Transcranial electrical stimulation techniques may enable exploration of the role of neural oscillations in the brain. Here, the authors provide a perspective on its potential across systems, species, theoretical and experimental scales.

Genome sequencing is enabling precision medicine—tailoring treatment to the unique constellation of variants in an individual’s genome. The impact of recurrent pathogenic variants is often understood, leaving a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

Negative emission technologies are central to avoiding catastrophic climate change. Deploying engineered solutions such as direct air capture requires a policy sequencing strategy that focuses on “incentives + mandates” in early adopters, while creating positive spillovers that incentivize follower countries to take policy action.

Endocrine therapy has been the mainstay for hormone responsive breast cancer treatment. Here, Garcia-Martinez and colleagues discuss epigenetic mechanisms regulating ER + breast cancer and endocrine therapy resistance, and highlight approaches to rewire the cancer epigenome to improve targeted therapies for this cancer.

Two-dimensional (2D) nanostructures are a frontier in materials chemistry as a result of their extraordinary properties. Metal-free 2D nanomaterials possess extra appeal due to their improved cost-effectiveness and lower toxicity with respect to many inorganic structures. The outstanding electronic characteristics of some metal-free 2D semiconductors have projected them into the world of organic synthesis, where they can function as high-performance photocatalysts to drive the sustainable synthesis of high-value organic molecules. Recent reports on this topic have inspired a stream of research and opened up a theme that we believe will become one of the most dominant trends in the forthcoming years.

Academic journals allowing for invisible name changes is a matter of fundamental respect and dignity for trans researchers, but there are currently no acceptable choices when dealing with name changes in a publishing record. This Perspective article proposes a centralized name change solution through ORCID iD to relieve the burden on trans researchers to contact every journal they have previously published with.

Pain management is an extremely important topic both medically and socio-economically. Here the authors offer an overview of the use of degrading polymeric materials for delivery of pharmaceutical agents for pain management and offer a perspective of the future directions of the field.

Clathrin-mediated endocytosis occurs via the assembly of clathrin-coated pits (CCPs) that invaginate and pinch off to form clathrin-coated vesicles (CCVs). It is well known that adaptor protein 2 (AP2) complexes trigger clathrin assembly on the plasma membrane, and biochemical and structural studies have revealed the nature of these interactions. Numerous endocytic accessory proteins collaborate with clathrin and AP2 to drive CCV formation. However, many questions remain as to the molecular events involved in CCP initiation, stabilization, and curvature generation. Indeed, a plethora of recent evidence derived from cell perturbation, correlative light and EM tomography, live-cell imaging, modeling, and high-resolution structural analyses has revealed more complexity and promiscuity in the protein interactions driving CCP maturation than anticipated. After briefly reviewing the evidence supporting prevailing models, we integrate these new lines of evidence to develop a more dynamic and flexible model for how redundant, dynamic, and competing protein interactions can drive endocytic CCV formation and suggest new approaches to test emerging models.

Fabricating artificial spider silk fibers in bulk scale has been a major goal in materials science for centuries. Two main routes have emerged for making such fibers. One method uses biomimetics in which the spider silk proteins (spidroins) are produced under nativelike conditions and then spun into fibers in a process that captures the natural, complex molecular mechanisms. However, these fibers do not yet match the mechanical properties of native silk fibers, potentially due to the small size of the designed spidroin used. The second route builds on biotechnological progress that enables production of large spidroins that can be spun into fibers by using organic solvents. With this approach, fibers that equal the native material in terms of mechanical properties can be manufactured, but the yields are too low for economically sustainable production. Hence, the need for new ideas is urgent. Herein, we introduce a structural-biology-based approach for engineering artificial spidroins that circumvents the laws with which spidroins, being secretory proteins, have to comply in order to avoid membrane insertion and provide a road map to the production of biomimetic silk fibers with improved mechanical properties.

Computational spectroscopy is becoming a mandatory tool for the interpretation of the complex, and often congested, spectral maps delivered by modern non-linear multi-pulse techniques. The fields of Electronic Structure Methods, Non-Adiabatic Molecular Dynamics, and Theoretical Spectroscopy represent the three pillars of the virtual ultrafast optical spectrometer, able to deliver transient spectra in silico from first principles. A successful simulation strategy requires a synergistic approach that balances between the three fields, each one having its very own challenges and bottlenecks. The aim of this Perspective is to demonstrate that, despite these challenges, an impressive agreement between theory and experiment is achievable now regarding the modeling of ultrafast photoinduced processes in complex molecular architectures. Beyond that, some key recent developments in the three fields are presented that we believe will have major impacts on spectroscopic simulations in the very near future. Potential directions of development, pending challenges, and rising opportunities are illustrated.

During the COVID-19 pandemic, model-based probabilistic forecasts of case, hospitalization, and death numbers can help to improve situational awareness and guide public health interventions. The COVID-19 Forecast Hub (https://covid19forecasthub.org/) collects such forecasts from numerous national and international groups. Systematic and statistically sound evaluation of forecasts is an important prerequisite to revise and improve models and to combine different forecasts into ensemble predictions. We provide an intuitive introduction to scoring methods, which are suitable for the interval/quantile-based format used in the Forecast Hub, and compare them to other commonly used performance measures.

Proton-coupled electron transfer (PCET) reactions are fundamental to energy transformation reactions in natural and artificial systems and are increasingly recognized in areas such as catalysis and synthetic chemistry. The interdependence of proton and electron transfer brings a mechanistic richness of reactivity, including various sequential and concerted mechanisms. Delineating between different PCET mechanisms and understanding why a particular mechanism dominates are crucial for the design and optimization of reactions that use PCET. This Perspective provides practical guidelines for how to discern between sequential and concerted mechanisms based on interpretations of thermodynamic data with temperature-, pressure-, and isotope-dependent kinetics. We present new PCET-zone diagrams that show how a mechanism can switch or even be eliminated by varying the thermodynamic (ΔG_PT^° and ΔG_ET^°) and coupling strengths for a PCET system. We discuss the appropriateness of asynchronous concerted PCET to rationalize observations in organic reactions, and the distinction between hydrogen atom transfer and other concerted PCET reactions. Contemporary issues and future prospects in PCET research are discussed.

Enantioselective functionalization of ubiquitous C(sp³)–H bonds via radical species has witnessed a renaissance in the past years. Here, the authors summarize the main achievements in the field by identifying two main reaction pathways determining the stereochemistry and give an outlook on future challenges and opportunities.

Synthetic biology engineering principles enable two-way communication between living and inanimate substrates. Here the authors consider the development of this bio-informational exchange and propose cyber-physical architectures and applications.

Ketamine is associated with rapid antidepressant effects and temporary dissociative experiences, and this review examines whether these dissociative symptoms are necessary for antidepressant efficacy. Although the current literature does not support this relationship, further work is needed to explore possible associations at the molecular, biomarker, and psychological levels.

Metal–halide perovskites transformed optoelectronics research and development during the past decade. They have also gained a foothold in photocatalytic and photoelectrochemical processes recently, but their sensitivity to the most commonly applied solvents and electrolytes together with their susceptibility to photocorrosion hinders such applications. Understanding the elementary steps of photocorrosion of these materials can aid the endeavor of realizing stable devices. In this Perspective, we discuss both thermodynamic and kinetic aspects of photocorrosion processes occurring at the interface of perovskite photocatalysts and photoelectrodes with different electrolytes. We show how combined in situ and operando electrochemical techniques can reveal the underlying mechanisms. Finally, we also discuss emerging strategies to mitigate photocorrosion (such as surface protection, materials and electrolyte engineering, etc.).