Browse Articles

Empowering safer socially sensitive autonomous vehicles using human-plausible cognitive encoding

Autonomous vehicles (AVs) will soon cruise our roads as a global undertaking. Beyond completing driving tasks, AVs are expected to incorporate ethical considerations into their operation. However, a critical challenge remains. When multiple road users are involved, their impacts on AV ethical decision-making are distinct yet interrelated. Current AVs lack social sensitivity in ethical decisions, failing to enable both differentiated consideration of road users and a holistic view of their collective impact. Drawing on research in AV ethics and neuroscience, we propose a scheme based on social concern and human-plausible cognitive encoding. Specifically, we first assess the individual impact that each road user poses to the AV based on risk. Then, social concern can differentiate these impacts by weighting the risks according to road user categories. Through cognitive encoding, these independent impacts are holistically encoded into a behavioral belief, which in turn supports ethical decisions that consider the collective impact of all involved parties. A total of two thousand benchmark scenarios from CommonRoad are used for evaluation. Empirical results show that our scheme enables safer and more ethical decisions, reducing overall risk by 26.3%, with a notable 22.9% decrease for vulnerable road users. In accidents, we enhance self-protection by 8.3%, improve protection for all road users by 17.6%, and significantly boost protection for vulnerable road users by 51.7%. As a human-inspired practice, this work renders AVs socially sensitive to overcome future ethical challenges in everyday driving.

Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation

We demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a proinflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.

Imaging a concussion and the ensuing immune response at the blood–brain barrier

Concussions can cause debilitating symptoms despite no evidence of structural changes on diagnostic imaging. The cellular events occurring in the brain parenchyma following concussion, especially repetitive concussion, are not well elucidated. We developed a concussion model to induce a confined area of injury without causing frank hemorrhage. Using intravital microscopy, we observe activation of the vasculature that supported neutrophil rolling and platelet adhesion but no overt cellular recruitment from blood into brain parenchyma. Activated resident, not monocyte-derived, macrophages relocated to the injury site via Cx3cr1 and phagocytosed dysfunctional/detached astrocytes via scavenger receptors and TLR4, particularly after repetitive concussion. Additionally, microglia sealed areas of blood–brain barrier (BBB) disruption via purinergic pathways. Using a splitCre approach to dissect microglia and perivascular macrophages, we show that microglial invasion into the injury site is key to reducing BBB disruption. Our data suggest that microglia repair the BBB following concussion, but in doing so significantly alter the cellular ultrastructure of the brain milieu.

Framework to identify innovative sources of value creation from platform technologies

Platform technologies are fundamentally reshaping the pharmaceutical industry, offering unprecedented potential for innovation across multiple therapeutic areas. However, traditional valuation models, focused on single-asset metrics, struggle to capture the full spectrum of value these technologies create. This paper presents a comprehensive framework for evaluating the innovative sources of value creation enabled by platform technologies throughout the drug development lifecycle. Through a systematic literature review, in-depth case studies, and framework development, we provide a structured methodology for capturing the diverse benefits of these technologies. Our findings reveal that platform technologies generate value across strategic, technical, and adaptive dimensions, requiring a multifaceted valuation approach. The proposed Platform Value Identification across Strategic, Technical, and Adaptive domains Framework defines key value drivers, specifies quantitative assessment metrics, and provides implementation guidance to inform strategic decision-making in research and development investment, portfolio management, and business development. Application of the framework to case studies of Alnylam’s RNAi platform, Genentech’s therapeutic antibody platform, and Moderna’s mRNA platform demonstrates its broad utility and impact potential. By adopting this holistic, data-driven approach, stakeholders can better assess the long-term value and competitive advantages of well-implemented platform technologies, accelerating the development of transformative therapies for patients.

A tethering mechanism underlies Pin1-catalyzed proline <i>cis–trans</i> isomerization at a noncanonical site

The prolyl isomerase Pin1 catalyzes the cis – trans isomerization of proline peptide bonds, a noncovalent posttranslational modification that influences cellular and molecular processes, including protein–protein interactions. Pin1 is a two-domain enzyme containing a WW domain that recognizes phosphorylated serine/threonine-proline (pS/pT-P) canonical motifs and an enzymatic PPIase domain that catalyzes proline cis – trans isomerization of pS/pT-P motifs. Here, we show that Pin1 uses a tethering mechanism to bind and catalyze proline cis – trans isomerization of a noncanonical motif in the disordered N-terminal activation function-1 (AF-1) domain of the human nuclear receptor PPARγ. NMR reveals multiple Pin1 binding regions within the PPARγ AF-1, including a canonical motif (pS112-P113) that when phosphorylated by the kinase ERK2 binds the Pin1 WW domain with high affinity. NMR methods reveal that Pin1 also binds and accelerates cis – trans isomerization of a noncanonical motif containing a tryptophan-proline motif (W39-P40) previously shown to be involved in an interdomain interaction with the C-terminal ligand-binding domain (LBD) of PPARγ. Cellular transcription studies combined with mutagenesis and Pin1 inhibitor treatment reveal a functional role for Pin1-mediated acceleration of cis – trans isomerization of the PPARγ W39-P40 motif. Our data inform a refined model of the Pin1 catalytic mechanism where the WW domain can bind a canonical pS/T-P motif and tether Pin1 to a target, which enables the PPIase domain to exert catalytic cis – trans isomerization at a distal noncanonical site.

Identification of the lydiamycin biosynthetic gene cluster in a plant pathogen guides structural revision and identification of molecular target

The natural products actinonin and matlystatin feature an N -hydroxy-2-pentyl-succinamyl (HPS) chemophore that facilitates metal chelation and confers their metalloproteinase inhibitory activity. Actinonin is the most potent natural inhibitor of peptide deformylase (PDF) and exerts antimicrobial and herbicidal bioactivity by disrupting protein synthesis. Here, we used a genomics-led approach to identify candidate biosynthetic gene clusters (BGCs) hypothesized to produce HPS-containing natural products. We show that one of these BGCs is on the pathogenicity megaplasmid of the plant pathogen Rhodococcus fascians and produces lydiamycin A, a macrocyclic pentapeptide. The presence of genes predicted to make an HPS-like chemophore informed the structural recharacterization of lydiamycin via NMR and crystallography to show that it features a rare 2-pentyl-succinyl chemophore. We demonstrate that lydiamycin A inhibits bacterial PDF in vitro and show that a cluster-situated PDF gene confers resistance to lydiamycin A, representing an uncommon self-immunity mechanism associated with the production of a PDF inhibitor . In planta competition assays showed that lydiamycin enhances the fitness of R. fascians during plant colonization. This study highlights how a BGC can inform the structure, biochemical target, and ecological function of a natural product.

A circuit model for transsaccadic space updating and mislocalization

We perceive a stable, continuous world despite drastic changes of retinal images across saccades. However, while persistent objects in daily life appear stable across saccades, stimuli flashed around saccades can be grossly mislocalized. We address this puzzle with our recently proposed circuit model for perisaccadic receptive-field (RF) remapping in the lateral interparietal area (LIP) and frontal eye fields (FEF). The model uses center-excitation/surround-inhibition connections to store a relevant stimulus’ retinal location in memory as a population activity. This activity profile is updated across each saccade by directional connections gated by the corollary discharge (CD) of the saccade command. The updating is a continuous backward (against the saccade) shift of the population activity (equivalent to continuous forward remapping of the RFs), whose cumulative effect across the saccade is a subtraction of the saccade vector. The model that correctly updates persistent stimuli, and flashes well before and after saccades, produces the observed forward and backward translational mislocalization for flashes around the saccade onset and offset, respectively, because of insufficient and unnecessary cumulative updating after the saccade, caused by visual response latency and sluggish CD time course. We confirm the model prediction that for perisaccadic RFs measured with flashes before the saccades, the forward remapping magnitudes across the saccades are smaller for later flashes. Our work suggests that transsaccadic perception is stable because the presaccadic retinal position of an object is updated to match the postsaccadic (reafferent) retinal position of the same object, and that the brain uses “unaware” decoders which do not distinguish between different origins of neurons’ activities.

Immune perturbation by the ileal microbiota in multiple sclerosis

AI assistance improves people’s ability to distinguish correct from incorrect eyewitness lineup identifications

Mistaken eyewitness identification is one of the leading causes of false convictions. Improving law enforcement’s ability to identify correct identifications could have profound implications for criminal justice. Across two experiments, we show that AI-assistance can improve people’s ability to distinguish between accurate and inaccurate eyewitness lineup identifications. Participants (Experiment 1: N = 1,092, Experiment 2: N = 1,809) saw an eyewitness’s lineup identification, accompanied by the eyewitness’s verbal confidence statement (e.g., “I’m pretty sure”) and either a featural (“I remember his eyes”), recognition (“I remember him”), or familiarity (“He looks familiar”) justification. They then judged the accuracy of the eyewitness’s identification. AI-assistance (vs. no assistance) improved people’s ability to distinguish between correct identifications and misidentifications, but only when they evaluated lineup identifications based on recognition or featural justifications. Discrimination of identifications based on familiarity justifications showed little improvement with AI-assistance. This project is a critical step in evaluating human-algorithm interactions before widespread use of AI-assistance by law enforcement.

Food Rx: Integrating horticulture research to improve nutrition and health

It is clear that the escalating epidemic of insulin resistance and type 2 diabetes has reached a crisis level in the United States, that overweight and obesity are drivers, and that diets and the food system have major roles. It is also clear that nutrition and medical research point to increased healthful fruit and vegetable intake as a key part of any strategy to manage the crisis. But although increasing healthful intake entails both expanding production of fruits and vegetables and improving their healthful characteristics, horticulture has generally been sidelined or taken for granted when strategies are envisioned. This article makes the case that horticulture research and practice can and should be equal partners with nutrition and medicine in the pressing search for effective crisis-management strategies. To do so, it first “runs the numbers” for the scale of the crisis, for trends in fruit and vegetable intake and production, for the scant federal support for horticultural crop production and research, and for horticulture research’s high return on investment. The article then sketches a roadmap to integrate horticulture research and community outreach with nutrition and healthcare, stressing new opportunities. The goal is a US food system that i) makes healthful fruits and vegetables accessible, affordable, and appealing for all and ii) complements a healthcare system spanning patient-based to population-based nutrition.

Little bites out of a big reef problem

Barremian tricolpate pollen from Portugal—New evidence for the age of eudicot-related angiosperms

New evidence on the timing of early angiosperm evolution is presented through the discovery of four well-dated tricolpate pollen grains from the Early Cretaceous midlatitudes. Recovered from nearshore marine sediments in the Lusitanian Basin of Portugal, these fossils significantly expand the pre-Aptian tricolpate pollen record and document a greater number of pre-Aptian tricolpate grains in the midlatitudes than previously recognized. The fossil evidence was obtained through the innovative application of advanced microscopy techniques and was precisely dated through biostratigraphy and strontium isotope stratigraphy on material from the same section. These findings extend the first occurrence of tricolpate pollen to the early late Barremian (~123.0 Ma) in Portugal and possibly worldwide. Our findings provide fossil evidence with minimal dating uncertainty, as both the fossils and their age determination come from the same well-constrained sections, eliminating the need for cross-correlation. This establishes the most reliable age for the first occurrence of tricolpate pollen, unequivocally linked to the eudicot clade—an early derived lineage within angiosperms. These fossils serve as a robust calibration point for phylogenetic studies. Additionally, our study emphasizes the importance of methodological advancements in refining the fossil plant record. The newly applied fluorescence screening method when adapted also in future research could further enhance the detection of rare fossils, offering insights into the diversification of angiosperms.

Multicenter external validation of a nomogram predicting conversion to open cholecystectomy during laparoscopic surgery for acute calculous cholecystitis: a cross-sectional study

Resonant valence bond Coulomb phase: From spins to phonons

Differentiation of canine and feline neoplasms using multi-modal imaging and machine learning

Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer’s disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

Structural and biomedical investigations of novel ruthenium schiff base complexes

Abstract Ruthenium(III) complexes with Schiff base ligands bearing diverse functional groups remain extensively underexplored, despite their promising potential in therapeutic applications. To address this gap, we designed and synthesized a new series of mononuclear octahedral Ru(III) complexes with the general formula [RuL 1–3 ], where L 1 , L 2 , and L 3 are deprotonated Schiff bases derived from functionalized aromatic precursors. These complexes were characterized through a suite of physicochemical and spectroscopic techniques, including FT-IR, 1H-NMR, UV-Vis spectroscopy, mass spectrometry, TGA, and elemental analysis, to confirm their structural features and coordination environment. To complement experimental findings, density functional theory (DFT/B3LYP) calculations were conducted, revealing stable, distorted octahedral geometries and supporting the proposed molecular configurations. Building upon the structural insights, we evaluated the biological activity of the complexes through in vitro cytotoxicity assays against HCT-116 (colorectal), MCF-7 (breast), and HepG2 (liver) cancer cell lines. Among them, RuL 2 exhibited the most potent activity against HCT-116 (IC₅₀ = 4.97 µg/mL), comparable to the standard drug Vinblastine. Finally, molecular docking simulations were employed to investigate the interaction of these complexes with key biological targets from Escherichia coli (PDB IDs: 4BJP and 1BNA), offering further insights into their potential modes of action. Together, these results demonstrate the importance of ligand design in tuning the coordination behavior and bioactivity of ruthenium complexes, highlighting their promise in anticancer and antimicrobial drug development.

The GRAS protein RAM1 interacts with WRI transcription factors to regulate plant genes required for arbuscule development and function

During arbuscular mycorrhiza (AM) symbiosis AM fungi form tree-shaped structures called arbuscules in root cortex cells of host plants. Arbuscules and their host cells are central for reciprocal nutrient exchange between the symbionts. REQUIRED FOR ARBUSCULAR MYCORRHIZATION1 ( RAM1 ) encodes a GRAS protein crucial for transcriptionally regulating plant genes needed for arbuscule development and nutrient exchange. Similar to other GRAS proteins, RAM1 likely does not bind to DNA and how RAM1 activates its target promoters remained elusive. Here, we demonstrate that RAM1 interacts with five AM-induced APETALA 2 (AP2) transcription factors of the WRINKLED1-like family called CTTC MOTIF-BINDING TRANSCRIPTION FACTOR1 (CBX1), WRI3, WRI5a, WRI5b, and WRI5c via a C-terminal domain containing the M2/M2a motif. This motif is conserved and enriched in WRI proteins encoded by genomes of AM-competent plants. RAM1 together with any of these WRI proteins activates the promoters of genes required for symbiotic nutrient exchange, namely RAM2 , STUNTED ARBUSCULES (STR), and PHOSPHATE TRANSPORTER 4 (PT4) , in Nicotiana benthamiana leaves. This activation as well as target promoter induction in Lotus japonicus hairy roots depends on MYCS ( MYCORRHIZA SEQUENCE )-elements and AW -boxes, previously identified as WRI-binding sites. The WRI genes are activated in two waves: Transcription of RAM1 , CBX1, and WRI3 is coregulated by calcium- and calmodulin-dependent protein kinase-activated CYCLOPS, through the AMCYC-RE in their promoter, and DELLA, while WRI5a , b, and c promoters contain MYCS -elements and AW -boxes and can be activated by RAM1 heterocomplexes with CBX1 or WRI3. We propose that RAM1 provides an activation domain to DNA-binding WRI proteins to activate genes with central roles in AM development and function.

Dipteran succession on decomposing domestic pig carcasses in a rural area of southeastern Brazil

Inferring neural population codes for <i>Drosophila</i> acoustic communication

Social communication between animals is often mediated by sequences of acoustic signals, sometimes spanning long timescales. How auditory neural circuits respond to extended input sequences to guide behavior is not understood. We address this problem using Drosophila acoustic communication, a behavior involving the male’s production of and female’s response to long, highly variable courtship songs. Here we ask whether female neural and behavioral responses to song are better described by a linear–nonlinear feature detection model vs. a nonlinear accumulation model. Comparing both models against head-fixed neural recordings and pure-behavioral recordings of unrestrained courtship, we found that while both models could explain the neural data, the accumulation model better predicted female locomotion during courtship, outperforming several alternative predictors. To understand how the accumulation model encoded song to predict locomotion, we analyzed the relationship between neural activity simulated by the model and female locomotion during courtship—this revealed the model’s reliance on heterogeneous nonlinear adaptation and slow integration. Finally, we asked how adaptation and integration processes could cooperate across the model neural population to encode temporal patterns in song. Simulations revealed how adaptation can transform song inputs prior to integration, allowing fine-scale song information to be retained in the population code for long periods. Thus, modeling fly auditory responses as a nonlinearly adaptive, accumulating population code accounts for female locomotor responses to song during courtship and suggests a biologically plausible mechanism for the online encoding of extended communication sequences.