Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care.

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.

Horizontal Cell Biology: Monitoring Global Changes of Protein Interaction States with the Proteome-Wide Cellular Thermal Shift Assay (CETSA).

The cellular thermal shift assay (CETSA) is a biophysical technique allowing direct studies of ligand binding to proteins in cells and tissues. The proteome-wide implementation of CETSA with mass spectrometry detection (MS-CETSA) has now been successfully applied to discover targets for orphan clinical drugs and hits from phenotypic screens, to identify off-targets, and to explain poly-pharmacology and drug toxicity. Highly sensitive multidimensional MS-CETSA implementations can now also access binding of physiological ligands to proteins, such as metabolites, nucleic acids, and other proteins. MS-CETSA can thereby provide comprehensive information on modulations of protein interaction states in cellular processes, including downstream effects of drugs and transitions between different physiological cell states. Such horizontal information on ligandmodulation in cells is largely orthogonal to vertical information on the levels of different proteins and therefore opens novel opportunities to understand operational aspects of cellular proteomes.

Pervasive Protein Thermal Stability Variation during the Cell Cycle.

Quantitative mass spectrometry has established proteome-wide regulation of protein abundance and post-translational modifications in various biological processes. Here, we used quantitative mass spectrometry to systematically analyze the thermal stability and solubility of proteins on a proteome-wide scale during the eukaryotic cell cycle. We demonstrate pervasive variation of these biophysical parameters with most changes occurring in mitosis and G1. Various cellular pathways and components vary in thermal stability, such as cell-cycle factors, polymerases, and chromatin remodelers. We demonstrate that protein thermal stability serves as a proxy for enzyme activity, DNA binding, and complex formation in situ. Strikingly, a large cohort of intrinsically disordered and mitotically phosphorylated proteins is stabilized and solubilized in mitosis, suggesting a fundamental remodeling of the biophysical environment of the mitotic cell. Our data represent a rich resource for cell, structural, and systems biologists interested in proteome regulation during biological transitions.

Modulation of Protein-Interaction States through the Cell Cycle.

Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of the biochemical processes determining cellular events. Using a proteome-wide implementation of the cellular thermal shift assay (CETSA) to study specific cell-cycle phases, we uncover changes of interaction states for more than 750 proteins during the cell cycle. Notably, many protein complexes are modulated in specific cell-cycle phases, reflecting their roles in processes such as DNA replication, chromatin remodeling, transcription, translation, and disintegration of the nuclear envelope. Surprisingly, only small differences in the interaction states were seen between the G1 and the G2 phase, suggesting similar hardwiring of biochemical processes in these two phases. The present work reveals novel molecular details of the cell cycle and establishes proteome-wide CETSA as a new strategy to study modulation of protein-interaction states in intact cells.

Ice-Binding Proteins and Their Function.

Ice-binding proteins (IBPs) are a diverse class of proteins that assist organism survival in the presence of ice in cold climates. They have different origins in many organisms, including bacteria, fungi, algae, diatoms, plants, insects, and fish. This review covers the gamut of IBP structures and functions and the common features they use to bind ice. We discuss mechanisms by which IBPs adsorb to ice and interfere with its growth, evidence for their irreversible association with ice, and methods for enhancing the activity of IBPs. The applications of IBPs in the food industry, in cryopreservation, and in other technologies are vast, and we chart out some possibilities.

Proteome plasticity in response to persistent environmental change.

Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.

Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins.

Fever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to α4 integrins, but not ß2 integrins, fever increased α4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the α4 tail and activated α4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-α4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-α4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.

Hierarchical bound states in heat transport.

Higher-order topological phases in non-Hermitian photonics revolutionize the understanding of wave propagation and modulation, which lead to hierarchical states in open systems. However, intrinsic insulating properties endorsed by the lattice symmetry of photonic crystals fundamentally confine the robust transport only at explicit system boundaries, letting alone the flexible reconfiguration in hierarchical states at arbitrary positions. Here, we report a dynamic topological platform for creating the reconfigurable hierarchical bound states in heat transport systems and observe the robust and nonlocalized higher-order states in both the real- and imaginary-valued bands. Our experiments showcase that the hierarchical features of zero-dimension corner and nontrivial edge modes occur at tailored positions within the system bulk states instead of the explicit system boundaries. Our findings uncover the mechanism of non-localized hierarchical non-trivial topological states and offer distinct paradigms for diffusive transport field management.

Plume-scale confinement on thermal convection.

Despite the ubiquity of thermal convection in nature and artificial systems, we still lack a unified formulation that integrates the system's geometry, fluid properties, and thermal forcing to characterize the transition from free to confined convective regimes. The latter is broadly relevant to understanding how convection transports energy and drives mixing across a wide range of environments, such as planetary atmospheres/oceans and hydrothermal flows through fractures, as well as engineering heatsinks and microfluidics for the control of mass and heat fluxes. Performing laboratory experiments in Hele-Shaw geometries, we find multiple transitions that are identified as remarkable shifts in flow structures and heat transport scaling, underpinning previous numerical studies. To unveil the mechanisms of the geometrically controlled transition, we focus on the smallest structure of convection, posing the following question: How free is a thermal plume in a closed system? We address this problem by proposing the degree of confinement [Formula: see text]-the ratio of the thermal plume's thickness in an unbounded domain to the lateral extent of the system-as a universal metric encapsulating all the physical parameters. Here, we characterize four convective regimes different in flow dimensionality and time dependency and demonstrate that the transitions across the regimes are well tied with [Formula: see text]. The introduced metric [Formula: see text] offers a unified characterization of convection in closed systems from the plume's standpoint.

On the engulfment of antifreeze proteins by ice.

Antifreeze proteins (AFPs) are remarkable biomolecules that suppress ice formation at trace concentrations. To inhibit ice growth, AFPs must not only bind to ice crystals, but also resist engulfment by ice. The highest supercooling, [Formula: see text], for which AFPs are able to resist engulfment is widely believed to scale as the inverse of the separation, [Formula: see text], between bound AFPs, whereas its dependence on the molecular characteristics of the AFP remains poorly understood. By using specialized molecular simulations and interfacial thermodynamics, here, we show that in contrast with conventional wisdom, [Formula: see text] scales as [Formula: see text] and not as [Formula: see text]. We further show that [Formula: see text] is proportional to AFP size and that diverse naturally occurring AFPs are optimal at resisting engulfment by ice. By facilitating the development of AFP structure-function relationships, we hope that our findings will pave the way for the rational design of AFPs.

A quantitative model of temperature-dependent diapause progression.

Winter diapause in insects is commonly terminated through cold exposure, which, like vernalization in plants, prevents development before spring arrives. Currently, quantitative understanding of the temperature dependence of diapause termination is limited, likely because diapause phenotypes are generally cryptic to human eyes. We introduce a methodology to tackle this challenge. By consecutively moving butterfly pupae of the species Pieris napi from several different cold conditions to 20 °C, we show that diapause termination proceeds as a temperature-dependent rate process, with maximal rates at relatively cold temperatures and low rates at warm and extremely cold temperatures. Further, we show that the resulting thermal reaction norm can predict P. napi diapause termination timing under variable temperatures. Last, we show that once diapause is terminated in P. napi, subsequent development follows a typical thermal performance curve, with a maximal development rate at around 31 °C and a minimum at around 2 °C. The sequence of these thermally distinct processes (diapause termination and postdiapause development) facilitates synchronous spring eclosion in nature; cold microclimates where diapause progresses quickly do not promote fast postdiapause development, allowing individuals in warmer winter microclimates to catch up, and vice versa. The unveiling of diapause termination as one temperature-dependent rate process among others promotes a parsimonious, quantitative, and predictive model, wherein winter diapause functions both as an adaptation against premature development during fall and winter and for synchrony in spring.

Localized and delocalized topological modes of heat.

The topological physics has sparked intensive investigations into topological lattices in photonic, acoustic, and mechanical systems, powering counterintuitive effects otherwise inaccessible with usual settings. Following the success of these endeavors in classical wave dynamics, there has been a growing interest in establishing their topological counterparts in diffusion. Here, we propose an additional real-space dimension in diffusion, and the system eigenvalues are transformed from "imaginary" to "real." By judiciously tailoring the effective Hamiltonian with coupling networks, localized and delocalized topological modes are realized in heat transfer. Simulations and experiments in active thermal lattices validate the effectiveness of the proposed theoretical strategy. This approach can be applied to establish various topological lattices in diffusion systems, offering insights into engineering topologically protected edge states in dynamic diffusive scenarios.

Fast, variable stiffness-induced braided coiled artificial muscles.

Biomimetic actuation technologies with high muscle strokes, cycle rates, and work capacities are necessary for robotic systems. We present a muscle type that operates based on changes in muscle stiffness caused by volume expansion. This muscle is created by coiling a mechanically strong braid, in which an elastomer hollow tube is adhesively attached inside. We show that the muscle reversibly contracts by 47.3% when driven by an oscillating input air pressure of 120 kilopascals at 10 Hz. It generates a maximum power density of 3.0 W/g and demonstrates a mechanical contractile efficiency of 74%. The muscle's low-pressure operation allowed for portable, thermal pneumatical actuation. Moreover, the muscle demonstrated bipolar actuation, wherein internal pressure leads to muscle length expansion if the initial muscle length is compressed and contraction if the muscle is not compressed. Modeling indicates that muscle expansion significantly alters its stiffness, which causes muscle actuation. We demonstrate the utility of BCMs for fast running and climbing robots.

Stabilizing Ti3C2Tx MXene flakes in air by removing confined water.

MXenes have demonstrated potential for various applications owing to their tunable surface chemistry and metallic conductivity. However, high temperatures can accelerate MXene film oxidation in air. Understanding the mechanisms of MXene oxidation at elevated temperatures, which is still limited, is critical in improving their thermal stability for high-temperature applications. Here, we demonstrate that Ti[Formula: see text]C[Formula: see text]T[Formula: see text] MXene monoflakes have exceptional thermal stability at temperatures up to 600[Formula: see text]C in air, while multiflakes readily oxidize in air at 300[Formula: see text]C. Density functional theory calculations indicate that confined water between Ti[Formula: see text]C[Formula: see text]T[Formula: see text] flakes has higher removal energy than surface water and can thus persist to higher temperatures, leading to oxidation. We demonstrate that the amount of confined water correlates with the degree of oxidation in stacked flakes. Confined water can be fully removed by vacuum annealing Ti[Formula: see text]C[Formula: see text]T[Formula: see text] films at 600[Formula: see text]C, resulting in substantial stability improvement in multiflake films (can withstand 600[Formula: see text]C in air). These findings provide fundamental insights into the kinetics of confined water and its role in Ti[Formula: see text]C[Formula: see text]T[Formula: see text] oxidation. This work enables the use of stable monoflake MXenes in high-temperature applications and provides guidelines for proper vacuum annealing of multiflake films to enhance their stability.

Long- and short-term coupling of sea surface temperature and atmospheric CO2 during the late Paleocene and early Eocene.

The late Paleocene and early Eocene (LPEE) are characterized by long-term (million years, Myr) global warming and by transient, abrupt (kiloyears, kyr) warming events, termed hyperthermals. Although both have been attributed to greenhouse (CO2) forcing, the longer-term trend in climate was likely influenced by additional forcing factors (i.e., tectonics) and the extent to which warming was driven by atmospheric CO2 remains unclear. Here, we use a suite of new and existing observations from planktic foraminifera collected at Pacific Ocean Drilling Program Sites 1209 and 1210 and inversion of a multiproxy Bayesian hierarchical model to quantify sea surface temperature (SST) and atmospheric CO2 over a 6-Myr interval. Our reconstructions span the initiation of long-term LPEE warming (~58 Ma), and the two largest Paleogene hyperthermals, the Paleocene-Eocene Thermal Maximum (PETM, ~56 Ma) and Eocene Thermal Maximum 2 (ETM-2, ~54 Ma). Our results show strong coupling between CO2 and temperature over the long- (LPEE) and short-term (PETM and ETM-2) but differing Pacific climate sensitivities over the two timescales. Combined CO2 and carbon isotope trends imply the carbon source driving CO2 increase was likely methanogenic, organic, or mixed for the PETM and organic for ETM-2, whereas a source with higher δ13C values (e.g., volcanic degassing) is associated with the long-term LPEE. Reconstructed emissions for the PETM (5,800 Gt C) and ETM-2 (3,800 Gt C) are comparable in mass to future emission scenarios, reinforcing the value of these events as analogs of anthropogenic change.

The Lorenz ratio as a guide to scattering contributions to transport in strongly correlated metals.

In many physical situations in which many-body assemblies exist at temperature T, a characteristic quantum-mechanical time scale of approximately [Formula: see text] can be identified in both theory and experiment, leading to speculation that it may be the shortest meaningful time in such circumstances. This behavior can be investigated by probing the scattering rate of electrons in a broad class of materials often referred to as "strongly correlated metals". It is clear that in some cases only electron-electron scattering can be its cause, while in others it arises from high-temperature scattering of electrons from quantized lattice vibrations, i.e., phonons. In metallic oxides, which are among the most studied materials, analysis of electrical transport does not satisfactorily identify the relevant scattering mechanism at "high" temperatures near room temperature. We therefore employ a contactless optical method to measure thermal diffusivity in two Ru-based layered perovskites, Sr3Ru2O7 and Sr2RuO4, and use the measurements to extract the dimensionless Lorenz ratio. By comparing our results to the literature data on both conventional and unconventional metals, we show how the analysis of high-temperature thermal transport can both give important insight into dominant scattering mechanisms and be offered as a stringent test of theories attempting to explain anomalous scattering.

Thermal suppression of charge disproportionation accelerates interface electron transfer of water electrolysis.

The sluggish electron transfer kinetics in electrode polarization driven oxygen evolution reaction (OER) result in big energy barriers of water electrolysis. Accelerating the electron transfer at the electrolyte/catalytic layer/catalyst bulk interfaces is an efficient way to improve electricity-to-hydrogen efficiency. Herein, the electron transfer at the Sr3Fe2O7@SrFeOOH bulk/catalytic layer interface is accelerated by heating to eliminate charge disproportionation from Fe4+ to Fe3+ and Fe5+ in Sr3Fe2O7, a physical effect to thermally stabilize high-spin Fe4+ (t2g3eg1), providing available orbitals as electron transfer channels without pairing energy. As a result of thermal-induced changes in electronic states via thermal comproportionation, a sudden increase in OER performances was achieved as heating to completely suppress charge disproportionation, breaking a linear Arrhenius relationship. The strategy of regulating electronic states by thermal field opens a broad avenue to overcome the electron transfer barriers in water splitting.

Phonon stability boundary and deep elastic strain engineering of lattice thermal conductivity.

Recent studies have reported the experimental discovery that nanoscale specimens of even a natural material, such as diamond, can be deformed elastically to as much as 10% tensile elastic strain at room temperature without the onset of permanent damage or fracture. Computational work combining ab initio calculations and machine learning (ML) algorithms has further demonstrated that the bandgap of diamond can be altered significantly purely by reversible elastic straining. These findings open up unprecedented possibilities for designing materials and devices with extreme physical properties and performance characteristics for a variety of technological applications. However, a general scientific framework to guide the design of engineering materials through such elastic strain engineering (ESE) has not yet been developed. By combining first-principles calculations with ML, we present here a general approach to map out the entire phonon stability boundary in six-dimensional strain space, which can guide the ESE of a material without phase transitions. We focus on ESE of vibrational properties, including harmonic phonon dispersions, nonlinear phonon scattering, and thermal conductivity. While the framework presented here can be applied to any material, we show as an example demonstration that the room-temperature lattice thermal conductivity of diamond can be increased by more than 100% or reduced by more than 95% purely by ESE, without triggering phonon instabilities. Such a framework opens the door for tailoring of thermal-barrier, thermoelectric, and electro-optical properties of materials and devices through the purposeful design of homogeneous or inhomogeneous strains.

Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.

IMPRINTS.CETSA and IMPRINTS.CETSA.app: an R package and a Shiny application for the analysis and interpretation of IMPRINTS-CETSA data.

IMPRINTS-CETSA (Integrated Modulation of Protein Interaction States-Cellular Thermal Shift Assay) provides a highly resolved means to systematically study the interactions of proteins with other cellular components, including metabolites, nucleic acids and other proteins, at the proteome level, but no freely available and user-friendly data analysis software has been reported. Here, we report IMPRINTS.CETSA, an R package that provides the basic data processing framework for robust analysis of the IMPRINTS-CETSA data format, from preprocessing and normalization to visualization. We also report an accompanying R package, IMPRINTS.CETSA.app, which offers a user-friendly Shiny interface for analysis and interpretation of IMPRINTS-CETSA results, with seamless features such as functional enrichment and mapping to other databases at a single site. For the hit generation part, the diverse behaviors of protein modulations have been typically segregated with a two-measure scoring method, i.e. the abundance and thermal stability changes. We present a new algorithm to classify modulated proteins in IMPRINTS-CETSA experiments by a robust single-measure scoring. In this way, both the numerical changes and the statistical significances of the IMPRINTS information can be visualized on a single plot. The IMPRINTS.CETSA and IMPRINTS.CETSA.app R packages are freely available on GitHub at https://github.com/nkdailingyun/IMPRINTS.CETSA and https://github.com/mgerault/IMPRINTS.CETSA.app, respectively. IMPRINTS.CETSA.app is also available as an executable program at https://zenodo.org/records/10636134.