Tools to Dissect Lipid Droplet Regulation, Players, and Mechanisms.

Spurred by the authors' own recent discovery of reactive metabolite-regulated nexuses involving lipid droplets (LDs), this perspective discusses the latest knowledge and multifaceted approaches toward deconstructing the function of these dynamic organelles, LD-associated localized signaling networks, and protein players. Despite accumulating knowledge surrounding protein families and pathways of conserved importance for LD homeostasis surveillance and maintenance across taxa, much remains to be understood at the molecular level. In particular, metabolic stress-triggered contextual changes in LD-proteins' localized functions, crosstalk with other organelles, and feedback signaling loops and how these are specifically rewired in disease states remain to be illuminated with spatiotemporal precision.

Organ-specific electrophile responsivity mapping in live C. elegans.

Proximity labeling technologies are limited to indexing localized protein residents. Such data-although valuable-cannot inform on small-molecule responsivity of local residents. We here bridge this gap by demonstrating in live C.

What is chemical biology?

Since its inception, the chemical biology field has undergone significant evolution, with its definition varying greatly based on individual perspectives. For the September 30 anniversary special issue of Cell Chemical Biology, we asked our readers from a range of backgrounds, what is chemical biology?

Toward decoding spatiotemporal signaling activities of reactive immunometabolites with precision immuno-chemical biology tools.

Immune-cell reprogramming driven by mitochondria-derived reactive electrophilic immunometabolites (mt-REMs-e.g., fumarate, itaconate) is an emerging phenomenon of major biomedical importance.

Let's get biophysical - How to get your favorite protein's digits.

In these days of information overload and high-throughput analysis, it is easy to lose focus on the study of individual proteins. It is our conjecture that such investigations are still crucially important and offer uniquely penetrative insights. We thus present a discussion of biophysical methods to allow readers to get to know their protein of interest better.

Climbing into their Skin to Understand Contextual Protein-Protein Associations and Localizations: Functional Investigations in Transgenic Live Model Organisms.

Borrowing some quotes from Harper Lee's novel "To Kill A Mockingbird" to help frame our manuscript, we discuss methods to profile local proteomes. We initially focus on chemical biology regimens that function in live organisms and use reactive biotin species for this purpose. We then consider ways to add new dimensions to these experimental regimens, principally by releasing less reactive (i.

Formaldehyde regulates one-carbon metabolism and epigenetics.

Recently, Pham et al. used an array of model systems to uncover a role for the enzyme methionine adenosyltransferase (MAT)-1A, which is mainly expressed in liver, in both sensing formaldehyde and regulating transcriptional responses that protect against it. This provides a new lens for understanding the effects of formaldehyde on gene regulation.

Tag, you're it: G-ICAT identifies p120-cysteine glutathionylation triggering E-cadherin destabilization.

Current methods have limited ability in directly quantifying the extent of glutathionylation on specific protein-cysteines. In this issue of Cell Chemical Biology, Ahn et al. report G-ICAT (glutathione-based isotope-coded affinity tag), aimed at addressing this limitation.

Monitoring On-Target Signaling Responses in Larval Zebrafish - Z-REX Unmasks Precise Mechanisms of Electrophilic Drugs and Metabolites.

Reactive metabolites and related electrophilic drugs are among the most challenging small molecules to study. Conventional approaches to deconstruct the mode of action (MOA) of such molecules leverage bulk treatment of experimental specimens with an excess of a specific reactive species. In this approach, the high reactivity of electrophiles renders non-discriminate labeling of the proteome in a time- and context-dependent manner; redox-sensitive proteins and processes can also be indirectly and often irreversibly affected.

Movement disorders in Indochina: Resource challenges and future solutions.

Movement disorders are a major cause of disability worldwide and their increasing prevalence predicts a substantial future burden of care. Impactful patient care requires availability of, and accessibility to, effective medications, knowledge, and disease awareness among both medical professionals and patients, driven by skilled personnel to harness and manage resources. The highest burden of movement disorders is in low-to-middle income countries where resources are often limited and infrastructure is insufficient to meet growing demands.

Z-REX: shepherding reactive electrophiles to specific proteins expressed tissue specifically or ubiquitously, and recording the resultant functional electrophile-induced redox responses in larval fish.

This Protocol Extension describes the adaptation of an existing Protocol detailing the use of targetable reactive electrophiles and oxidants, an on-demand redox targeting toolset in cultured cells. The adaptation described here is for use of reactive electrophiles and oxidants technologies in live zebrafish embryos (Z-REX). Zebrafish embryos expressing a Halo-tagged protein of interest (POI)-either ubiquitously or tissue specifically-are treated with a HaloTag-specific small-molecule probe housing a photocaged reactive electrophile (either natural electrophiles or synthetic electrophilic drug-like fragments).

Finding a vocation for validation: taking proteomics beyond association and location.

First established in the seventies, proteomics, chemoproteomics, and most recently, spatial/proximity-proteomics technologies have empowered researchers with new capabilities to illuminate cellular communication networks that govern sophisticated decision-making processes. With an ever-growing inventory of these advanced proteomics tools, the onus is upon the researchers to understand their individual advantages and limitations, such that we can ensure rigorous implementation and conclusions derived from critical data interpretations backed up by orthogonal series of functional validations. This perspective-based on the authors' experience in applying varied proteomics workflows in complex living models-underlines key book-keeping considerations, comparing and contrasting most-commonly-deployed modern proteomics profiling technologies.

Percutaneous coronary intervention in patients aged 80 years old and above: a systematic review and meta-analysis.

Background: Ischaemic heart disease remains the main cause of death in the world. With increasing age, frailty and comorbidities, senior patients aged 80 years old and above who undergo percutaneous coronary intervention (PCI) are at higher risk of mortality and other complications.

Aims: We aimed to examine the overall outcomes for this group of patients.

Z-REX uncovers a bifurcation in function of Keap1 paralogs.

Studying electrophile signaling is marred by difficulties in parsing changes in pathway flux attributable to on-target, vis-à-vis off-target, modifications. By combining bolus dosing, knockdown, and Z-REX-a tool investigating on-target/on-pathway electrophile signaling, we document that electrophile labeling of one zebrafish-Keap1-paralog (zKeap1b) stimulates Nrf2- driven antioxidant response (AR) signaling (like the human-ortholog). Conversely, zKeap1a is a dominant-negative regulator of electrophile-promoted Nrf2-signaling, and itself is nonpermissive for electrophile-induced Nrf2-upregulation.

Still no Rest for the Reductases: Ribonucleotide Reductase (RNR) Structure and Function: An Update.

Herein we present a multidisciplinary discussion of ribonucleotide reductase (RNR), the essential enzyme uniquely responsible for conversion of ribonucleotides to deoxyribonucleotides. This chapter primarily presents an overview of this multifaceted and complex enzyme, covering RNR's role in enzymology, biochemistry, medicinal chemistry, and cell biology. It further focuses on RNR from mammals, whose interesting and often conflicting roles in health and disease are coming more into focus.

A Journey through the Life of Professor David A. Evans.

By taking a journey through the events that happened during Professor David A. Evans' lifetime in the context of chemical synthesis and drug discovery, this in-focus article reflects upon Professor Evans' lifelong scientific and padegogical impacts on the broader fields influenced by organic chemistry.

Utilization of Postnatal Care Services among Thai Women during the COVID-19 Pandemic: Results of a Web-Based Survey.

The postnatal period is an underserved aspect of maternity care, potentially worsened by the COVID-19 pandemic. This study aims to identify postnatal care (PNC) use by health personnel within the 42 days of childbirth among postpartum mothers in Thailand. This web-based, cross-sectional study was conducted from July to October 2021 ( = 840).

Hiding in Plain Sight: The Issue of Hidden Variables.

Here we discuss "hidden variables", which are typically introduced during an experiment as a consequence of the application of two independent variables together to create a stimulus. With increased sophistication in modern chemical biology tools and related precision interrogation techniques, hidden variables have become integral to many chemical biologists' routine experiments. For instance, they can appear in the use of light-activatable chemical probes (e.

Keap 1: The new Janus word on the block.

Here we draw insights from the latest serendipitous findings made on the opposing roles of a proposed drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell-survival- vs. cell-death-promoting behaviors.

Function-guided proximity mapping unveils electrophilic-metabolite sensing by proteins not present in their canonical locales.

Enzyme-assisted posttranslational modifications (PTMs) constitute a major means of signaling across different cellular compartments. However, how nonenzymatic PTMs-despite their direct relevance to covalent drug development-impinge on cross-compartment signaling remains inaccessible as current target-identification (target-ID) technologies offer limited spatiotemporal resolution, and proximity mapping tools are also not guided by specific, biologically-relevant, ligand chemotypes. Here we establish a quantitative and direct profiling platform (Localis-rex) that ranks responsivity of compartmentalized subproteomes to nonenzymatic PTMs.