Proteostasis governs differential temperature sensitivity across embryonic cell types.

Embryonic development is remarkably robust, but temperature stress can degrade its ability to generate animals with invariant anatomy. Phenotypes associated with environmental stress suggest that some cell types are more sensitive to stress than others, but the basis of this sensitivity is unknown. Here, we characterize hundreds of individual zebrafish embryos under temperature stress using whole-animal single-cell RNA sequencing (RNA-seq) to identify cell types and molecular programs driving phenotypic variability. We find that temperature perturbs the normal proportions and gene expression programs of numerous cell types and also introduces asynchrony in developmental timing. The notochord is particularly sensitive to temperature, which we map to a specialized cell type: sheath cells. These cells accumulate misfolded protein at elevated temperature, leading to a cascading structural failure of the notochord and anatomic defects. Our study demonstrates that whole-animal single-cell RNA-seq can identify mechanisms for developmental robustness and pinpoint cell types that constitute key failure points.

Chilling with cephalopods: Temperature-responsive RNA editing in octopus and squid.

The molecular mechanisms that generate the developmental and physiological complexity found within cephalopods are not well understood. In this issue of Cell, Birk et al. and Rangan and Reck-Peterson show that cephalopods differentially edit their RNA in response to temperature changes and that this editing has consequences on protein function.

Temperature-dependent RNA editing in octopus extensively recodes the neural proteome.

In poikilotherms, temperature changes challenge the integration of physiological function. Within the complex nervous systems of the behaviorally sophisticated coleoid cephalopods, these problems are substantial. RNA editing by adenosine deamination is a well-positioned mechanism for environmental acclimation. We report that the neural proteome of Octopus bimaculoides undergoes massive reconfigurations via RNA editing following a temperature challenge. Over 13,000 codons are affected, and many alter proteins that are vital for neural processes. For two highly temperature-sensitive examples, recoding tunes protein function. For synaptotagmin, a key component of Ca2+-dependent neurotransmitter release, crystal structures and supporting experiments show that editing alters Ca2+ binding. For kinesin-1, a motor protein driving axonal transport, editing regulates transport velocity down microtubules. Seasonal sampling of wild-caught specimens indicates that temperature-dependent editing occurs in the field as well. These data show that A-to-I editing tunes neurophysiological function in response to temperature in octopus and most likely other coleoids.

Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress.

Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human monoclonal antibodies (mAbs) with diverse patterns of recognition for alphaviruses (ranging from Eastern equine encephalitis virus [EEEV]-specific to alphavirus cross-reactive) from survivors of natural EEEV infection. Antibody binding patterns and epitope mapping experiments identified differences in E1 reactivity based on exposure of epitopes on the glycoprotein through pH-dependent mechanisms or presentation on the cell surface prior to virus egress. Therapeutic efficacy in vivo of these mAbs corresponded with potency of virus egress inhibition in vitro and did not require Fc-mediated effector functions for treatment against subcutaneous EEEV challenge. These studies reveal the molecular basis for broad and protective antibody responses to alphavirus E1 proteins.

Not Going with the Flow: How Cells Adapt Internal Physics.

Defining the principles underlying the organization of biomolecules within cells is a key challenge of current cell biology research. Persson et al. now identify a powerful layer of regulation that allows cells to decouple diffusion from temperature by modulating their intracellular viscosity. This so-called viscoadaptation is mediated through trehalose and glycogen activities, which alter diffusion dynamics and self-assembly propensity inside the cell globally.

Cellular Control of Viscosity Counters Changes in Temperature and Energy Availability.

Cellular functioning requires the orchestration of thousands of molecular interactions in time and space. Yet most molecules in a cell move by diffusion, which is sensitive to external factors like temperature. How cells sustain complex, diffusion-based systems across wide temperature ranges is unknown. Here, we uncover a mechanism by which budding yeast modulate viscosity in response to temperature and energy availability. This "viscoadaptation" uses regulated synthesis of glycogen and trehalose to vary the viscosity of the cytosol. Viscoadaptation functions as a stress response and a homeostatic mechanism, allowing cells to maintain invariant diffusion across a 20°C temperature range. Perturbations to viscoadaptation affect solubility and phase separation, suggesting that viscoadaptation may have implications for multiple biophysical processes in the cell. Conditions that lower ATP trigger viscoadaptation, linking energy availability to rate regulation of diffusion-controlled processes. Viscoadaptation reveals viscosity to be a tunable property for regulating diffusion-controlled processes in a changing environment.

Gene Expression Changes and Community Turnover Differentially Shape the Global Ocean Metatranscriptome.

Ocean microbial communities strongly influence the biogeochemistry, food webs, and climate of our planet. Despite recent advances in understanding their taxonomic and genomic compositions, little is known about how their transcriptomes vary globally. Here, we present a dataset of 187 metatranscriptomes and 370 metagenomes from 126 globally distributed sampling stations and establish a resource of 47 million genes to study community-level transcriptomes across depth layers from pole-to-pole. We examine gene expression changes and community turnover as the underlying mechanisms shaping community transcriptomes along these axes of environmental variation and show how their individual contributions differ for multiple biogeochemically relevant processes. Furthermore, we find the relative contribution of gene expression changes to be significantly lower in polar than in non-polar waters and hypothesize that in polar regions, alterations in community activity in response to ocean warming will be driven more strongly by changes in organismal composition than by gene regulatory mechanisms. VIDEO ABSTRACT.

Regulation of Energy Expenditure by Brainstem GABA Neurons.

Homeostatic control of core body temperature is essential for survival. Temperature is sensed by specific neurons, in turn eliciting both behavioral (i.e., locomotion) and physiologic (i.e., thermogenesis, vasodilatation) responses. Here, we report that a population of GABAergic (Vgat-expressing) neurons in the dorsolateral portion of the dorsal raphe nucleus (DRN), hereafter DRNVgat neurons, are activated by ambient heat and bidirectionally regulate energy expenditure through changes in both thermogenesis and locomotion. We find that DRNVgat neurons innervate brown fat via a descending projection to the raphe pallidus (RPa). These neurons also densely innervate ascending targets implicated in the central regulation of energy expenditure, including the hypothalamus and extended amygdala. Optogenetic stimulation of different projection targets reveals that DRNVgat neurons are capable of regulating thermogenesis through both a "direct" descending pathway through the RPa and multiple "indirect" ascending pathways. This work establishes a key regulatory role for DRNVgat neurons in controlling energy expenditure.

Functional Ontogeny of Hypothalamic Agrp Neurons in Neonatal Mouse Behaviors.

Hypothalamic Agrp neurons regulate food ingestion in adult mice. Whether these neurons are functional before animals start to ingest food is unknown. Here, we studied the functional ontogeny of Agrp neurons during breastfeeding using postnatal day 10 mice. In contrast to adult mice, we show that isolation from the nursing nest, not milk deprivation or ingestion, activated Agrp neurons. Non-nutritive suckling and warm temperatures blunted this effect. Using in vivo fiber photometry, neonatal Agrp neurons showed a rapid increase in activity upon isolation from the nest, an effect rapidly diminished following reunion with littermates. Neonates unable to release GABA from Agrp neurons expressed blunted emission of isolation-induced ultrasonic vocalizations. Chemogenetic overactivation of these neurons further increased emission of these ultrasonic vocalizations, but not milk ingestion. We uncovered important functional properties of hypothalamic Agrp neurons during mouse development, suggesting these neurons facilitate offspring-to-caregiver bonding.

Atoms to Phenotypes: Molecular Design Principles of Cellular Energy Metabolism.

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore's structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells.

Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites.

Liquid-liquid phase separation (LLPS) is believed to underlie formation of biomolecular condensates, cellular compartments that concentrate macromolecules without surrounding membranes. Physical mechanisms that control condensate formation/dissolution are poorly understood. The RNA-binding protein fused in sarcoma (FUS) undergoes LLPS in vitro and associates with condensates in cells. We show that the importin karyopherin-ß2/transportin-1 inhibits LLPS of FUS. This activity depends on tight binding of karyopherin-ß2 to the C-terminal proline-tyrosine nuclear localization signal (PY-NLS) of FUS. Nuclear magnetic resonance (NMR) analyses reveal weak interactions of karyopherin-ß2 with sequence elements and structural domains distributed throughout the entirety of FUS. Biochemical analyses demonstrate that most of these same regions also contribute to LLPS of FUS. The data lead to a model where high-affinity binding of karyopherin-ß2 to the FUS PY-NLS tethers the proteins together, allowing multiple, distributed weak intermolecular contacts to disrupt FUS self-association, blocking LLPS. Karyopherin-ß2 may act analogously to control condensates in diverse cellular contexts.

mTOR Regulates Phase Separation of PGL Granules to Modulate Their Autophagic Degradation.

The assembly of phase-separated structures is thought to play an important role in development and disease, but little is known about the regulation and function of phase separation under physiological conditions. We showed that during C. elegans embryogenesis, PGL granules assemble via liquid-liquid phase separation (LLPS), and their size and biophysical properties determine their susceptibility to autophagic degradation. The receptor SEPA-1 promotes LLPS of PGL-1/-3, while the scaffold protein EPG-2 controls the size of PGL-1/-3 compartments and converts them into less dynamic gel-like structures. Under heat-stress conditions, mTORC1-mediated phosphorylation of PGL-1/-3 is elevated and PGL-1/-3 undergo accelerated phase separation, forming PGL granules that are resistant to autophagic degradation. Significantly, accumulation of PGL granules is an adaptive response to maintain embryonic viability during heat stress. We revealed that mTORC1-mediated LLPS of PGL-1/-3 acts as a switch-like stress sensor, coupling phase separation to autophagic degradation and adaptation to stress during development.

Temperature matters: the potential impact of thermoregulatory mechanisms in brain-body physiology.

Thermoregulation, responsible for maintaining a stable core temperature during wide fluctuations in external and internal thermal environments, is an iconic homeostatic process. However, we suggest that despite its fundamental physiological significance, the potential for required cool housing temperatures and thermoregulatory mechanisms to influence the interpretation of experimental data is not sufficiently appreciated. Moreover, although it is generally assumed that the major thermoregulatory pathways are well understood, here we discuss new research that suggests otherwise and reveals the emergence of a new wave of exciting ideas for this "old" field of research.

Phase transition of spindle-associated protein regulate spindle apparatus assembly.

Spindle assembly required during mitosis depends on microtubule polymerization. We demonstrate that the evolutionarily conserved low-complexity protein, BuGZ, undergoes phase transition or coacervation to promote assembly of both spindles and their associated components. BuGZ forms temperature-dependent liquid droplets alone or on microtubules in physiological buffers. Coacervation in vitro or in spindle and spindle matrix depends on hydrophobic residues in BuGZ. BuGZ coacervation and its binding to microtubules and tubulin are required to promote assembly of spindle and spindle matrix in Xenopus egg extract and in mammalian cells. Since several previously identified spindle-associated components also contain low-complexity regions, we propose that coacervating proteins may be a hallmark of proteins that comprise a spindle matrix that functions to promote assembly of spindles by concentrating its building blocks.

Self-oscillating polymeric refrigerator with high energy efficiency.

Electrocaloric1,2 and electrostrictive3,4 effects concurrently exist in dielectric materials. Combining these two effects could achieve the lightweight, compact localized thermal management that is promised by electrocaloric refrigeration5. Despite a handful of numerical models and schematic presentations6,7, current electrocaloric refrigerators still rely on external accessories to drive the working bodies8-10 and hence result in a low device-level cooling power density and coefficient of performance (COP). Here we report an electrocaloric thin-film device that uses the electro-thermomechanical synergy provided by polymeric ferroelectrics. Under one-time a.c. electric stimulation, the device is thermally and mechanically cycled by the working body itself, resulting in an external-driver-free, self-cycling, soft refrigerator. The prototype offers a directly measured cooling power density of 6.5 W g-1 and a peak COP exceeding 58 under a zero temperature span. Being merely a 30-µm-thick polymer film, the device achieved a COP close to 24 under a 4 K temperature span in an open ambient environment (32% thermodynamic efficiency). Compared with passive cooling, the thin-film refrigerator could immediately induce an additional 17.5 K temperature drop against an electronic chip. The soft, polymeric refrigerator can sense, actuate and pump heat to provide automatic localized thermal management.

Evidence of human influence on Northern Hemisphere snow loss.

Documenting the rate, magnitude and causes of snow loss is essential to benchmark the pace of climate change and to manage the differential water security risks of snowpack declines1-4. So far, however, observational uncertainties in snow mass5,6 have made the detection and attribution of human-forced snow losses elusive, undermining societal preparedness. Here we show that human-caused warming has caused declines in Northern Hemisphere-scale March snowpack over the 1981-2020 period. Using an ensemble of snowpack reconstructions, we identify robust snow trends in 82 out of 169 major Northern Hemisphere river basins, 31 of which we can confidently attribute to human influence. Most crucially, we show a generalizable and highly nonlinear temperature sensitivity of snowpack, in which snow becomes marginally more sensitive to one degree Celsius of warming as climatological winter temperatures exceed minus eight degrees Celsius. Such nonlinearity explains the lack of widespread snow loss so far and augurs much sharper declines and water security risks in the most populous basins. Together, our results emphasize that human-forced snow losses and their water consequences are attributable-even absent their clear detection in individual snow products-and will accelerate and homogenize with near-term warming, posing risks to water resources in the absence of substantial climate mitigation.

Metals strengthen with increasing temperature at extreme strain rates.

The strength of materials depends on the rate at which they are tested, as defects, for example dislocations, that move in response to applied strains have intrinsic kinetic limitations1-4. As the deformation strain rate increases, more strengthening mechanisms become active and increase the strength4-7. However, the regime in which this transition happens has been difficult to access with traditional micromechanical strength measurements. Here, with microballistic impact testing at strain rates greater than 106 s-1, and without shock conflation, we show that the strength of copper increases by about 30% for a 157 °C increase in temperature, an effect also observed in pure titanium and gold. This effect is counterintuitive, as almost all materials soften when heated under normal conditions. This anomalous thermal strengthening across several pure metals is the result of a change in the controlling deformation mechanism from thermally activated strengthening to ballistic transport of dislocations, which experience drag through phonon interactions1,8-10. These results point to a pathway to better model and predict materials properties under various extreme strain rate conditions, from high-speed manufacturing operations11 to hypersonic transport12.

A self-healing multispectral transparent adhesive peptide glass.

Despite its disordered liquid-like structure, glass exhibits solid-like mechanical properties1. The formation of glassy material occurs by vitrification, preventing crystallization and promoting an amorphous structure2. Glass is fundamental in diverse fields of materials science, owing to its unique optical, chemical and mechanical properties as well as durability, versatility and environmental sustainability3. However, engineering a glassy material without compromising its properties is challenging4-6. Here we report the discovery of a supramolecular amorphous glass formed by the spontaneous self-organization of the short aromatic tripeptide YYY initiated by non-covalent cross-linking with structural water7,8. This system uniquely combines often contradictory sets of properties; it is highly rigid yet can undergo complete self-healing at room temperature. Moreover, the supramolecular glass is an extremely strong adhesive yet it is transparent in a wide spectral range from visible to mid-infrared. This exceptional set of characteristics is observed in a simple bioorganic peptide glass composed of natural amino acids, presenting a multi-functional material that could be highly advantageous for various applications in science and engineering.

Climate velocities and species tracking in global mountain regions.

Mountain ranges contain high concentrations of endemic species and are indispensable refugia for lowland species that are facing anthropogenic climate change1,2. Forecasting biodiversity redistribution hinges on assessing whether species can track shifting isotherms as the climate warms3,4. However, a global analysis of the velocities of isotherm shifts along elevation gradients is hindered by the scarcity of weather stations in mountainous regions5. Here we address this issue by mapping the lapse rate of temperature (LRT) across mountain regions globally, both by using satellite data (SLRT) and by using the laws of thermodynamics to account for water vapour6 (that is, the moist adiabatic lapse rate (MALRT)). By dividing the rate of surface warming from 1971 to 2020 by either the SLRT or the MALRT, we provide maps of vertical isotherm shift velocities. We identify 17 mountain regions with exceptionally high vertical isotherm shift velocities (greater than 11.67 m per year for the SLRT; greater than 8.25 m per year for the MALRT), predominantly in dry areas but also in wet regions with shallow lapse rates; for example, northern Sumatra, the Brazilian highlands and southern Africa. By linking these velocities to the velocities of species range shifts, we report instances of close tracking in mountains with lower climate velocities. However, many species lag behind, suggesting that range shift dynamics would persist even if we managed to curb climate-change trajectories. Our findings are key for devising global conservation strategies, particularly in the 17 high-velocity mountain regions that we have identified.

2023 summer warmth unparalleled over the past 2,000 years.

Including an exceptionally warm Northern Hemisphere summer1,2, 2023 has been reported as the hottest year on record3-5. However, contextualizing recent anthropogenic warming against past natural variability is challenging because the sparse meteorological records from the nineteenth century tend to overestimate temperatures6. Here we combine observed and reconstructed June-August surface air temperatures to show that 2023 was the warmest Northern Hemisphere extra-tropical summer over the past 2,000 years exceeding the 95% confidence range of natural climate variability by more than 0.5 °C. Comparison of the 2023 June-August warming against the coldest reconstructed summer in CE 536 shows a maximum range of pre-Anthropocene-to-2023 temperatures of 3.93 °C. Although 2023 is consistent with a greenhouse-gases-induced warming trend7 that is amplified by an unfolding El Niño event8, this extreme emphasizes the urgency to implement international agreements for carbon emission reduction.