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Spatial Patterning Analysis of Cellular Ensembles (SPACE) finds complex spatial organization at the cell and tissue levels

Spatial patterns of cells and other biological elements drive physiologic and pathologic processes within tissues. While many imaging and transcriptomic methods document tissue organization, discerning these patterns is challenging, especially when they involve multiple elements in complex arrangements. To address this challenge, we present Spatial Patterning Analysis of Cellular Ensembles (SPACE), an R package for analysis of high-plex spatial data. SPACE is compatible with any data collection modality that records values (i.e., categorical cell/structure types or quantitative expression levels) at fixed spatial coordinates (i.e., 2d pixels or 3d voxels). SPACE detects not only broad patterns of co-occurrence but also context-dependent associations, quantitative gradients and orientations, and other organizational complexities. Via a robust information theoretic framework, SPACE explores all possible ensembles of tissue elements—single elements, pairs, triplets, and so on—and ranks the most strongly patterned ensembles. For single images, rankings reflect differences from random assortment. For sets of images, rankings reflect differences across sample groups (e.g., genotypes, treatments, timepoints, etc.). Further tools then characterize the nature of each pattern for intuitive interpretation. We validate SPACE and demonstrate its advantages using murine lymph node images for which ground truth has been defined. We then detect new patterns across varied datasets, including tumors and tuberculosis granulomas.

Carbon benefits through agroforestry transitions on unmanaged fallow agricultural land in Hawaiʻi

Observed declines in upper ocean phosphate-to-nitrate availability

Climate warming is increasing ocean stratification, which in turn should decrease the nutrient flux to the upper ocean. This may slow marine primary productivity, causing cascading effects throughout food webs. However, observing changes in upper ocean nutrients is challenging because surface concentrations are often below detection limits. We show that the nutricline depth, where nutrient concentrations reach well-detected levels, is tied to productivity and upper ocean nutrient availability. Next, we quantify nutricline depths from a global database of observed vertical nitrate and phosphate profiles to assess contemporary trends in global nutrient availability (1972–2022). We find strong evidence that the P-nutricline (phosphacline) is mostly deepening, especially throughout the southern hemisphere, but the N-nutricline (nitracline) remains mostly stable. Earth System Model (ESM) simulations support the hypothesis that reduced iron stress and increased nitrogen fixation buffer the nitracline, but not phosphacline, against increasing stratification. These contemporary trends are expected to continue in the coming decades, leading to increasing phosphorus but not nitrogen stress for marine phytoplankton, with important ramifications for ocean biogeochemistry and food web dynamics.

Adaptability and stability analysis via GGE biplot in single, double, and interpopulation maize hybrids

Impact of <i>APOE</i> , <i>Klotho,</i> and sex on cognitive decline with aging

The effects of apolipoprotein E ( APOE ) and Klotho genes, both implicated in aging, on human cognition as a function of sex and age are yet to be definitively established. Here, we showed in the largest cohort studied to date ( N = 320,861) that APOE homozygous ε4 carriers had a greater decline in cognition with aging compared to ε3 carriers (ε3/ε4 and ε3/ε3) as well as smaller hippocampi and amygdala ( N = 29,510). Critically, sex and age differentially affected the decline in cognition. Younger (40 to 50 y) female homozygous ε4 carriers showed a cognitive advantage over female ε3 carriers, but this advantage was not present in males. By contrast, Klotho-VS heterozygosity did not affect cognition or brain volume, regardless of APOE genotype, sex, or age. These cognitive trajectories with aging demonstrate clear sex-dependent antagonistic pleiotropy effects of APOE ε4, but no effects of Klotho genotype on cognition and brain volume.

A comparative study of antibiotic resistance patterns in Mycobacterium tuberculosis

Intracranial substrates of meditation-induced neuromodulation in the amygdala and hippocampus

Meditation is an accessible mental practice associated with emotional regulation and well-being. Loving-kindness meditation (LKM), a specific subtype of meditative practice, involves focusing one’s attention on thoughts of well-being for oneself and others. Meditation has been proven to be beneficial in a variety of settings, including therapeutic applications, but the neural activity underlying meditative practices and their positive effects are not well understood. It has been difficult to understand the contribution of deep limbic structures given the difficulty of studying neural activity directly in the human brain. Here, we leverage a unique patient population, epilepsy patients chronically implanted with responsive neurostimulation devices that allow chronic, invasive electrophysiology recording to investigate the physiological correlates of LKM in the amygdala and hippocampus of novice meditators. We find that LKM-associated changes in physiological activity were specific to periodic, but not aperiodic, features of neural activity. LKM was associated with an increase in γ (30 to 55 Hz) power and an alternation in the duration of β (13 to 30 Hz) and γ oscillatory bursts in both the amygdala and hippocampus, two regions associated with mood disorders. These findings reveal the nature of LKM-induced modulation of limbic activity in first-time meditators.

An efficient multi-objective parrot optimizer for global and engineering optimization problems

Abstract The Parrot Optimizer (PO) has recently emerged as a powerful algorithm for single-objective optimization, known for its strong global search capabilities. This study extends PO into the Multi-Objective Parrot Optimizer (MOPO), tailored for multi-objective optimization (MOO) problems. MOPO integrates an outward archive to preserve Pareto optimal solutions, inspired by the search behavior of Pyrrhura Molinae parrots. Its performance is validated on the Congress on Evolutionary Computation 2020 (CEC’2020) multi-objective benchmark suite. Additionally, extensive testing on four constrained engineering design challenges and eight popular confined and unconstrained test cases proves MOPO’s superiority. Moreover, the real-world multi-objective optimization of helical coil springs for automotive applications is conducted to depict the reliability of the proposed MOPO in solving practical problems. Comparative analysis was performed with seven recently published, state-of-the-art algorithms chosen for their proven effectiveness and representation of the current research landscape-Improved Multi-Objective Manta-Ray Foraging Optimization (IMOMRFO), Multi-Objective Gorilla Troops Optimizer (MOGTO), Multi-Objective Grey Wolf Optimizer (MOGWO), Multi-Objective Whale Optimization Algorithm (MOWOA), Multi-Objective Slime Mold Algorithm (MOSMA), Multi-Objective Particle Swarm Optimization (MOPSO), and Non-Dominated Sorting Genetic Algorithm II (NSGA-II). The results indicate that MOPO consistently outperforms these algorithms across several key metrics, including Pareto Set Proximity (PSP), Inverted Generational Distance in Decision Space (IGDX), Hypervolume (HV), Generational Distance (GD), spacing, and maximum spread, confirming its potential as a robust method for addressing complex MOO problems.

Engineering drive–selection balance for localized population suppression with neutral dynamics

While the release of sterile males has been highly successful in suppressing some pest populations, it is impractical for many species due to the males disappearing after a single generation, necessitating large, repeated releases to maintain sufficient impact. Synthetic gene drives promise more efficient approaches since they can increase in frequency from rare, yet this also allows them to spread across a landscape, which may not always be desired. Between these two extremes are selectively neutral genetic constructs which persist at the frequency they are released, offering the potential for efficient suppression that remains localized. One way to achieve this would be to have perfect balance, at all construct frequencies, between gene drive increasing frequency and selection decreasing it. Here, we describe a way to closely approximate this balance using a toxin–antidote genetic construct that causes recessive lethality or sterility, encodes a genomic editor that makes dominant lethal or sterile edits in the genome, and provides protection against the action or consequences of the editing. Computer modeling shows that this design can be 100-fold more efficient than sterile males, increasing to 1,000-fold when released alongside a genetic booster. We describe designs for CRISPR-based molecular construction, including options that avoid using recoded genes as antidotes.

Hematological biochemical and liver function changes associated with BTEX exposure in a six year retrospective cohort study

Human beauty illustrates the economic impact of heritable physical traits

Intergenerational transmission of inequality is a central question in the social sciences. We use one trait, beauty, to infer how much parents’ physical characteristics transmit inequality across generations. Analyses of a large-scale longitudinal dataset in the United States, and a much smaller dataset of Chinese parents and children, show that increases in parents’ looks are associated with increases in their child’s looks. A large dataset of U.S. siblings shows a positive correlation of their beauty. The appropriate weighted average from the three samples shows that a one SD increase in ratings of both parents’ looks is associated with a 0.25 SD increase in their child’s. Coupling these estimates with those from large literatures measuring the impact of beauty on earnings and the intergenerational elasticity of income suggests that a one SD difference in parents’ looks is correlated with a 0.074 SD difference in their adult child’s earnings, about U.S. $2,170 annually.

Water resource utilization and future supply–demand scenarios in energy cities of semi-arid regions

The revised elastic field of an edge dislocation

We modify the traditional linear-elastic field of an edge dislocation. The modifications stem from symmetry and energy requirements imposed in terms of embedded (deformed) coordinates. These requirements are satisfied if a line force is added to the dislocation field. The modification to the stress field is expressed by coefficients that are a function only of Poisson’s ratio. Qualitatively, the field of the dislocation is increased in the glide direction and decreased in the climb direction. There are small changes to the field of a screw dislocation that do not entail the addition of a line force. Effects of nonlinearity, anisotropic elasticity, and image forces are briefly considered.

Validation of two swabbing methods to sample DNA for genotyping Atlantic bluefin tuna (Thunnus thynnus)

Abstract In fisheries, genetic based assignment of individuals to their population of origin can benefit efforts aimed at monitoring and managing stocks. Assignment combined with knowledge of the migration history of individuals can provide powerful insights into mechanisms of genetic mixing, for which refined sampling methods are required to minimise any impacts. In this study we tested two minimally invasive swabbing techniques for sampling DNA when attaching electronic satellite tags to Atlantic bluefin tuna (Thunnus thynnus) for migration studies. First, DNA was sampled by skin swabbing (hereafter skin swabs) individuals from which there were corresponding fin clip samples. Second, swabs were taken from the applicator poles used to attach electronic tags (hereafter pole swabs). Quantification of DNA from the different sources revealed decreasing yields moving from fin clips, to skin swabs, to pole swabs. The utility of the DNA obtained by both swabbing methods for individual genotyping was then assessed by sequencing of the mtDNA control region and genotyping of six microsatellite loci. In all cases successful genotyping was achieved. For mtDNA an 868 bp fragment was successfully amplified in all samples with 775 bp aligned across individuals revealing 26 haplotypes (overall haplotype diversity = 0.987). All six microsatellites were successfully amplified including a largest allele size of 291 bp. mtDNA and microsatellite genotypes for the skin swabs matched with the corresponding fin clip samples. Although no tissue replicates were available for the pole swab samples the genotypes obtained were unambiguous, consistent across repeated PCRs, and reported no evidence of PCR issues such as large allele drop out. Overall, the genetic data suggested high variability among individuals sampled, comparable to levels of genetic diversity seen within the species’ Atlantic range. The study demonstrates that non-invasive sampling can be used to obtain DNA for population assignment studies and that valuable material can be sampled from tagging equipment.

Identification of a central regulator of ginkgolide biosynthesis in <i>Ginkgo biloba</i> that integrates jasmonate and light signaling

Ginkgolides are secondary metabolites unique to Ginkgo biloba with the potential to prevent and treat cardiovascular and cerebrovascular diseases. Although the biosynthetic pathways of ginkgolides have been partly uncovered, the mechanism regulating their biosynthesis is still largely unknown. Here, using multiomic and genetic analyses, we report the identification of a transcription factor, named ETHYLENE RESPONSE FACTOR ASSOCIATED WITH GINKGOLIDE BIOSYNTHESIS (GbEAG), as a critical regulator of ginkgolide biosynthesis. GbEAG is highly expressed in the roots of G. biloba, and its expression is significantly induced by methyl jasmonate (MeJA). Ginkgolide content was significantly increased in roots by overexpressing GbEAG using a “cut-dip-regeneration” system. GbEAG positively regulates ginkgolide biosynthesis by directly binding to the GCC-boxes in the promoter regions of genes involved in the biosynthesis of ginkgolides, such as ISOPENTENYL DIPHOSPHATE ISOMERASE ( GbIDI ) and CYTOCHROME P450 7005C3 ( GbCYP7005C3 ). GbEAG mediates the jasmonic acid (JA)-activated ginkgolide synthesis through its direct interaction with the JASMONATE ZINC-FINGER INFLORESCENCE MERISTEM DOMAIN 3 (GbJAZ3) repressor. Importantly, we also found that the central light-response regulator ELONGATED HYPOCOTYL 5 (GbHY5) mediates light induction of ginkgolide biosynthesis by binding to the G-box in the GbEAG promoter. Our findings provide mechanistic insights into the coordinated regulation of ginkgolide biosynthesis via JA and light signals, with GbEAG as a central regulator in G. biloba, and shed light on the potential to develop ginkgolide-rich varieties through molecular breeding and gene editing.

Development and validation of a predictive model for carotid atherosclerosis in postmenopausal women

Biochemical and structural bases for talin ABSs–F-actin interactions

Focal adhesions (FAs) are large intracellular macromolecular assemblies that play a critical role in cell polarization and migration. Talin serves as a direct connection between integrin receptor and actomyosin cytoskeleton within FAs. Talin contains three actin-binding sites (ABS1-3) that engage discreetly during the development of FAs, thus acting as a critical player in FA initiation and maturation. However, the molecular basis of the ABS–F-actin interactions remains unknown. Here, we explore interactions of ABSs with F-actin to understand the multivalent behavior of talin. Particularly, the cryo-EM structure of the F-actin–ABS3 complex at 2.9 Å shows ABS3 spanning through two actin monomers along the filament axis, each occupied by the R13 rod subdomain and the DD domain. The dimerization of ABS3 occurs through the DD domain where both protomers interact on the actin surface, and the dimerization of talin to the actin surface is necessary for the engagement to F-actin. The R13 helical bundle is distorted upon binding to F-actin and releases the H1 helix from the rest of the bundle. This phenomenon has also been observed with other tension-sensing proteins like vinculin and α-catenin, highlighting that unfolding is relevant for its force sensing activity. On the contrary, ABS2 (R4R8 subdomains), which is thought to be critical for the maintenance of mature FAs, had multiple F-actin-binding regions within ABS2 and the binding likely occurred by these subdomains running through the surface of F-actin, thus strengthening the interactions upon the maturation of FAs.

Vibrotactile stimulus duration threshold for perception of pulse to vibration transition

Abstract This study investigates the minimum stimulus duration required to perceive the transition from pulse to vibration sensations, a critical parameter for optimizing information transmission via haptic interfaces such as smartphones, tablets, smartwatches, game consoles, and sensory substitution systems. Efficient transmission relies on minimizing stimulus duration, enabling more information to be conveyed in less time. A preliminary experiment established intensity perception thresholds—the minimum vibration intensities detectable—at 40, 80, 150, 250, 300, and 590 Hz, frequencies primarily activating the Pacinian (Rapid Adapting II) psychophysical channel. Subsequently, 35 participants determined the minimum durations needed to perceive the transition from pulse to vibration sensations across this frequency range. Results revealed a consistent minimum duration of approximately 30 ms, contrasting with findings in audition, where shorter durations suffice at higher frequencies, but aligning with prior studies in tactile perception.

Human MAIT cell response profiles biased toward IL-17 or IL-10 are distinct effector states directed by the cytokine milieu

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that mediate rapid antimicrobial immune responses to antigens derived from microbial riboflavin pathway metabolites presented by the evolutionarily conserved MR1 molecules. MAIT cells represent a large pre-expanded T cell subset in humans and are involved in both protective immunity and inflammatory immunopathology. However, what controls the functional heterogeneity of human MAIT cell responses is still largely unclear. Here, combining functional and transcriptomic analyses, we investigate how MAIT cell response programs are influenced by the cytokine milieu at the time of antigen recognition. Activation by MR1-presented antigen together with IL-12 induces intermediate levels of IFNγ and TNF, as well as a regulatory profile with substantial IL-10 production and elevated expression of TIM-3, LAG-3, and PD-1. Activation by the combination of antigen and IL-12 induces a c-MAF-dependent program required for IL-10 production. The MAIT cell-derived IL-10 mediates both autocrine and paracrine immune regulation. In contrast, coactivation of MAIT cells with IL-18 induces IL-17, GM-CSF, IFNγ, and TNF, without IL-10. Notably, IL-18 dominantly counteracts IL-10 expression. The activation states biased toward IL-10 or IL-17 production are reversible and do not represent stable subsets. Finally, MR1-restricted TCR-mediated activation without cytokine coactivation drives primarily granzyme B cytolytic arming. Altogether, these findings demonstrate that human MAIT cells adapt their functional effector response during antigen recognition to cytokine cues in the microenvironment, and identify programs biased toward either regulatory c-MAF-dependent IL-10 expression, or an inflammatory IL-17 and GM-CSF profile.

Comparative analysis and process optimization for manufacturing CAR-T using the PiggyBac system derived from cryopreserved versus fresh PBMCs

Abstract Chimeric antigen receptor T (CAR-T) therapy holds promise for cancer treatment but faces challenges with using fresh patient cells, including manufacturing failures and logistical hurdles. Cryopreserved peripheral blood mononuclear cells (PBMCs) offer a potential solution, and while lentiviral processes have been reported for generating CAR-T from these cells, few studies have demonstrated successful PiggyBac electroporation methods. Therefore, the objectives of our study were twofold: Firstly, to conduct a comparative study on cryopreserved PBMCs, fresh PBMCs, and their respective preparations of CAR-T. Secondly, to establish a PiggyBac electroporation CAR-T preparation process using cryopreserved PBMCs through process optimization. The results revealed that long-term frozen PBMCs viability in a relatively stable manner. CAR-T generated from cryopreserved PBMCs exhibited comparable expansion potential, cell phenotype, differentiation profiles, exhaustion markers, and cytotoxicity against human ovarian cancer cell line (SKOV-3) cells to those derived from fresh PBMCs. Moreover, through process optimization, we further enhanced the proliferation and toxicity of CAR-T. This approach has the potential to revolutionize the CAR-T production model by utilizing healthy donor cells instead of patient cells. This shift could mitigate issues affecting treatment efficacy, such as suboptimal cell condition following illness or delays in cell preparation.