The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model

Author Posting. © American Chemical Society, 2020. This is an open access article published under an ACS AuthorChoice License. The definitive version was published in Chemical Research in Toxicology, 33(4), (2020): 860-879, doi:10.1021/acs.chemrestox.9b00476.The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins (“dioxins”), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.This review is dedicated in memory of the career of Alan Poland, one of the truly great minds in pharmacology and toxicology. This work was supported by the National Institutes of Health Grants R35-ES028377, T32-ES007015, P30-CA014520, P42-ES007381, and U01-ES1026127, The UW SciMed GRS Program, and The Morgridge Foundation. The authors would like to thank Catherine Stanley of UW Media Solutions for her artwork

Neural Circuit Synthesis from Specification Patterns

We train hierarchical Transformers on the task of synthesizing hardware circuits directly out of high-level logical specifications in linear-time temporal logic (LTL). The LTL synthesis problem is a well-known algorithmic challenge with a long history and an annual competition is organized to track the improvement of algorithms and tooling over time. New approaches using machine learning might open a lot of possibilities in this area, but suffer from the lack of sufficient amounts of training data. In this paper, we consider a method to generate large amounts of additional training data, i.e., pairs of specifications and circuits implementing them. We ensure that this synthetic data is sufficiently close to human-written specifications by mining common patterns from the specifications used in the synthesis competitions. We show that hierarchical Transformers trained on this synthetic data solve a significant portion of problems from the synthesis competitions, and even out-of-distribution examples from a recent case study

Search for Alternative Two‐Step‐Absorption Photoinitiators for 3D Laser Nanoprinting

Recent studies have opened the door to a new generation of photoinitiators for 3D laser nanoprinting. Therein, the simultaneous absorption of two photons, commonly referred to as two-photon absorption, is replaced by the sequential absorption of two photons in two consecutive one-photon absorption processes. This process has been termed two-step absorption. Importantly, two-step absorption can be accomplished by inexpensive compact low-power continuous-wave blue laser diodes instead of femtosecond laser systems in the red spectral region. Red-shifting the second absorption step with respect to the first one results in an and-type optical nonlinearity based on two-color two-step absorption. Herein, alternatives are systematically explored to the few already reported one- and two-color two-step-absorption photoinitiators, including the search for photoinitiators that can be excited by one-color two-step absorption and be de-excited by a disparate laser color.</p

Deep Learning for Temporal Logics

Temporal logics are a well established formal specification paradigm to specify the behavior of systems, and serve as inputs to industrial-strength verification tools. We report on current advances in applying deep learning to temporal logical reasoning tasks, showing that models can even solve instances where competitive classical algorithms timed out

Topological Interactions in Warped Extra Dimensions

Topological interactions will be generated in theories with compact extra dimensions where fermionic chiral zero modes have different localizations. This is the case in many warped extra dimension models where the right-handed top quark is typically localized away from the left-handed one. Using deconstruction techniques, we study the topological interactions in these models. These interactions appear as trilinear and quadrilinear gauge boson couplings in low energy effective theories with three or more sites, as well as in the continuum limit. We derive the form of these interactions for various cases, including examples of Abelian, non-Abelian and product gauge groups of phenomenological interest. The topological interactions provide a window into the more fundamental aspects of these theories and could result in unique signatures at the Large Hadron Collider, some of which we explore.Comment: 40 pages, 10 figures, 2 tables; modifications in the KK parity discussion, final version at JHE

Revealing missing human protein isoforms based on Ab initio prediction, RNA-seq and proteomics

Biological and biomedical research relies on comprehensive understanding of protein-coding transcripts. However, the total number of human proteins is still unknown due to the prevalence of alternative splicing. In this paper, we detected 31,566 novel transcripts with coding potential by filtering our ab initio predictions with 50 RNA-seq datasets from diverse tissues/cell lines. PCR followed by MiSeq sequencing showed that at least 84.1% of these predicted novel splice sites could be validated. In contrast to known transcripts, the expression of these novel transcripts were highly tissue-specific. Based on these novel transcripts, at least 36 novel proteins were detected from shotgun proteomics data of 41 breast samples. We also showed L1 retrotransposons have a more significant impact on the origin of new transcripts/genes than previously thought. Furthermore, we found that alternative splicing is extraordinarily widespread for genes involved in specific biological functions like protein binding, nucleoside binding, neuron projection, membrane organization and cell adhesion. In the end, the total number of human transcripts with protein-coding potential was estimated to be at least 204,950.publishedVersio

Derivation of an endogenous small RNA from double-stranded Sox4 sense and natural antisense transcripts in the mouse brain

Natural antisense transcripts (NATs) are involved in cellular development and regulatory processes. Multiple NATs at the Sox4 gene locus are spatiotemporally regulated throughout murine cerebral corticogenesis. In the study, we evaluated the potential functional role of Sox4 NATs at Sox4 gene locus. We demonstrated Sox4 sense and NATs formed dsRNA aggregates in the cytoplasm of brain cells. Over expression of Sox4 NATs in NIH/3T3 cells generally did not alter the level of Sox4 mRNA expression or protein translation. Upregulation of a Sox4 NAT known as Sox4ot1 led to the production of a novel small RNA, Sox4_sir3. Its biogenesis is Dicer1-dependent and has characteristics resemble piRNA. Expression of Sox4_sir3 was observed in the marginal and germinative zones of the developing and postnatal brains suggesting a potential role in regulating neurogenesis. We proposed that Sox4 sense-NATs serve as Dicer1-dependent templates to produce a novel endo-siRNA- or piRNA-like Sox4_sir3

ZENK expression in the auditory pathway of black-capped chickadees (Poecile atricapillus) as a function of D note number and duty cycle of chick-a-dee calls

Black-capped chickadees (Poecile atricapillus) use their namesake chick-a-dee call for multiple functions, altering the features of the call depending on context. For example, duty cycle (the proportion of time filled by vocalizations) and fine structure traits (e.g., number of D notes) can encode contextual factors, such as predator size and food quality. Wilson and Mennill (2011) found that chickadees show stronger behavioral responses to playback of chick-a-dee calls with higher duty cycles, but not to the number of D notes. That is, independent of the number of D notes in a call, but dependent on the overall proportion of time filled with vocalization, birds responded more to higher duty cycle playback compared to lower duty cycle playback. Here we presented chickadees with chick-a-dee calls that contained either two D (referred to hereafter as 2 D) notes with a low duty cycle, 2 D notes with a high duty cycle, 10 D notes with a high duty cycle, or 2 D notes with a high duty cycle but played in reverse (a non-signaling control). We then measured ZENK expression in the auditory nuclei where perceptual discrimination is thought to occur. Based on the behavioral results of Wilson and Mennill, 2011, we predicted we would observe the highest ZENK expression in response to forward-playing calls with high duty cycles; we predicted we would observe no significant difference in ZENK expression between forward-playing high duty cycle playbacks (2 D or 10 D). We found no significant difference between forward-playing 2 D and 10 D high duty cycle playbacks. However, contrary to our predictions, we did not find any effects of altering the duty cycle or note number presented

In depth analysis of the Sox4 gene locus that consists of sense and natural antisense transcripts

SRY (Sex Determining Region Y)-Box 4 or Sox4 is an important regulator of the pan-neuronal gene expression during post-mitotic cell differentiation within the mammalian brain. Sox4 gene locus has been previously characterized with multiple sense and overlapping natural antisense transcripts [1] and [2]. Here we provide accompanying data on various analyses performed and described in Ling et al. [2]. The data include a detail description of various features found at Sox4 gene locus, additional experimental data derived from RNA-Fluorescence in situ Hybridization (RNA-FISH), Western blotting, strand-specific reverse-transcription quantitative polymerase chain reaction (RT-qPCR), gain-of-function and in situ hybridization (ISH) experiments. All the additional data provided here support the existence of an endogenous small interfering- or PIWI interacting-like small RNA known as Sox4_sir3, which origin was found within the overlapping region consisting of a sense and a natural antisense transcript known as Sox4ot1