Browse Articles

Experimental study on dynamic mechanical properties of concrete for hydraulic dams with PVA fiber

Sex representation in trials relative to indication-specific disease burden in FDA-approved drugs (2015–2023)

Abstract Sex-based disparities in disease burden and therapeutic response motivate efforts to prioritize women’s health in drug development. We analyzed 195 drugs across 98 indications approved by the United States Food and Drug Administration (FDA) between 2015 and 2023 to assess whether industry focus and clinical trial enrollment reflect disease prevalence among males and females. Here, we show that therapies for female-predominant indications receive 1.5 times more approvals than male-predominant indications. Additionally, among trials leading to approval, female participation aligns with or exceeds disease prevalence in 67% of cases. Alignment is strongest in oncology, whereas cardiovascular and autoimmune diseases most often under-enroll women, with no improvement over time. We discuss that gains in female enrollment have plateaued and that further progress will require advances in diagnostics, greater use of objective endpoints, and improved tools to assess risks for women of reproductive potential.

Non-cell-autonomous mechanisms of tumor initiation and relapse by chromosomal instability

Chromosomal instability (CIN) is a hallmark of cancer, and a primary cause of genetic heterogeneity in tumors. Depending on the degree of CIN and the affected tissue, CIN can promote or suppress tumor formation, and high CIN induction has been proposed as a therapeutic strategy. How CIN achieves these effects is unclear. Here we use a conditional mouse model of graded CIN in combination with longitudinal monitoring of DMBA/TPA-initiated skin tumors to show that low CIN increases the frequency of skin tumor initiation, while higher CIN accelerates tumor onset and growth rates. Strikingly, gene recombination analysis of the tumors reveals that upon high CIN induction the fast-growing tumors originate from rare low CIN cells, suggesting a strong non-cell-autonomous effect of high CIN. Gene expression analysis and immunohistochemistry show that high CIN causes epidermal hyperplasia, immune evasion, and a regenerative response that stimulates low CIN tumor growth beyond what is achieved by induction of low CIN alone. Such cell-extrinsic effects may be a common mechanism of tumor formation by CIN, as we observe it also in CIN-induced tumors of the intestine, breast, and mesentery. When high CIN is induced in established skin tumors, mimicking CIN-based therapy, tumors regress but relapse quickly. Relapsed tumors, too, arose from rare low CIN cells. Our findings have implications for our understanding of the contributions of CIN to cancer initiation and progression and give caution to the rationale for CIN therapies.

Explainable machine learning for climate change attribution and hotspot identification: spatial cross-validation analysis in South Asian Region

Pulmonary inflammation in severe pneumonia is characterised by compartmentalised and mechanistically distinct sub-phenotypes

Abstract Pneumonia is the leading infectious disease killer worldwide and commonly requires admission to critical care. Despite its prevalence, the underpinning biology of severe pneumonia remains incompletely understood. Here we perform multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically characterise a cohort of patients with suspected severe pneumonia. Our data implicate three lung-restricted transcriptionally defined severe pneumonia endotypes (termed ‘Pneumotypes’ (Pn)). All three Pneumotypes have comparable clinical presentations and severity of respiratory failure but experience divergent outcomes. Pn1, the most common, is characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 is characterised by immature neutrophil infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displays the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. We identify and validate mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, implicating targets for personalised therapy.

Mathematical modeling of <i>JAK2V617F</i> clonal expansion in a general population cohort

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers characterized by overproduction of one or more types of blood cells, which can lead to thrombosis and other complications. MPNs develop slowly and are driven by a relatively small set of mutations in the hematopoietic stem cells (HSCs). Their slow development (over the course of decades) affords a unique opportunity to study their onset, but until recently few data have been available from individuals not yet showing overt disease. Thanks to the ambitious Danish General Suburban Population Study conducted in suburban Zealand, Denmark, we have identified a ( n = 67 ) cohort of individuals harboring the most common driver mutation in MPN (namely JAK2V617F ) and have obtained follow-up measurements of their variant allele fraction (VAF) spanning over 10 y. We show that these data are consistent with a Moran model governing the competition between healthy and mutated HSCs, and estimate the selective advantage of the mutant clone for each individual. Notably, we find that for many individuals, the change in VAF over many years is statistically consistent with zero, or even negative, selective advantage. This is in contrast to prior studies that have focused on patients diagnosed with overt MPN disease, in whom the mutant cells are almost always found to outcompete the healthy cells. Our results have implications for our understanding of the very early phases of MPN disease, and may contribute to early detection and personalized prediction of disease progression.

A simple technique for characterizing flexible materials using pressurised tubes

Saccharomycetes and Malassezia fungi associate with early-life gut maturation and allergic disease risk in childhood

The dynamic mesoscale sink and source niches for eukaryotic phytoplankton in a subtropical gyre

By tracking the water mass histories of genetic samples, we investigated the biophysical dynamics shaping eukaryotic phytoplankton populations in a nutrient-deplete subtropical gyre, where cyanobacteria have a competitive advantage. Triplicate seawater samples were filtered every ∼ 46 km along a 2,382 km North Pacific transect, spiked with genomic internal standards, and amplified with a three-domain primer set to obtain absolute 16S and 18S rRNA volumetric gene abundances. The transport histories of each sample were simulated by advecting mesoscale Lagrangian particle clouds in satellite remote sensing velocity fields. Consistent with previous field studies, eukaryotic phytoplankton were anomalously abundant within eddies and along eddy-edges, where vertical circulations redistribute nutrients. Outside of eddies, we found a statistically significant decline in eukaryotes as a function of lateral coherence: Waters that recently mixed from multiple origins supported eukaryote anomalies resembling those of eddies, whereas eukaryotic populations were depressed from isolation in waters that were coherent for three or more months. In these coherent outside-eddy water masses, we estimate taxon-dependent eukaryote population half-lives range from 8 to 17 mo. Such physical conditions are relatively rare, given that &gt; 90% of the entire gyre during the sampling campaign was composed of eddies and recently mixed waters. These results derived from empirical observations substantiate the theory that eukaryotic phytoplankton would face exclusion in the subtropics on timescales of ∼ years due to competitive pressure from cyanobacteria, yet are sustained in small numbers by regular disturbances promoting opportunistic growth and dispersal.

Finite element analysis of variable hollowness and experimental validation of optimized uniformly tapered layered hollow roller bearings

Ligand-mediated suppression of Ostwald ripening enables low-temperature sol-gel ZnO for efficient inverted flexible organic photovoltaics

Defiance of stable lysogeny reveals hidden infection dynamics of phage Lambda

Stable prophage establishment is considered a quintessential response of temperate phages when faced with host cell depletion. Scrutinizing this behavior in model phage λ, however, revealed that many λ-chromosomes avoid stable integration in the host chromosome, and rather assume a nonintegrated prophage-like (or pλ) state inside the cell that keeps expressing CI-based immunity and becomes asymmetrically segregated. This creates a heterogeneous population of host cells that are either i) immune by stably carrying an integrated λ prophage, ii) immune by carrying a pλ-episome, or iii) λ-free and transiently immune by segregating from a pλ-carrier. Superinfection of these immune cells drains the number of λ-virions and creates more pλ-episomes that prolong the immunity and expansion of the λ-free subpopulation. The subsequent decline in λ-virions causes cytoplasmically inherited CI-levels in λ-free siblings to dilute out, poising them for renewed lytic consumption by λ. These overlooked pλ-dynamics attenuate the importance of prophage establishment and permit a more productive phage–host coexistence.

Floristic composition and plant community types in Mehal Wonz-Zego forest, north Shewa zone, Amhara regional state, Ethiopia

Strength-ductility synergy in lightweight aluminium alloys with nano-layered fibres and core-shell nano-particles

<i>Pyrodictium abyssi</i> AbpX reveals a calcium-responsive family of microbial biomatrix proteins that form thermostable hydrogels

Evolutionary pressure on microbial communities propagating under extreme environmental conditions often results in unique structural adaptations to promote cell survival. Here, we report an investigation of AbpX, a biomatrix protein identified in cultures of the hyperthermophilic archaeon Pyrodictium abyssi . Under ex vivo and in vitro conditions, AbpX assembles into a paracrystalline lattice composed of semiflexible fibrils. CryoEM analysis of recombinant AbpX fibrils reveals that the precursor protein polymerizes through donor strand complementation (DSC), a process previously reported for chaperone-usher fimbriae in Gram-negative bacteria. Unlike the latter DSC protein polymers, AbpX undergoes chaperone-free polymerization in the presence of calcium ions, which are sequestered at the donor strand-acceptor groove interface between protomers in the fibril. Using a combination of cryoEM and crystallographic information, a structural model is proposed for the AbpX lattice that provides insight into its potential role in biofilm formation. These findings suggest that calcium ion coordination may contribute to fibril assembly and preorganize fibrils for incorporation into the protein lattice. Bioinformatic analysis indicates that AbpX exemplifies a distinct and broadly distributed clade of calcium ion responsive biomatrix proteins within the TasA superfamily that can be fabricated into hydrogel biomaterials in vitro under environmentally benign conditions.

Chemical composition and antioxidant properties of selected mangrove species from the Sine Saloum Delta (Senegal) using UHPLC-MS/MS and molecular networking

Context-dependent regulation of IgH V(D)J recombination by cohesin-STAG1 and cohesin-STAG2

FcRL4 is an IgA receptor that primarily binds the joining chain

Immunoglobulin A (IgA) is a crucial component of the human immune system, and its interaction with receptors is essential for immune regulation. Fc-receptor-like 4 (FcRL4) is an IgA receptor that selectively binds systemic IgA containing the joining chain (J-chain). The molecular mechanism of this interaction has remained unclear. Here, we present a cryo-EM structure of FcRL4 complexed with the dIgA core (Fcα dimer and J-chain), revealing a 1:1 binding stoichiometry. FcRL4 primarily interacts with the J-chain but can nevertheless discriminate against J-chain-containing IgM through an entropic penalty mechanism. Our structure also explains why FcRL4 does not bind secretory IgA, as the secretory component would hinder FcRL4 binding. Functional studies indicate that FcRL4 lacks the ability to internalize IgA or IgA immune complex. These findings provide fresh insights into IgA biology.

Sustainable utilization of fly ash in AA8011 metal matrix composites for enhanced wear performance: implications for energy efficiency and resource optimization

Scaling active spaces in simulations of surface reactions through sample-based quantum diagonalization

Abstract Quantum-chemical simulations are essential for predicting energies of chemical reactions. Accurately solving the many-body Schrödinger equation for reagent and product states of most relevant chemical processes is, however, unfeasible. Quantum computing offers a pathway for predicting energies of correlated electronic systems with localized interactions. Here, we apply a quantum embedding approach for investigating oxygen reduction reactions at the electrode surface in Lithium batteries, a representative example of energetic analysis in localized chemical reactions. We employ an active space selection method based on density difference analysis for identifying the orbitals involved in the reaction. Leveraging the Local Unitary Cluster Jastrow ansatz for state preparation, the active-space orbitals are then processed on a quantum computer. As quantum algorithms, we use Sample-based Quantum Diagonalization, SQD, and its extended version, Ext-SQD, which integrates electronic excitations into the quantum-selected electronic configuration subspace. The largest configurations are represented by quantum circuits mapped onto 80 qubits of an IBM Heron R2 quantum processing unit. For up to 12 orbitals, we are able to benchmark the quantum-computed reaction energies against results obtained with Complete Active Space Configuration Interaction. For benchmarking results in active spaces as large as 32 orbitals, we resort to Heat-Bath Configuration Interaction and Coupled Cluster Singles and Doubles calculations, respectively. At 27 orbitals, the Ext-SQD results exhibit prediction accuracy improvements with regard to the standard, quantum-chemical reference methods that remain computationally feasible at that scale. The results indicate the potential of sample-based quantum diagonalization for performing high-accuracy reaction modeling in chemistry and materials science.