Personalized 3-Gene Panel for Prostate Cancer Target Therapy

Many years and billions spent for research did not yet produce an effective answer to prostate cancer (PCa). Not only each human, but even each cancer nodule in the same tumor, has unique transcriptome topology. The differences go beyond the expression level to the expression control and networking of individual genes. The unrepeatable heterogeneous transcriptomic organization among men makes the quest for universal biomarkers and “fit-for-all” treatments unrealistic. We present a bioinformatics procedure to identify each patient’s unique triplet of PCa Gene Master Regulators (GMRs) and predict consequences of their experimental manipulation. The procedure is based on the Genomic Fabric Paradigm (GFP), which characterizes each individual gene by the independent expression level, expression variability and expression coordination with each other gene. GFP can identify the GMRs whose controlled alteration would selectively kill the cancer cells with little consequence on the normal tissue. The method was applied to microarray data on surgically removed prostates from two men with metastatic PCas (each with three distinct cancer nodules), and DU145 and LNCaP PCa cell lines. The applications verified that each PCa case is unique and predicted the consequences of the GMRs’ manipulation. The predictions are theoretical and need further experimental validation.

Agonism and grooming behaviour explain social status effects on physiology and gene regulation in rhesus macaques

Variation in social status predicts molecular, physiological and life-history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on datasets from one such study—experimental manipulation of dominance rank in captive female rhesus macaques—to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioural interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behaviour. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioural interactions that define an individual's daily experiences reveal the proximate drivers of social status-related differences and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct. This article is part of the theme issue ‘The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies’.

Envy and Environmental Decision Making: The Mediating Role of Self-Control

Emotions have strong impacts on decision making, yet research on the association between social interpersonal emotion and environmental decisions is limited. The present study uses experimental manipulation and cross-sectional investigation to examine how envy state and personality trait envy influence environmental actions. In Study 1, participants were manipulated to elicit benign and malicious envy, and it was found that benign envy acts as an antecedent of pro-environmental behavior, while malicious envy could contribute to behavior harmful to the environment. Study 2 replicated the results of Study 1 and examined the mediator of self-control through a correlational study. Consequently, people who are high in malicious envy tend to engage in more environmentally harmful activities rather than living a sustainable life, while dispositional benign envy could significantly predict pro-environmental behavior. Moreover, the link between dispositional malicious envy and environmental behavior can be explained by trait self-control, while the mediating effect was silent in dispositional benign envy. The findings shed new light on the impact of social interpersonal emotion on making environmental decisions and its related psychological mechanisms.

A Xenopus neuromast bioassay for chemical ototoxicity

Background: Ototoxic chemicals can impair the senses of hearing and balance in mammals through irreversible damage to the mechanosensory bundles of inner ear hair cells. Fish and amphibians are useful models for investigating ototoxicity because their inner ear hair cells, like those of mammals, are susceptible to damage by ototoxins. Moreover, amphibian mechanosensation is augmented by a lateral line organ on the body surface that comprises external mechanosensory hair cells. The lateral line hair cells are arranged in clusters (neuromasts) and are structurally and functionally similar to inner ear hair cells, but are more accessible for experimental manipulation. Herein, we implemented neuromasts of the amphibian (Xenopus) lateral line as an organ system for evaluating the effects of ototoxic chemicals, such as antibiotics, on mechanosensory hair cell bundles. Methods: We examined the ultrastructure of larval Xenopus laevis neuromasts with scanning electron microscopy (SEM) after larvae were continuously exposed to ototoxic aminoglycoside antibiotics at sub-lethal concentrations (gentamicin; streptomycin; neomycin) for 72 hours. Results: SEM images demonstrated that 72 hours of exposure to antibiotic concentrations greater than 25 μM reduced the hair cell bundle number in lateral line neuromasts. Conclusion: Therapeutic drug studies will benefit from the incorporation of bioassay strategies that evaluate ototoxicity across multiple species including genera of amphibian origin such as Xenopus. Our outcomes support the use of the Xenopus lateral line for identification of potential ototoxic chemicals and suggest that Xenopus neuromast hair cell bundles can withstand antibiotic exposure. The Xenopus bioassay presented here can be incorporated into drug discovery methodology as a high-resolution phenotypic screen for ototoxic effects.

Leader or Leaderess? Consequences of Using Feminatives for the Perception of Leadership

According to the Implicit Leadership Theory, leadership roles are assigned in the process of social construction and depend upon the level of congruence with the cognitive representation of a leader. Previous studies show that this cognitive representation is much more likely to involve a leader being a male rather than a female. The article presents the results of an experiment aimed at tentatively verifying whether the use of the feminine forms could increase the cognitive availability of the representation of a woman as a leader. In the experiment, 135 teams (N = 307 respondents) were randomly assigned to one of two experimental conditions: 1) generic instruction (without the use of feminatives, “Please, draw a leader”), 2) inclusive instruction (using feminatives, “Please, draw a leader/leaderess”). The results showed a significant interaction between the experimental manipulation and the proportion of women in the team. The use of feminine forms increased the percentage of females drawn as leaders only in teams with a high female-to-male ratio.

Opto-Katanin: An Optogenetic Tool for Localized Microtubule Disassembly

Microtubules are major cytoskeletal filaments that drive chromosome separation during cell division, serve as rails for intracellular transport and as a scaffold for organelle positioning. Experimental manipulation of microtubules is widely used in cell and developmental biology, but tools for precise subcellular spatiotemporal control of microtubule integrity are currently lacking. Here, we exploit the dependence of the mammalian microtubule-severing protein katanin on microtubule-targeting co-factors to generate a light-activated system for localized microtubule disassembly that we named opto-katanin. Targeted illumination with blue light induces rapid and localized opto-katanin recruitment and local microtubule depolymerization, which is quickly reversible after stopping light-induced activation. Opto-katanin can be employed to locally perturb microtubule-based transport and organelle morphology in dividing cells and differentiated neurons with high spatiotemporal precision. We show that different microtubule-associated proteins can be used to recruit opto-katanin to microtubules and induce severing, paving the way for spatiotemporally precise manipulation of specific microtubule subpopulations.

Out from under the wing: reconceptualizing the insect wing gene regulatory network as a versatile, general module for body-wall lobes in arthropods

Body plan evolution often occurs through the differentiation of serially homologous body parts, particularly in the evolution of arthropod body plans. Recently, homeotic transformations resulting from experimental manipulation of gene expression, along with comparative data on the expression and function of genes in the wing regulatory network, have provided a new perspective on an old question in insect evolution: how did the insect wing evolve? We investigated the metamorphic roles of a suite of 10 wing- and body-wall-related genes in a hemimetabolous insect, Oncopeltus fasciatus . Our results indicate that genes involved in wing development in O. fasciatus play similar roles in the development of adult body-wall flattened cuticular evaginations. We found extensive functional similarity between the development of wings and other bilayered evaginations of the body wall. Overall, our results support the existence of a versatile development module for building bilayered cuticular epithelial structures that pre-dates the evolutionary origin of wings. We explore the consequences of reconceptualizing the canonical wing-patterning network as a bilayered body-wall patterning network, including consequences for long-standing debates about wing homology, the origin of wings and the origin of novel bilayered body-wall structures. We conclude by presenting three testable predictions that result from this reconceptualization.

Parent of origin DNA methylation as a potential mechanism for genomic imprinting in bees.

Genomic imprinting is defined as parent-of-origin allele-specific expression. In order for genes to be expressed in this manner an `imprinting' mark must be present to distinguish the parental alleles within the genome. In mammals imprinted genes are primarily associated with DNA methylation. Genes exhibiting parent-of-origin expression have recently been identified in two species of Hymenoptera with functional DNA methylation systems; Apis mellifera and Bombus terrestris. We carried out whole genome bisulfite sequencing of parents and offspring from reciprocal crosses of two B. terrestris subspecies in order to identify parent-of-origin DNA methylation. We were unable to survey a large enough proportion of the genome to draw a conclusion on the presence of parent-of-origin DNA methylation however we were able to characterise the sex- and caste-specific methylomes of B. terrestris for the first time. We find males differ significantly to the two female castes, with differentially methylated genes involved in many histone modification related processes. We also analysed previously generated honeybee whole genome bisulfite data to see if genes previously identified as showing parent-of-origin DNA methylation in the honeybee show consistent allele-specific methylation in independent data sets. We have identified a core set of 12 genes in female castes which may be used for future experimental manipulation to explore the functional role of parent-of-origin DNA methylation in the honeybee. Finally, we have also identified allele-specific DNA methylation in honeybee male thorax tissue which suggests a role for DNA methylation in ploidy compensation in this species.

Negative effects of ant-plant interaction on pollination: costs of a mutualism

The mutualism of ants and extrafloral nectary (EFN)-bearing plants is known to reduce rates of herbivory. However, ants may have negative impacts on other mutualisms such as pollination, constituting an indirect cost of a facultative mutualism. For instance, when foraging on or close to reproductive plant parts ants might attack pollinators or inhibit their visits. We tested the hypothesis that ants on EFN-bearing plants may negatively influence pollinator behavior, ultimately reducing plant fitness (fruit set). The study was done in a reserve at Brazilian savannah using the EFN-bearing plant Banisteriopsis malifolia (Malpighiaceae). The experimental manipulation was carried out with four groups: control (free visitation of ants), without ants (ant-free branches), artificial ants (isolated branches with artificial ants on flowers) and plastic circles (isolated branches with plastic circles on flowers). We made observations on flower visitors and their interactions, and measured fruit formation as a proxy for plant fitness. Our results showed that pollinators hesitated to visit flowers with artificial ants, negatively affecting pollination, but did not hesitate to visit flowers with plastic circles, suggesting that they recognize the specific morphology of the ants. Pollinators spent more time per flower on the ant-free branches, and the fruiting rate was lower in the group with artificial ants. Our results confirm an indirect cost in this facultative mutualism, where the balance between these negative and positive effects of ants on EFN-bearing plants are not well known.

Alzheimer’s Disease: Current Perspectives and Advances in Physiological Modeling

Though Alzheimer’s disease (AD) is the most common cause of dementia, complete disease-modifying treatments are yet to be fully attained. Until recently, transgenic mice constituted most in vitro model systems of AD used for preclinical drug screening; however, these models have so far failed to adequately replicate the disease’s pathophysiology. However, the generation of humanized APOE4 mouse models has led to key discoveries. Recent advances in stem cell differentiation techniques and the development of induced pluripotent stem cells (iPSCs) have facilitated the development of novel in vitro devices. These “microphysiological” systems—in vitro human cell culture systems designed to replicate in vivo physiology—employ varying levels of biomimicry and engineering control. Spheroid-based organoids, 3D cell culture systems, and microfluidic devices or a combination of these have the potential to replicate AD pathophysiology and pathogenesis in vitro and thus serve as both tools for testing therapeutics and models for experimental manipulation.