Browse Articles

A Common Ancestry-Specific Sodium Channel Variant Increases Susceptibility to Drug-Induced QTc Prolongation: Evidence From a Large Biobank

Response by Balligand and Michel to Letter Regarding Article, “An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress”

Linearity in Regression Models: Meaning, Implications, and How to Handle it

Quantitative Identification of High-Risk Tricuspid Regurgitation by Cardiac Magnetic Resonance

BACKGROUND: The role of cardiac magnetic resonance (CMR) quantification of tricuspid regurgitation (TR) to identify high-risk patients with TR remains poorly defined. The aim of this study was to assess the prognostic relevance of TR quantification and of its consequences by CMR in a large real-world cohort. METHODS: Comprehensive clinical, echocardiographic, and CMR data were collected from patients referred to clinical CMR between 2019 and 2024 and who had TR quantification using tricuspid regurgitant fraction (TRF) and parametric mapping analysis for liver extracellular volume (L-ECV). The primary end point was the composite of all-cause mortality and heart failure hospitalization, both under medical management accounting for the timing of tricuspid intervention for those that received it; the secondary outcome was all-cause mortality. RESULTS: In the 489 patients (median age, 68 years; 41% women) included into this retrospective observational study, median TRF was 21% (interquartile range, 14%–33%). Relative hazard of the composite end point analysis identified TRF thresholds of ≥20% and ≥40% as associated with increased hazard ratios >1 and >2 of the primary outcome, respectively. During a median follow-up of 2.3 years, Kaplan-Meier curves showed that survival free from both outcomes was inversely associated with increasing TRF severity ( P <0.001). A TRF≥40% independently predicted both end points after multivariable adjustment. Among 371 with liver mapping data, L-ECV ≥32% was strongly associated with manifestations of right-sided heart failure and with long-term adverse outcomes (all P <0.001), providing incremental prognostic value in survival analysis. Patients with TRF ≥20% and L-ECV ≥32% had the highest rate of adverse events compared with those with TRF ≥20% but L-ECV <32% ( P <0.001 for the primary and P =0.012 for the secondary outcome). CONCLUSIONS: In this large cohort, CMR provided several markers of high risk among patients with TR, with TRF thresholds considered by current guidelines as “moderate” TR already associated with worse long-term prognosis. TRF ≥40% was independently associated with both death and heart failure hospitalization. Moreover, L-ECV emerged as a novel imaging biomarker of systemic venous congestion, identifying right heart failure and adding incremental prognostic value to define high-risk patients with TR.

Seeding opportunities for Black atmospheric scientists

Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5

The somatostatin receptor subtype 5 (SSTR5) is a critical pharmacological target involved in neuroendocrine signaling, metabolic regulation, and tumorigenesis. Despite its therapeutic potential, the structural mechanisms underlying SSTR5 inhibition by nonpeptide antagonists remain largely unresolved. In this study, we present high-resolution cryoelectron microscopy structures of human SSTR5 in complex with two selective small-molecule antagonists, antagonist 1 and S5A1, revealing the receptor’s inactive conformation. Both antagonists induce a unique remodeling of extracellular loop 2, which adopts a capping architecture that sterically occludes the orthosteric site, thus preventing agonist access and stabilizing receptor inactivation. Structural analyses and functional experiments elucidate how distinct molecular moieties of the antagonists differentially contribute to inhibitory efficacy, and subtype selectivity. Furthermore, we delineate rational avenues for molecular optimization to enhance therapeutic index and mitigate off-target liabilities. These findings, complementing our previous agonist-bound structures, establish a comprehensive structural foundation for developing improved nonpeptidic SSTR5 antagonists with potential therapeutic applications for type 2 diabetes and related endocrine disorders.

High-speed X-ray tomography for 4D imaging

Capturing high-rate spatiotemporal deformation of materials in three dimensions (3D) remains a significant challenge with current X-ray imaging techniques. We present a methodology that combines advances in neural rendering techniques with volume correlation methods to accurately reconstruct complex, high-rate 3D spatiotemporal structural evolutions. The fidelity and versatility of the method, which requires no pretraining, are demonstrated for a diverse set of intricate 3D-printed microarchitected solids. Using laboratory-based X-ray tomography, we capture the 3D growth of a high-rate crush band on a timescale of less than 100 ms. By broadening this idea to a stereo X-ray concept, we eliminate the need to rotate the image object, thereby extending the technique to significantly faster timescales. Our neural rendering framework opens possibilities for 3D observations of viscoelastic responses of biological materials to 3D investigations of numerous poorly understood dynamic processes, such as the runaway failure of batteries, all using laboratory X-ray systems.

Band pattern formation of erythrocytes in density gradients is due to competing aggregation and net buoyancy

Centrifugation of biological matter in density gradient solutions is a standard method for separating cell types or components. It is also used to separate red blood cells (RBCs) by age, as they lose water and become denser over their lifespan. When the density gradient is prepared with Percoll, discrete bands of RBCs are systematically observed along the gradient, despite the continuous density distribution of RBCs. Early studies suggested that cell aggregation might influence spatial distribution, but it remains debated whether a continuous density population can form discrete bands. We developed a continuity equation incorporating cell aggregation to describe the macroscopic evolution of RBC volume fraction in a density gradient, considering a continuous RBC density distribution. Numerical solutions demonstrate that the competition between net buoyancy and aggregation is sufficient to create band patterns. Our model reproduces the temporal evolution observed in experiments, but also predicts several types of bifurcation-like behaviors for the steady-state patterns in constant gradients, depending on RBC volume fraction and aggregation energy. This demonstrates that the competition between RBC aggregation and net buoyancy is a mechanism driving pattern formation.

Anyon delocalization transitions out of a disordered fractional quantum anomalous Hall insulator

Motivated by the experimental discovery of the fractional quantum anomalous Hall effect, we develop a theory of doping-induced transitions out of the ν = 2 / 3 lattice Jain state in the presence of quenched disorder. We show that disorder strongly affects the evolution into the conducting phases described in our previous work. The delocalization of charge 2 / 3 anyons leads to a chiral superconductor through a direct second-order transition for a smooth random potential with long-wavelength modulations. The longitudinal resistance has a universal peak at the associated quantum critical point. Close to the transition, we show that the superconducting ground state is an “Anomalous Vortex Glass” stabilized in the absence of an external magnetic field. For short-wavelength disorder, this transition generically splits into three distinct ones with intermediate insulating topological phases. If instead, the charge 1 / 3 anyon delocalizes, then at low doping the resulting phase is a Reentrant Integer Quantum Hall state with ρ xy = h / e 2 . At higher doping this undergoes a second transition to a Fermi liquid metal. We show that this framework provides a plausible explanation for the complex phase diagram recently observed in twisted MoTe 2 near ν = 2 / 3 and discuss future experiments that can test our theory in more detail.

Correction for Huang et al., Impulsivity is a stable, measurable, and predictive psychological trait

Locomotion-dependent use of geometric and body cues in humans mapping 3D space

The ability to represent locations across multiple dimensions of space is a core function of cognitive maps. While the influence of boundary-dependent environmental geometry on spatial representations has been extensively studied in 2D spaces, less is known about the role of boundaries for volumetric spatial memory. Research in humans and other animals has demonstrated distinct processing of the vertical and horizontal spatial dimensions, likely related to species-specific modes of locomotion. Here, we investigate whether different locomotion modes, flying and walking, affect the use of vertical boundaries, leading to possibly distinct volumetric representations. In a Virtual Reality experiment, human participants memorized objects within a symmetric 3D enclosure, and then were asked to replace them in either the familiar or geometrically deformed environments. We found that the flying group exhibited lower vertical than horizontal spatial memory precision, whereas the walking group showed the opposite pattern, an effect related to using their body axis as a vertical “ruler”. Within deformed environments, object replacements in the flying group followed the predictions from a 3D-extended boundary-vector-cell-like computational model of spatial mapping that treated all boundaries equally, whereas those in the walking condition favored a modified model that prioritized the ground boundary. Our findings suggest that gravity-related movement constraints promote different utilization of geometric and body-related cues, resulting in flexible representations of volumetric space.

Correction for Michael et al., A cascade of structural rearrangements positions peptide release factor 2 for polypeptide hydrolysis on the ribosome

Correction for AbuHammad et al., Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

Neutral theory of cooperative dynamics

Mutualistic interactions are widespread in nature, from plant communities and microbiomes to human organizations. Along with competition for resources, cooperative interactions shape biodiversity and contribute to the robustness of complex ecosystems. We present a stochastic neutral theory of cooperator species. Our model shares with the classic neutral theory of biodiversity the assumption that all species are equivalent, but crucially differs in requiring cooperation between species for replication. With low migration, our model displays a bimodal species-abundance distribution, with a high-abundance mode associated with a core of cooperating species. This core is responsible for maintaining a diverse pool of long-lived species, which are present even at very small migration rates. We derive analytical expressions of the steady-state species abundance distribution, as well as scaling laws for diversity, number of species, and residence times. With high migration, our model recovers the results of classic neutral theory. We briefly discuss implications of our analysis for research on the microbiome, synthetic biology, and the origin of life.

Emergent eukaryotic directional sensing via receptor degradation and diffusion

Directional sensing enables eukaryotic cells to detect spatial gradients of extracellular ligands, allowing them to orient and migrate within complex environments. Prevalent models explain this computation through a circuit where signaling species with distinct diffusion constants act incoherently on a downstream readout. Here, we propose a fundamentally different mechanism of directional sensing based on simple receptor-level processes. Our model integrates three ubiquitous receptor processes-lateral diffusion, basal ligand-independent activation, and active receptor degradation, THAT together synergize to generate robust directional sensing. In the absence of diffusion, active receptor degradation and basal activity implement an integral feedback that adapts active receptor levels to a ligand-independent set point while depleting receptors in relatively ligand-rich regions. Diffusion then redistributes receptors from regions of relatively low ligand exposure to regions with higher ligand exposure. This creates a spatial mismatch between activity and feedback that drives asymmetric receptor activity relative to the set point. The model predicts an optimal diffusion constant that maximizes polarization, reveals that receptors can encode relative rather than absolute ligand concentrations, and identifies the optimal basal activity that maximizes the signal-to-noise ratio in stochastic regimes. A survey of kinetic parameters across receptor families suggests that this diffusion-degradation synergy constitutes a broadly applicable, receptor-level mechanism for directional sensing.

Platelet-engineered CAR-T cells as adjuvant therapy after cancer surgery

Surgery remains the mainstay treatment for many kinds of solid tumors, while tumor recurrence frequently occurs. Adjuvant therapy can reduce the risk of recurrence and improve the prognosis of surgery. Chimeric antigen receptor (CAR)-T cell therapy can be leveraged as an alternative adjuvant therapy to clear residual cancer cells and prevent tumor recurrence. However, systemic administration of CAR-T often results in insufficient tumor infiltration and side effects to normal organs. Given that platelets can preferentially accumulate at postsurgical wounds, we proposed that conjugating platelets to CAR-T cells may enhance the accumulation of the CAR-T cells within the surgical bed after the resection of solid tumors. In this study, we conjugated platelets to B7-H3.CAR-T cells via click chemistry. In postsurgical human pancreatic cancer mouse models, platelet-CAR-T cells showed enhanced tumor infiltration and elevated antitumor cytokine levels, resulting in superior suppression effects on tumor recurrence, compared with CAR-T cells. Additionally, platelet-CAR-T cells showed enhanced efficacy in inhibiting metastasis and prolonging the survival time of the mice in postsurgical triple-negative breast cancer (TNBC) models. Mechanistic studies revealed that platelet activation could improve the CAR-T cell activity and persistence, as evidenced by an upregulation of genes associated with T cell infiltration and a downregulation of genes related to T cell exhaustion. Finally, we further validated the biosafety profile and efficacy of platelet-CAR-T in a postsurgical patient-derived xenograft TNBC-bearing humanized mouse model. The results suggested that the CAR-T cell strengthened by platelet engineering is a promising adjuvant therapy against postsurgical tumor recurrence.

Intrinsic neuronal network organization of a mammalian peripheral nervous system

The vertebrate nervous system is traditionally parceled topographically into central and peripheral divisions. The peripheral nervous system (PNS) in turn is commonly viewed functionally as a set of nerves and ganglia transmitting input and output signals between the central nervous system (CNS) and other bodily systems to regulate physiology and behavior. Here, we collate and analyze neuroanatomical data on putative directed and weighted axonal connections between peripheral ganglia in a mammal (rat). The resulting network reveals a sparse but broad intra-PNS neuronal architecture with over 100 connections among 52 of the 84 sensory and autonomic ganglia identified. Local network differentiation of the associated 52×52 connection matrix (connectome) was examined with cluster analysis. It identified 22 modules (subsystems or subnetworks) within a six-level nested hierarchy, including seven first-order modules and 14 end modules, spatially distributed from rostral to caudal along the CNS–body axis. Global features of the intra-PNS neuronal network based on node (ganglion) centrality measures identified two hubs (the bilateral myenteric plexus ganglia that control digestive tract functionality), no rich club, and small-world properties comparable to those reported for the rat brain. These findings suggest that the PNS is not merely a series of parallel nerves and associated ganglia but instead forms a structured and recurrently connected neuronal network. Its full extent and functional relevance remain to be elucidated using contemporary structure–function neuroscience approaches.

Convergent mutation trajectories convert functional self-tolerance in IGHV4-34 B cells to genetic tolerance encoded in the antibody

Preventing autoantibody secretion by rendering self-reactive B cells functionally silent through clonal anergy has long posed the question of why fill the circulating B cell repertoire with cells that cannot secrete antibody? Here we address this question from the perspective of B cells that comprise 5 to 10% of the human circulating repertoire, expressing self-reactive surface immunoglobulins employing the IGHV4-34 heavy chain variable element. Using gene targeting to construct mice expressing a representative human IGHV4-34 antibody on the surface of many B cells, we show these cells are prevented from autoantibody secretion by B cell clonal anergy marked by downregulation of surface IgM, induction of tolerance-response mRNAs, and exclusion from the marginal zone and B1 cell subsets. This functionally tolerant state is overridden when the IGHV4-34 B cells cross-react with a virus, which stimulates the self-reactive B cells to hypermutate in germinal centers. Within 16 d of infection, 99% of daughter cells have acquired one of five heavy chain mutations that diminish binding to self but preserve virus binding, and 33% had combined 2 or 3 of these mutations to make their antibodies genetically self-tolerant and virus specific. These results demonstrate, from the perspective of a pathologically important human autoantibody class and the world’s most successful virus vaccine, how human antibody specificity is sculpted in the progeny of anergic B cells to yield antibodies that bind a virus but not self.

MTHFR allele and one-carbon metabolic profile predict severity of COVID-19

While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are thousands of new hospitalizations and hundreds of deaths per week in the United States, many of whom develop long COVID. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here, we report an untargeted, longitudinal plasma metabolomics study of COVID-19 patients. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. Targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a preexisting contributor to disease trajectory—patients that show aberrant one-carbon metabolite levels and that are homozygous for the MTHFR C677T, have higher incidence of severe COVID. Our results raise the possibility that MTHFR variant status may inform precision COVID-19 treatment strategies.

Electroextraction of low-concentration redox-active heavy metals with E ^θ < 0 V from acid mine drainage

Electrochemical recovery of heavy metals from acid mine drainage (AMD) offers a sustainable solution to global AMD contamination, yet remains challenged by thermodynamic and kinetic barriers in reducing redox-active metals with negative standard reduction potentials (E θ < 0 V), especially at low concentrations. Here, using Cd as a model system, we demonstrate that the formation of a metastable intermediate, Cd 2 SO 4 (OH) 2 , plays a crucial role in facilitating the efficient electrochemical reduction of low-concentration Cd(II) to metallic Cd 0 in acidic solutions. A combination of experimental and theoretical analyses reveals that in situ generated OH − at the cathode, in conjunction with bulk-phase SO 4 2− , drives the formation of this metal-inorganic complex, which mediates electron transfer by overcoming redox limitations. By optimizing flow dynamics and incorporating hierarchical electrode configurations, we enhance intermediate formation and achieve 96.81% Cd recovery from real AMD, with effluent Cd concentrations below 0.5 mg L −1 . Economic analysis estimates a net-positive return of 2.32 CNY per ton of treated AMD. Life cycle assessment further shows that the electroextraction process substantially outperforms lime neutralization with respect to all major environmental indicators. This work establishes a mechanistically driven, economically viable, and environmentally superior strategy for recovering valuable metals from AMD, advancing the prospects of circular resource recovery and sustainable wastewater management.