal immunization against alloantigens carried on paternal platelet glycoproteins (GP). Although common antigens and their corresponding antibodies can be reliably detected, about two-thirds of suspected cases of NATP go unresolved. We are investigating the extent to which maternal immunization against low frequency antigens not usually tested for contributes to the relatively low diagnostic yield in NATP evaluations. In the course of this work, we have identified eight previously undescribed amino acid substitutions located in four different platelet GPs (Table 1). Table 1. Eight new mutations identified in platelet glycoproteins Name Sta Kno Sol Brc Bec Aus Rou2 Rou1 GP IIIa IIb IIIa Ia IIIa Ibb IIb IIb Mutation K137Q T619M E628K E505V K646E D13H G790S T9A The incidence of each mutation in the general population is less than 1.0%. Antigens Sta and Kno were each identified in fathers of suspected NATP cases and in the affected infants. In addition, maternal antibodies reacted with recombinant GPs modified to contain the relevant mutations, making it very likely that the antibodies were the cause of NATP in these instances. Antigen Sol was identified in the father and maternal antibody reacted strongly with paternal GPIIb/IIIa. However, the infant has not yet been typed. It is likely, but not certain that immunization against Sol caused NATP in this case. Mutation Brc was found in the father of an infant with possible NATP. However maternal serum failed to react with GPIa from father’s platelets and it was not possible to type the affected infant. Mutations Bec, Aus and Rou2 were identified in paternal DNA but the affected infants were negative for these mutations. Mutation Rou1 was identified in maternal DNA and could not have been an immunogen. It is highly likely that three of the eight new mutations (Sta, Kno, and Sol) caused maternal immunization leading to NATP. However, the other five (Bec, Aus, Brc, Rou1 and Rou2) appear to have been identified incidentally in the course of the NATP evaluations. Before concluding that maternal-fetal incompatibility for a rare antigen identified in the father is the immunogen responsible for triggering NATP these findings emphasize the importance of typing an affected infant to determine whether a low frequency antigen identified in the father was inherited. In addition it is necessary to confirm that maternal serum reacts with the suspected paternal antigen incorporated into a recombinant protein or carried on platelets from an unrelated individual.

Gene Copy Number Analysis for Family Data Using Semiparametric Copula Model

Gene copy number changes are common characteristics of many genetic disorders. A new technology, array comparative genomic hybridization (a-CGH), is widely used today to screen for gains and losses in cancers and other genetic diseases with high resolution at the genome level or for specific chromosomal region. Statistical methods for analyzing such a-CGH data have been developed. However, most of the existing methods are for unrelated individual data and the results from them provide explanation for horizontal variations in copy number changes. It is potentially meaningful to develop a statistical method that will allow for the analysis of family data to investigate the vertical kinship effects as well. Here we consider a semiparametric model based on clustering method in which the marginal distributions are estimated nonparametrically, and the familial dependence structure is modeled by copula. The model is illustrated and evaluated using simulated data. Our results show that the proposed method is more robust than the commonly used multivariate normal model. Finally, we demonstrated the utility of our method using a real dataset.