Sodium acetate increases the productivity of HEK293 cells expressing the ECD-Her1 protein in batch cultures: experimental results and metabolic flux analysis.

Human Embryonic Kidney cells (HEK293) are a popular host for recombinant protein expression and production in the biotechnological industry. This has driven within both, the scientific and the engineering communities, the search for strategies to increase their protein productivity. The present work is inserted into this search exploring the impact of adding sodium acetate (NaAc) into a batch culture of HEK293 cells. We monitored, as a function of time, the cell density, many external metabolites, and the supernatant concentration of the heterologous extra-cellular domain ECD-Her1 protein, a protein used to produce a candidate prostate cancer vaccine. We observed that by adding different concentrations of NaAc (0, 4, 6 and 8 mM), the production of ECD-Her1 protein increases consistently with increasing concentration, whereas the carrying capacity of the medium decreases. To understand these results we exploited a combination of experimental and computational techniques. Metabolic Flux Analysis (MFA) was used to infer intracellular metabolic fluxes from the concentration of external metabolites. Moreover, we measured independently the extracellular acidification rate and oxygen consumption rate of the cells. Both approaches support the idea that the addition of NaAc to the culture has a significant impact on the metabolism of the HEK293 cells and that, if properly tuned, enhances the productivity of the heterologous ECD-Her1 protein.

Statistical indices of masculinity-femininity: A theoretical and practical framework.

Statistical indices of masculinity-femininity (M-F) summarize multivariate profiles of sex-related traits as positions on a single continuum of individual differences, from masculine to feminine. This approach goes back to the early days of sex differences research; however, a systematic discussion of alternative M-F indices (including their meaning, their mutual relations, and their psychometric properties) has been lacking. In this paper I present an integrative theoretical framework for the statistical assessment of masculinity-femininity, and provide practical guidance to researchers who wish to apply these methods to their data. I describe four basic types of M-F indices: sex-directionality, sex-typicality, sex-probability, and sex-centrality. I examine their similarities and differences in detail, and consider alternative ways of computing them. Next, I discuss the impact of measurement error on the validity of these indices, and outline some potential remedies. Finally, I illustrate the concepts presented in the paper with a selection of real-world datasets on body morphology, brain morphology, and personality. An R function is available to easily calculate multiple M-F indices from empirical data (with or without correction for measurement error) and draw summary plots of their individual and joint distributions.

Prosocial motives underlie scientific censorship by scientists: A perspective and research agenda.

Science is among humanity's greatest achievements, yet scientific censorship is rarely studied empirically. We explore the social, psychological, and institutional causes and consequences of scientific censorship (defined as actions aimed at obstructing particular scientific ideas from reaching an audience for reasons other than low scientific quality). Popular narratives suggest that scientific censorship is driven by authoritarian officials with dark motives, such as dogmatism and intolerance. Our analysis suggests that scientific censorship is often driven by scientists, who are primarily motivated by self-protection, benevolence toward peer scholars, and prosocial concerns for the well-being of human social groups. This perspective helps explain both recent findings on scientific censorship and recent changes to scientific institutions, such as the use of harm-based criteria to evaluate research. We discuss unknowns surrounding the consequences of censorship and provide recommendations for improving transparency and accountability in scientific decision-making to enable the exploration of these unknowns. The benefits of censorship may sometimes outweigh costs. However, until costs and benefits are examined empirically, scholars on opposing sides of ongoing debates are left to quarrel based on competing values, assumptions, and intuitions.

Relative density clouds: Visualizing and exploring multivariate patterns of group differences.

This paper introduces relative density clouds, a simple but powerful method to visualize the relative density of two groups in multivariate space. Relative density clouds employ k-nearest neighbor density estimates to provide information about group differences throughout the entire distribution of the variables. The method can also be used to decompose overall group differences into the specific contributions of differences in location, scale, and covariation. Existing relative distribution methods offer a flexible toolkit for the analysis of univariate differences; relative density clouds bring some of the same advantages to fruition in the context of multivariate research. They can assist in the exploration of complex patterns of group differences, and help break them down into simpler, more interpretable effects. An easy-to-use R function is provided to make this visualization method widely accessible to researchers.

An integrative evolutionary framework for psychopathology.

The field of psychopathology is in a transformative phase, and is witnessing a renewed surge of interest in theoretical models of mental disorders. While many interesting proposals are competing for attention in the literature, they tend to focus narrowly on the proximate level of analysis and lack a broader understanding of biological function. In this paper, we present an integrative framework for mental disorders built on concepts from life history theory, and describe a taxonomy of mental disorders based on its principles, the fast-slow-defense model (FSD). The FSD integrates psychopathology with normative individual differences in personality and behavior, and allows researchers to draw principled distinctions between broad clusters of disorders, as well as identify functional subtypes within current diagnostic categories. Simulation work demonstrates that the model can explain the large-scale structure of comorbidity, including the apparent emergence of a general "p factor" of psychopathology. A life history approach also provides novel integrative insights into the role of environmental risk/protective factors and the developmental trajectories of various disorders.

A general motivational architecture for human and animal personality.

To achieve integration in the study of personality, researchers need to model the motivational processes that give rise to stable individual differences in behavior, cognition, and emotion. The missing link in current approaches is a motivational architecture-a description of the core set of mechanisms that underlie motivation, plus a functional account of their operating logic and inter-relations. This paper presents the initial version of such an architecture, the General Architecture of Motivation (GAM). The GAM offers a common language for individual differences in humans and other animals, and a conceptual toolkit for building species-specific models of personality. The paper describes the main components of the GAM and their interplay, and examines the contribution of these components to the emergence of individual differences. The final section discusses how the GAM can be used to construct explicit functional models of personality, and presents a roadmap for future research.

FOXA1 regulates alternative splicing in prostate cancer.

Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1. By controlling trans-acting factor expression, FOXA1 exploits an "exon definition" mechanism calibrating alternative splicing toward dominant isoform production. This regulation especially impacts splicing factors themselves and leads to a reduction of nonsense-mediated decay (NMD)-targeted isoforms. Inclusion of the NMD-determinant FLNA exon 30 by FOXA1-controlled oncogene SRSF1 promotes cell growth in vitro and predicts disease recurrence. Overall, we report a role for FOXA1 in rewiring the alternative splicing landscape in prostate cancer through a cascade of events from chromatin access, to splicing factor regulation, and, finally, to alternative splicing of exons influencing patient survival.

Hormone ratios suffer from striking lack of robustness to measurement error.

Hormone ratios are often used to capture the joint effect (or "balance") of two hormones with opposing or mutually suppressive effects. Despite some statistical and interpretative problems, hormone ratios are being increasingly used to examine associations of testosterone/cortisol, estradiol/progesterone, testosterone/estradiol, and other hormone pairs. Here we discuss a methodological problem that has not been previously recognized, namely, the striking lack of robustness of raw hormone ratios in the face of measurement error. Hormone levels are measured with error, both due to inability of assays to perfectly assess concentrations "in the tube" and due to discrepancies between levels at the time of sample collection and effective levels that produce the physiological and/or behavioral effect of interest. Noise in measured hormone levels can be substantially exaggerated by ratios, especially when the distribution of the hormone at the denominator is positively skewed, as is frequently observed. To evaluate the extent of this problem and explore the conditions that exacerbate it, we present two sets of simulations, one using idealized distributions and one using empirically observed distributions from studies of estrogen and progesterone. Results show that the validity of raw hormone ratios-the correlation between measured levels and underlying effective levels-drops rapidly in the presence of realistic levels of measurement error. Log-ratios are much more robust to measurement error, and their validity is more stable across samples; under some conditions (e.g., moderate amounts of noise with positively correlated hormone levels), they may provide a more valid measurement of the underlying raw ratio than the measured raw ratio itself. These findings have important implications for research that uses hormone ratios as predictors.

Growing points in attachment disorganization: looking back to advance forward.

In this special issue paper we reflect on the next generation of attachment research with a focus on disorganization, a central but still poorly understood topic in this area. We suggest that progress will be facilitated by a return to attachment theory's evolutionary roots, and to the emphasis on biological function that inspired Bowlby's original thinking. Increased interdisciplinary cross-fertilization and collaborations would enable novel and generative research on some of the long-standing questions surrounding attachment disorganization. Accordingly, we present an agenda for future research that encompasses contributions of modern ethology and neurobiology, novel hypotheses based on the concept of adaptive decanalization, connections with neurodevelopmental vulnerability and risk for mental disorders such as schizophrenia, and the possibility of sex differences in the behavioral manifestations of attachment disorganization. We believe that these avenues of theory and research offer exciting potential for innovative work in attachment disorganization in the years ahead.

Artificial Intelligence in Bulk and Single-Cell RNA-Sequencing Data to Foster Precision Oncology.

Artificial intelligence, or the discipline of developing computational algorithms able to perform tasks that requires human intelligence, offers the opportunity to improve our idea and delivery of precision medicine. Here, we provide an overview of artificial intelligence approaches for the analysis of large-scale RNA-sequencing datasets in cancer. We present the major solutions to disentangle inter- and intra-tumor heterogeneity of transcriptome profiles for an effective improvement of patient management. We outline the contributions of learning algorithms to the needs of cancer genomics, from identifying rare cancer subtypes to personalizing therapeutic treatments.

Initial cell density encodes proliferative potential in cancer cell populations.

Individual cells exhibit specific proliferative responses to changes in microenvironmental conditions. Whether such potential is constrained by the cell density throughout the growth process is however unclear. Here, we identify a theoretical framework that captures how the information encoded in the initial density of cancer cell populations impacts their growth profile. By following the growth of hundreds of populations of cancer cells, we found that the time they need to adapt to the environment decreases as the initial cell density increases. Moreover, the population growth rate shows a maximum at intermediate initial densities. With the support of a mathematical model, we show that the observed interdependence of adaptation time and growth rate is significantly at odds both with standard logistic growth models and with the Monod-like function that governs the dependence of the growth rate on nutrient levels. Our results (i) uncover and quantify a previously unnoticed heterogeneity in the growth dynamics of cancer cell populations; (ii) unveil how population growth may be affected by single-cell adaptation times; (iii) contribute to our understanding of the clinically-observed dependence of the primary and metastatic tumor take rates on the initial density of implanted cancer cells.

Are complex causal models less likely to be true than simple ones? A critical comment on Trafimow (2017).

Trafimow (2017) used probabilistic reasoning to argue that more complex causal models are less likely to be true than simpler ones, and that researchers should be skeptical of causal models involving more than a handful of variables (or even a single correlation coefficient) [Trafimow, D. (2017). The probability of simple versus complex causal models in causal analyses. Behavior Research Methods, 49, 739-746]. In this comment, I point out that Trafimow's argument is misleading, and reduces to the observation that more informative models (that make definite statements about certain causal relations) are less likely to be true than less informative models (that remain silent about those relations, by omitting some variables from consideration). This correct but trivial statement does not deliver the epistemological leverage promised in the paper. When complexity is evaluated with reasonable criteria (such as the number of nonzero effects in alternative models involving the same variables), more complex models can be more, less, or equally likely to be true compared with simpler ones. I also discuss Trafimow's claim that, if a model is unlikely to be true a priori, researchers will seldom be able to gather evidence of sufficient quality to support it; in practice, even low-probability models can receive strong support without the need for extraordinary evidence. Researchers should evaluate the plausibility of causal models on a case-by-case basis, and be skeptical of overblown claims about the dangers of complex theories.

Effective Dimensionality: A Tutorial.

The topic of this tutorial is the effective dimensionality (ED) of a dataset, that is, the equivalent number of orthogonal dimensions that would produce the same overall pattern of covariation. The ED quantifies the total dimensionality of a set of variables, with no assumptions about their underlying structure. The ED of a dataset has important implications for the "curse of dimensionality"; it can be used to inform decisions about data analysis and answer meaningful empirical questions. The tutorial offers an accessible introduction to ED, distinguishes it from the related but distinct concept of intrinsic dimensionality, critically reviews various ED estimators, and gives indications for practical use with examples from personality research. An R function is provided to implement the techniques described in the tutorial.

Distinct retrograde microtubule motor sets drive early and late endosome transport.

Although subcellular positioning of endosomes significantly impacts on their functions, the molecular mechanisms governing the different steady-state distribution of early endosomes (EEs) and late endosomes (LEs)/lysosomes (LYs) in peripheral and perinuclear eukaryotic cell areas, respectively, are still unsolved. We unveil that such differences arise because, while LE retrograde transport depends on the dynein microtubule (MT) motor only, the one of EEs requires the cooperative antagonism of dynein and kinesin-14 KIFC1, a MT minus end-directed motor involved in cancer progression. Mechanistically, the Ser-x-Ile-Pro (SxIP) motif-mediated interaction of the endoplasmic reticulum transmembrane protein stromal interaction molecule 1 (STIM1) with the MT plus end-binding protein 1 (EB1) promotes its association with the p150Glued subunit of the dynein activator complex dynactin and the distinct location of EEs and LEs/LYs. The peripheral distribution of EEs requires their p150Glued-mediated simultaneous engagement with dynein and SxIP motif-containing KIFC1, via HOOK1 and HOOK3 adaptors, respectively. In sum, we provide evidence that distinct minus end-directed MT motor systems drive the differential transport and subcellular distribution of EEs and LEs in mammalian cells.

MicroRNAs organize intrinsic variation into stem cell states.

Pluripotent embryonic stem cells (ESCs) contain the potential to form a diverse array of cells with distinct gene expression states, namely the cells of the adult vertebrate. Classically, diversity has been attributed to cells sensing their position with respect to external morphogen gradients. However, an alternative is that diversity arises in part from cooption of fluctuations in the gene regulatory network. Here we find ESCs exhibit intrinsic heterogeneity in the absence of external gradients by forming interconverting cell states. States vary in developmental gene expression programs and display distinct activity of microRNAs (miRNAs). Notably, miRNAs act on neighborhoods of pluripotency genes to increase variation of target genes and cell states. Loss of miRNAs that vary across states reduces target variation and delays state transitions, suggesting variable miRNAs organize and propagate variation to promote state transitions. Together these findings provide insight into how a gene regulatory network can coopt variation intrinsic to cell systems to form robust gene expression states. Interactions between intrinsic heterogeneity and environmental signals may help achieve developmental outcomes.