Multiple Genes Core to ERAD, Macroautophagy and Lysosomal Degradation Pathways Participate in the Proteostasis Response in α1-Antitrypsin Deficiency.

Background & Aims: In the classic form of α1-antitrypsin deficiency (ATD), the misfolded α1-antitrypsin Z (ATZ) variant accumulates in the endoplasmic reticulum (ER) of liver cells. A gain-of-function proteotoxic mechanism is responsible for chronic liver disease in a subgroup of homozygotes. Proteostatic response pathways, including conventional endoplasmic reticulum-associated degradation and autophagy, have been proposed as the mechanisms that allow cellular adaptation and presumably protection from the liver disease phenotype.

DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD.

Expressed Barcoding Enables High-Resolution Tracking of the Evolution of Drug Tolerance.

Unlabelled: For a majority of patients with non-small cell lung cancer with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi.

Genome-wide CRISPR screen identifies protein pathways modulating tau protein levels in neurons.

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time.

An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells.

VPS34 is a key regulator of endomembrane dynamics and cargo trafficking, and is essential in cultured cell lines and in mice. To better characterize the role of VPS34 in cell growth, we performed unbiased cell line profiling studies with the selective VPS34 inhibitor PIK-III and identified RKO as a VPS34-dependent cellular model. Pooled CRISPR screen in the presence of PIK-III revealed endolysosomal genes as genetic suppressors.

Political attitudes vary with detection of androstenone.

Building on a growing body of research suggesting that political attitudes are part of broader individual and biological orientations, we test whether the detection of the hormone androstenone is predictive of political attitudes. The particular social chemical analyzed in this study is androstenone, a nonandrogenic steroid found in the sweat and saliva of many mammals, including humans. A primary reason for scholarly interest in odor detection is that it varies so dramatically from person to person.

IRF2 is a master regulator of human keratinocyte stem cell fate.

Resident adult epithelial stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. The stem cell potential of human epidermal keratinocytes is retained in vitro but lost over time suggesting extrinsic and intrinsic regulation. Transcription factor-controlled regulatory circuitries govern cell identity, are sufficient to induce pluripotency and transdifferentiate cells.

YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury.

Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/β-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing.

Bile acid analogues are activators of pyrin inflammasome.

Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite.

From conceptual to computational: Cost and benefits of lizard thermoregulation revisited.

A classic paper detailed conceptual analyses of behavioral thermoregulation (Huey and Slatkin, 1976) and has served as the theoretical foundation for hundreds of investigative studies. Most recently, investigators have revisited this theoretical presentation to offer additional interpretation for both heterogeneity and spatial structure of temperature and how it may influence energetic costs (Sears and Angilletta, 2015). Interestingly, this foundational presentation by Huey and Slatkin, over 40 years ago, has never received formal computational analyses to address mathematically the postulates of this conceptual model.

Mathematical modeling of continuous and intermittent androgen suppression for the treatment of advanced prostate cancer.

Prostate cancer is one of the most prevalent types of cancer among men. It is stimulated by the androgens, or male sexual hormones, which circulate in the blood and diffuse into the tissue where they stimulate the prostate tumor to grow. One of the most important treatments for advanced prostate cancer has become androgen deprivation therapy (ADT).

Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62.

SQSTM1 is an adaptor protein that integrates multiple cellular signaling pathways and whose expression is tightly regulated at the transcriptional and post-translational level. Here, we describe a forward genetic screening paradigm exploiting CRISPR-mediated genome editing coupled to a cell selection step by FACS to identify regulators of SQSTM1. Through systematic comparison of pooled libraries, we show that CRISPR is superior to RNAi in identifying known SQSTM1 modulators.

Liberals and conservatives: Non-convertible currencies.

Duarte et al. are correct that the social science enterprise would improve on several fronts if the number of politically conservative researchers were to increase; however, because they misunderstand the degree to which liberals and conservatives are dispositionally different, they fail to appreciate the full range of reasons that conservatives are reluctant to enter the modern social sciences.

Synthesis and Site-Specific Incorporation of Red-Shifted Azobenzene Amino Acids into Proteins.

A series of red-shifted azobenzene amino acids were synthesized in moderate-to-excellent yields via a two-step procedure in which tyrosine derivatives were first oxidized to the corresponding quinonoidal spirolactones followed by ceric ammonium nitrate-catalyzed azo formation with the substituted phenylhydrazines. The resulting azobenzene-alanine derivatives exhibited efficient trans/cis photoswitching upon irradiation with a blue (448 nm) or green (530 nm) LED light. Moreover, nine superfolder green fluorescent protein (sfGFP) mutants carrying the azobenzene-alanine analogues were expressed in E.

The genetic and environmental foundations of political, psychological, social, and economic behaviors: a panel study of twins and families.

Here we introduce the Genetic and Environmental Foundations of Political and Economic Behaviors: A Panel Study of Twins and Families (PIs Alford, Hatemi, Hibbing, Martin, and Smith). This study was designed to explore the genetic and environmental influences on social, economic, and political behaviors and attitudes. It involves identifying the psychological mechanisms that operate on these traits, the heritability of complex economic and political traits under varying conditions, and specific genetic correlates of attitudes and behaviors.

Nonpolitical images evoke neural predictors of political ideology.

Political ideologies summarize dimensions of life that define how a person organizes their public and private behavior, including their attitudes associated with sex, family, education, and personal autonomy. Despite the abstract nature of such sensibilities, fundamental features of political ideology have been found to be deeply connected to basic biological mechanisms that may serve to defend against environmental challenges like contamination and physical threat. These results invite the provocative claim that neural responses to nonpolitical stimuli (like contaminated food or physical threats) should be highly predictive of abstract political opinions (like attitudes toward gun control and abortion).

Negativity bias and political preferences: a response to commentators.

A broad, multidisciplinary empirical literature reports that individual-level differences in psychology and biology map onto variation in political orientation. In our target article we argued that negativity bias can explain a surprisingly large share of these findings. The commentators generally support the negativity bias hypothesis but suggest theoretical and empirical revisions and refinements.

Differences in negativity bias underlie variations in political ideology.

Disputes between those holding differing political views are ubiquitous and deep-seated, and they often follow common, recognizable lines. The supporters of tradition and stability, sometimes referred to as conservatives, do battle with the supporters of innovation and reform, sometimes referred to as liberals. Understanding the correlates of those distinct political orientations is probably a prerequisite for managing political disputes, which are a source of social conflict that can lead to frustration and even bloodshed.

Cortisol and politics: variance in voting behavior is predicted by baseline cortisol levels.

Participation in electoral politics is affected by a host of social and demographics variables, but there is growing evidence that biological predispositions may also play a role in behavior related to political involvement. We examined the role of individual variation in hypothalamic-pituitary-adrenal (HPA) stress axis parameters in explaining differences in self-reported and actual participation in political activities. Self-reported political activity, religious participation, and verified voting activity in U.

Modeling energetic and theoretical costs of thermoregulatory strategy.

Poikilothermic ectotherms have evolved behaviours that help them maintain or regulate their body temperature (T (b)) around a preferred or 'set point' temperature (T (set)). Thermoregulatory behaviors may range from body positioning to optimize heat gain to shuttling among preferred microhabitats to find appropriate environmental temperatures. We have modelled movement patterns between an active and non-active shuttling behaviour within a habitat (as a biased random walk) to investigate the potential cost of two thermoregulatory strategies.

Biology, ideology, and epistemology: how do we know political attitudes are inherited and why should we care?

Evidence that political attitudes and behavior are in part biologically and even genetically instantiated is much discussed in political science of late. Yet the classic twin design, a primary source of evidence on this matter, has been criticized for being biased toward finding genetic influence. In this article, we employ a new data source to test empirically the alternative, exclusively environmental, explanations for ideological similarities between twins.

Disgust sensitivity and the neurophysiology of left-right political orientations.

Disgust has been described as the most primitive and central of emotions. Thus, it is not surprising that it shapes behaviors in a variety of organisms and in a variety of contexts--including homo sapien politics. People who believe they would be bothered by a range of hypothetical disgusting situations display an increased likelihood of displaying right-of-center rather than left-of-center political orientations.

Effect of benzyl alcohol on recombinant human interleukin-1 receptor antagonist structure and hydrogen-deuterium exchange.

Benzyl alcohol, a preservative commonly added to multidose therapeutic protein formulations, can accelerate aggregation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra). To investigate the interactions between benzyl alcohol and rhIL-1ra, we used nuclear magnetic resonance to observe the effect of benzyl alcohol on the chemical shifts of amide resonances of rhIL-1ra and to measure hydrogen-deuterium exchange rates of individual rhIL-1ra residues. Addition of 0.

Political attitudes vary with physiological traits.

Although political views have been thought to arise largely from individuals' experiences, recent research suggests that they may have a biological basis. We present evidence that variations in political attitudes correlate with physiological traits. In a group of 46 adult participants with strong political beliefs, individuals with measurably lower physical sensitivities to sudden noises and threatening visual images were more likely to support foreign aid, liberal immigration policies, pacifism, and gun control, whereas individuals displaying measurably higher physiological reactions to those same stimuli were more likely to favor defense spending, capital punishment, patriotism, and the Iraq War.