Browse Articles

Material properties of biomolecular condensates emerge from nanoscale dynamics

Biomolecular condensates form by phase separation of biological polymers and have important functions in the cell—functions that are inherently linked to their physical properties at different scales. A notable aspect of such membraneless organelles is that their viscoelastic properties can vary by orders of magnitude, but it has remained unclear how these pronounced differences are rooted in the nanoscale dynamics at the molecular level. Here, we investigate a series of condensates formed by complex coacervation of highly charged disordered proteins and polypeptides that span about two orders of magnitude in bulk viscosity. We find that their viscosity is highly correlated with protein translational diffusion and nano- to microsecond chain dynamics. Remarkably, analytical relations from polymer physics can predict condensate viscosity from diffusivity and chain dynamics, and vice versa, even for more hydrophobic disordered proteins and for synthetic polyelectrolytes, indicating a mechanistic link across several decades of length- and timescales. Atomistic simulations reveal that the observed differences in friction—a key quantity underlying these relations—reflect differences in interresidue contact lifetimes as a function of arginine content and salt concentration, leading to the vastly different dynamics among condensates. The rapid exchange of interresidue contacts we observe may be a general mechanism for preventing dynamic arrest in compartments densely packed with polyelectrolytes, such as the cell nucleus.

Modification of [2.2]Paracyclophanes via Cobalt/Salox‐Catalyzed Enantioselective Electrooxidative or Photoredox C─H Acyloxylation and Alkoxylation

Abstract Chiral [2.2]paracyclophanes (PCPs) have widespread application in asymmetric catalysis and materials science. However, enantioselective C─H activation of PCPs remains elusive and challenging due to steric hindrance, which differs significantly from conventional aryl C─H bonds. Herein, we present a cobalt/Salox‐catalyzed enantioselective dehydrogenative C─H acyloxylation and alkoxylation of racemic PCPs with carboxylic acids and alcohols under electrooxidative or photoredox conditions. This innovative approach leverages traceless electrons or oxygen to replace traditional stoichiometric metal oxidants, allowing the reaction to proceed under mild conditions. The method enables the efficient synthesis of oxygenated optically enriched PCPs, achieving yields of up to 50% with 99% ee, as well as up to 49% yields and 99% ee for the recovered starting materials, resulting in exceptional s ‐factors of up to 1057. The reaction exhibits a broad scope, accommodating a diverse array of carboxylic acids, including complicated natural products and pharmaceutical molecules. This strategy not only provides an efficient route for synthesizing optically enriched PCP compounds but also highlights the potential of electrooxidative and photoredox methodologies in asymmetric C─H activation reactions.

Climate warming increases global oceanic dimethyl sulfide emissions

Oceanic dimethyl sulfide (DMS) is the largest natural source of atmospheric sulfur. DMS is biologically produced in seawater and emitted into the atmosphere, where its oxidation products contribute to aerosol formation with consequences for cloud albedo and the Earth’s radiative budget and climate. Climate model projections of how DMS emissions change with global warming are largely uncertain, even contradictory. Here, we use machine-learning models trained with biome-resolved global observations to simulate seawater DMS concentrations (1850 to 2100) using physico-chemical and biological predictors from eight CMIP6 models. The scatter in current projections is largely reduced, and globally averaged seawater DMS concentrations are predicted to decrease in the coming decades. However, global DMS emissions will increase due to rising surface wind speeds and sea surface temperatures which contradicts the current AR6 assessment that the DMS flux will reduce in the future. Concurrence of increasing DMS emissions and declining anthropogenic sulfur dioxide emissions suggests an increase in the relative importance of DMS to sulfate aerosol formation and its climate cooling impact.

Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial

BACKGROUND: Both GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter-2) inhibitors (SGLT2i) improve cardiovascular outcomes in people with type 2 diabetes and cardiovascular or chronic kidney disease. However, there are limited data about the effect of combining these agents on cardiovascular and safety outcomes. METHODS: The SOUL trial (Semaglutide Cardiovascular Outcomes Trial; NCT03914326) randomized 9650 participants with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease to oral semaglutide or placebo. As prespecified, participants were analyzed according to baseline use of SGLT2i (yes, n=2596; no, n=7054), and subsequently for any use of SGLT2i during the trial (yes, n=4718; no, n=4932). The primary outcome was time to first major adverse cardiovascular event, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Safety was evaluated by comparing the incidence of serious adverse events. RESULTS: Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide versus placebo (hazard ratio, 0.86; 95% CI, 0.77–0.96). In those taking SGLT2i at baseline, there were 143 of 1296 (semaglutide) versus 158 of 1300 (placebo) primary outcome events (hazard ratio, 0.89; 95% CI, 0.71–1.11); and 436 of 3529 versus 510 of 3525, respectively, in participants not taking SGLT2i at baseline (hazard ratio, 0.84; 95% CI, 0.74–0.95; P -interaction, 0.66). An analysis of major adverse cardiovascular events by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar. CONCLUSIONS: Oral semaglutide reduced major adverse cardiovascular event outcomes independently of concomitant SGLT2i treatment, and this combination appeared to be safe. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03914326.

MyD88 knockdown by RNAi prevents bacterial stimulation of tubeworm metamorphosis

Diverse animals across the tree of life undergo the life-history transition of metamorphosis in response to bacteria. Although immunity has been implicated in this metamorphosis in response to bacteria, no functional connection has yet been demonstrated between immunity and metamorphosis. We investigated a host–microbe interaction involving a marine tubeworm, Hydroides elegans , that undergoes metamorphosis in response to Pseudoalteromonas luteoviolacea , a metamorphosis-inducing marine bacterium. By creating a marine bacteria–mediated RNA interference approach, we show that myeloid differentiation factor 88 (MyD88), a critical immune adaptor for Toll-like receptor and interleukin pathways, is necessary for the stimulation of metamorphosis in response to bacteria. In addition to a developmental role, we show that MyD88 is necessary for survival during exposure to the bacterial pathogen Pseudomonas aeruginosa , showing that Hydroides utilizes MyD88 during both development and an immune response. These results provide a functional characterization of the innate immune system involved in an animal's metamorphosis.

<i>N</i> ‐(Acyldithio)Saccharin: Design, Synthesis and Applications in Catalytic Enantioselective Disulfuration/Amination of Alkenes

Abstract We have designed and successfully synthesized N ‐(acyldithio)saccharin, which is a highly electrophilic, bench‐stable, and user‐friendly disulfurating reagent. This reagent can undergo reactions with diverse N‐, S‐, and C‐nucleophiles at room temperature. In most cases, no additional catalyst is required, and the desired disulfides were readily obtained in moderate to excellent yields. With this reagent, late‐stage disulfuration of pharmaceuticals and biomolecules was readily accomplished. For the first time, catalytic enantioselective disulfuration/amination of unactivated alkenes was achieved using this reagent. A series of chiral disulfides were obtained with high enantioselectivities and yields. The chiral disulfide products can be readily further transformed into chiral sulfonyl fluoride, chiral thiol, and structurally diverse disulfide products. Furthermore, we have evaluated the electrophilic reactivity of a series of disulfurating reagents based on density functional theory calculations, verifying the high reactivity of N ‐(acyldithio)saccharin both experimentally and theoretically.

Letter by Pan et al Regarding Article, “Complete Versus Culprit-Only Revascularization in Older Patients With ST-Segment–Elevation Myocardial Infarction: An Individual Patient Meta-Analysis”

Suborbital- and millennial-scale monsoon variability during Pleistocene interglacials

Observational and modeling results show that the frequency and amplitude of extreme climatic events have increased significantly in the context of global warming. However, whether abrupt climate changes intensified during past warm periods remains poorly constrained due to the lack of high-resolution geological records. Here, we report a 512-m predominantly lacustrine sedimentary record from the Weihe Basin (North China), revealing that lake levels fluctuated significantly on suborbital (half- and quarter-precession) and millennial timescales over the last 2 Ma. Grain-size results reveal that magnitudes of rapid lake level fluctuations increased dramatically during Pleistocene interglacials, differing from glacial amplification of abrupt climate events recorded in North Atlantic marine sediments. Model results indicate that summer insolation maxima in low-latitude region of both hemispheres can lead to intensified monsoon precipitation in East Asia. Our proxy-model comparison highlights the importance of low-latitude bihemispheric insolation maxima in driving millennial-scale hydroclimatic variability in a warming future.

Revisiting the Open Vein Hypothesis to Reduce the Postthrombotic Syndrome: Implications for Multidisciplinary Care and Research: A Scientific Statement From the American Heart Association

The “open vein hypothesis” postulates that early thrombus clearance and restoration of venous blood flow may prevent postthrombotic syndrome after proximal deep vein thrombosis. Since its proposal several decades ago, new insights from basic and clinical studies have motivated a re-evaluation and refinement of this hypothesis. According to data from these studies, susceptibility to postthrombotic syndrome occurs as a result of differences in genetic composition, thrombophilic conditions, predilection to inflammation and fibrosis, endogenous fibrinolytic capability, timing of symptom presentation and treatment initiation, and efficacy of antithrombotic therapy. Although initial restoration of an open vein appears to be beneficial for selected patient groups, freedom from postthrombotic syndrome is more likely in the setting of long-term venous patency, reduced recurrent thrombotic episodes, and reduced perithrombotic (eg, vein wall and valve) inflammation. These underlying biological mechanisms need further elucidation, with a long-term goal of personalizing treatment by mapping the individuals’ clinical presentation with their underlying risk factors and assessing time-dependent biological processes that occur as a clinical venous thrombosis resolves. This scientific statement (1) highlights historical fundamentals of the open vein hypothesis and then showcases new research insights into the pathophysiological factors driving postthrombotic syndrome; (2) discusses advantages and disadvantages of imaging modalities for deep vein thrombosis used in clinical practice, including the potential to depict thrombus chronicity and status of vein wall injury; (3) proposes measures to develop integrated multidisciplinary care for deep vein thrombosis focused on the reduction of postthrombotic syndrome; and (4) identifies priority areas and questions for further research.

Multiple sources of atmospheric CO ₂ activated by AMOC recovery at the onset of interglacial MIS 9

Using high-precision ice core measurements of CO 2 , δ 13 C–CO 2 , CH 4 , and N 2 O, this study provides carbon isotope constraints on a sizeable, centennial-scale CO 2 jump at the onset of Marine Isotope Stage 9 (MIS 9). The very end of the Heinrich stadial (HS) characterizing Termination IV (T-IV, ca. 343 to 333 ka ago) shows a 250-y-long jump in greenhouse gas concentrations, followed by a 1.3 ka gradual decline back to the initial concentration. During this so-called overshoot, CO 2 and CH 4 reach their highest levels (about 303 ppm and 800 ppb, respectively) over the past 800 ka prior to industrialization. The jump in CO 2 is not accompanied by a change in δ 13 C–CO 2, suggesting that multiple mechanisms contributed to the exceptionally elevated CO 2 values. Following the jump, a slow 0.2‰ enrichment in δ 13 C–CO 2 occurs. We propose that during the jump, the sudden resumption of deepwater formation in the North Atlantic (NA) triggered an amplified release of CO 2 from the Southern Ocean (SO) by a northward shift of the Intertropical Convergence Zone (ITCZ) and the SO westerlies, potentially in combination with a rapid land carbon release. The latter is expected from temporally enhanced wildfire activity related to higher fuel load and regionally changing weather conditions in connection to the ITCZ shift. A combination of marine proxy records and box model simulation suggests that the δ 13 C–CO 2 decrease expected from these processes is compensated by a net temperature increase in global sea surface temperature (SST) at the time of the AMOC resumption.

Decatungstate‐Driven Photocatalytic Pathways for Sustainable and Cleaner Recovery of Precious Metals

Abstract The recovery of precious metals from waste streams is crucial for sustainable resource utilization but remains hindered by traditional methods involving high toxicity, energy consumption, and environmental pollution. Here, we present a photocatalytic strategy employing hydrothermally synthesized decatungstate ([W 10 O 32 ] 4− ) homogeneous ion catalysts to achieve simultaneous oxidation and reduction of precious metals under ambient conditions. This innovative approach integrates solvent‐controlled reaction pathways, enabling efficient dissolution and recovery of precious metals from diverse waste sources, including electronic waste (e‐waste), platinum membrane electrodes, and platinum‐containing catalysts. The decatungstate catalyst exhibits exceptional performance, with an apparent quantum yield of 0.027%—nearly double that of commercial TiO 2 (0.014%)—and achieves recovery efficiency of 80%–100% for platinum, surpassing 21 tested photocatalysts. The process adheres to a solid‐phase dissolution model and remains against ionic interference. Time‐dependent density functional theory (TD‐DFT) calculations corroborate experimental UV–vis spectra, while electron‐hole pair analyses elucidate atomic and molecular contributions to photocatalytic activity. Density functional theory (DFT) further validates the thermodynamic feasibility of the reaction pathways. By combining high efficiency, ambient operational conditions, and scalability, this work establishes decatungstates as a sustainable benchmark for green precious metal recovery, addressing the limitations of traditional methods and advancing innovation in resource circularity.

Response by Campo and Pavasini to Letter Regarding Article, “Complete Versus Culprit-Only Revascularization in Older Patients With ST-Segment–Elevation Myocardial Infarction: An Individual Patient Meta-Analysis”

Anthropogenic iron alters the spring phytoplankton bloom in the North Pacific transition zone

Industrial activities have increased the supply of iron to the ocean, but the magnitude of anthropogenic input and its ecological consequences are not well-constrained by observations. Across four expeditions to the North Pacific transition zone, we document a repeated supply of isotopically light iron from an atmospheric source in spring, reflecting an estimated 39 ± 9 % anthropogenic contribution to the surface ocean iron budget. Expression of iron-stress genes in metatranscriptomes, and evidence for colimitation of ecosystem productivity by iron and nitrogen, indicates that enhanced iron supply should spur spring phytoplankton blooms, accelerating the seasonal drawdown of nitrate delivered by winter mixing. This effect is consistent with regional trends in satellite ocean color, which show a shorter, more intense spring bloom period, followed by an earlier arrival of oligotrophic conditions in summer. Continued iron emissions may contribute to poleward shifts in transitional marine ecosystems, compounding the anticipated impacts from ocean warming and stratification.

Development of an Automated Workflow for Screening the Assembly and Host–Guest Behavior of Metal‐Organic Cages Towards Accelerated Discovery

Abstract Metal‐organic cages (MOCs) are a class of self‐assembled materials with promising applications in chemical purifications, sensing, and catalysis. Their potential is, however, hampered by challenges in the targeted design of MOCs with desirable properties. MOC discovery is thus often reliant on trial‐and‐error approaches and brute‐force manual screening, which are time‐consuming, costly, and material‐intensive. Translating the synthesis and property screening of MOCs to an automated workflow is therefore attractive, to both accelerate discovery and provide the datasets crucial for data‐led approaches to accelerate MOC discovery and to realize their targeted properties for specific applications. Here, an automated workflow for the streamlined assembly and property screening of MOCs was developed, incorporating automated high‐throughput screening of variables pertinent to MOC synthesis, data curation and automated analysis, and development of a host–guest assay to rapidly assess binding behavior. Computational modelling supplemented this automated experimental workflow for post priori rationalization of experimental outcomes. This study lays the groundwork for future large‐scale MOC screening: from a relatively modest screen of 24 precursor combinations under one set of reaction conditions, 3 clean MOC species were identified, and subsequent screening of their host–guest behavior highlighted trends in binding and the identification of potential applications in molecular separations.

Lymphatic Endothelial Branched-Chain Amino Acid Catabolic Defects Undermine Cardiac Lymphatic Integrity and Drive HFpEF

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. METHODS: We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. RESULTS: In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC C156S ) that selectively activates vascular endothelial growth factor receptor 3 (VEGFR3) in LECs restored cardiac lymphatic integrity and substantially alleviated HFpEF. Through discovery-driven approaches, defective branched-chain amino acid (BCAA) catabolism was identified as a predominant metabolic signature in HFpEF cardiac LECs. Overexpression of branched-chain ketoacid dehydrogenase kinase (encoded by the Bckdk gene), which inactivates branched-chain ketoacid dehydrogenase (the rate-limiting enzyme in BCAA catabolism), resulted in spontaneous lymphangiogenic defects in LECs. In mice, inducible Bckdk gene deletion in LECs to enhance their BCAA catabolism preserved cardiac lymphatic integrity and protected against HFpEF. BCAA catabolic defects caused ligand-independent phosphorylation of VEGFR3 in the cytoplasm by Src kinase, leading to lysosomal degradation of VEGFR3 instead of its trafficking to the cell membrane. Reduced VEGFR3 availability on the cell surface impeded downstream Akt (protein kinase B) activation, hindered glucose uptake and utilization, and inhibited lymphangiogenesis in LECs with BCAA catabolic defects. CONCLUSIONS: Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF.

Location, location, location: Cholesterol in lipid droplets as a driver of MASH progression

New Classification to Describe Clinical Presentation in Aortic Stenosis: Stable, Progressive, and Acute Valve Syndrome

Early dynamics of chromatin decompaction drive nuclear stiffening

FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1

BACKGROUND: Cardiac hypertrophy, as an important pathological change, contributes to heart failure. Recent studies indicate that the mitochondria-associated endoplasmic reticulum membranes (MAMs) play key roles in this pathological process. However, the molecular mechanism remains unclear. This study aims to elucidate the effects and mechanisms of MAM-resident FMO2 (flavin-containing monooxygenase 2) in cardiac hypertrophy and heart failure. METHODS: We performed bulk RNA-sequencing analysis using heart tissue from patients with cardiac hypertrophy and carried out MAM-targeted mass spectrometry analysis using heart tissue from a mouse model of pathological cardiac hypertrophy. In vitro cell culture using neonatal rat cardiomyocytes was used to study how MAMs formation affected cardiomyocyte functions. By generating different genetic mouse models combined with using adeno-associated virus 9 under the cardiac troponin T promoter techniques, we further investigated and confirmed the effects of MAM structure changes on cardiac hypertrophy. RESULTS: We detected an unexpected component of MAMs structure, which was the FMO2, an endoplasmic reticulum–resident protein. FMO2 levels decreased during pathological cardiac hypertrophy. The deletion and overexpression of FMO2 can either worsen or prevent the pathological heart failure progression in vivo, respectively. Our data further demonstrated that FMO2 localizes to MAM structure, where it binds to inositol 1,4,5-trisphosphate type 2 receptor (IP3R2) as a component of the IP3R2–Grp75 (glucose-regulated protein 75)–VDAC1 (voltage-dependent anion channel protein 1) complex, maintaining endoplasmic reticulum–mitochondria contact and regulating mitochondrial Ca 2+ signaling for bioenergetics. Last, we showed that a synthetic peptide-enhancing endoplasmic reticulum–mitochondria contact promoted Ca 2+ transfer and prevented pathological cardiac hypertrophy. CONCLUSIONS: Our findings reveal a key role of FMO2 in myocardial hypertrophy and that FMO2 plays a pivotal role in maintaining MAM structure and function, which may represent a novel mechanism and therapeutic target for cardiac hypertrophy and heart failure.

Summer solstice optimizes the thermal growing season

Multiple studies have recently proposed the summer solstice as a universal cue for major plant physiological processes. While this would have strong implications for fundamental plant biology and climate change forecasting, we currently have no clear mechanisms to explain the emergence and importance of solstice as a cue. Here, we analyze temperature accumulation patterns in relation to the summer solstice across Europe and North America—in past, historical, and projected future climates. We show that, on average, the summer solstice coincides with a thermal optimum during the growing season. However, we also find significant local variation in the timing of this optimum across different climates—suggesting the potential of alternative cues.