Anatomical fit of the oneKNEE tibia design using statistical shape modeling

Abstract: Modern tibial implants should be designed to achieve an optimal anatomical fit. The aim of this study was to evaluate how well a newly developed tibial implant design (oneKNEE® - B. Braun Aesculap, Tuttlingen, Germany) matches patient anatomy compared to three existing implant systems, using Statistical Shape Models (SSM). SSMs for Caucasian and Asian populations were generated using CT scans of 120 Caucasian and 112 Asian osteoarthritic patients. Border anatomical variations were represented by individual anatomies from 14 Caucasian and 12 Asian patients. Tibial components were positioned in accordance with strict protocols established by senior knee surgeons (YM, NK). The anatomical fit was analyzed across all four implant systems in terms of antero-posterior and medio-lateral dimensions, tibial coverage and cortical bone support. Global tests for homogeneity and Dunnett's tests were performed. Bony coverage for Asian and Caucasian populations ranged from 82.9% to 88.4% for long-established designs and from 85.0% to 91.2% for more recently introduced designs. Among all designs, the oneKNEE® implant demonstrated superior bony coverage and cortical support, followed by Attune® (Depuy-Synthes, Warsaw, IN, USA), Columbus® (B. Braun Aesculap), and PFC Sigma® (Depuy-Synthes). For average anatomies, oneKNEE® showed significantly better bony coverage and cortical score compared to Columbus® and PFC Sigma® (P < 0.01). In less average anatomies, oneKNEE® exhibited statistically superior bony coverage compared to PFC Sigma®, although no significant difference was observed in cortical support. Compared with established tibial implant designs, the new design demonstrated improved virtual anatomical fit and coverage metrics based on computational modeling. These findings reflect a theoretical design‑level improvement and require biomechanical and clinical validation.

Dupraz I
Minoda Y
Kornilov N
Altermann B
Hauff P
Bollinger A
Richter B
Grupp TM

Humans
Tibia
Prosthesis Design
Models, Statistical
Tomography, X-Ray Computed
Female
Male
Asian People
White People
Aged
Knee Prosthesis
Middle Aged
Arthroplasty, Replacement, Knee
Osteoarthritis, Knee
Models, Anatomic


Spatial atlas of the human brain vasculature reveals specialized cell ensembles

Abstract: The brain vasculature comprises diverse specialized cells that are essential for brain function, yet their spatial organization remains poorly understood. Here, we construct a comprehensive cerebrovascular cell atlas encompassing 314,535 transcriptomes that captures the arteriovenous axis and defines consensus cell states. We then perform spatial transcriptomics to map 1,529,740 cells across the human temporal cortex and hippocampus, uncovering stereotyped micro-communities termed vascular cell ensembles. These ensembles comprise specialized subsets of endothelial cells, mural cells, fibroblasts, and perivascular macrophages that align with the arteriovenous architecture to coordinate segment-specific functions, such as neurovascular coupling, blood-brain barrier transport, and immune surveillance. By overlaying genetic risk and pharmacologic reactivity, we identify ensemble-specific susceptibilities and candidate therapeutic targets across neurological diseases, including small vessel disease and stroke. This study provides a resource to dissect the spatial and functional logic underlying human cerebrovascular biology and establishes a blueprint for decoding neurological disease susceptibility and therapeutic response.

Wang JC
Sanchez D
Arul S
Gülsuyu B
Gopinadhan A
Mukhtar T
Kim J
Andrews JP
Alonso Cee Williams M
Jung Y
Hashimoto ML
Kim CN
Bhalla S
Ewing-Crystal NA
Bernabei JM
Letchuman V
Haddad AF
Hemphill K
Weinsheimer SM
Kim H
Narsinh KH
Cooke DL
Cadwell CR
Wälchli T
Elahi FM
Yang AC
He P
Chang EF
Molofsky AB
Winkler EA


Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection

Abstract: Amino acid levels fluctuate across diverse pathological conditions. Whether such amino acid modulations directly shape pathophysiology by regulating host gene expression remains unknown. We found that extracellular arginine restriction, observed in cancer and infection, represses specific arginine tRNAs-directly suppressing translation of major histocompatibility complex I (MHC class I) and antigen presentation. Arginine regulation of MHC class I was codon-usage dependent, as synonymous codon mutations prevented MHC class I modulation. Dietary arginine restriction impaired anti-viral immunity against influenza and SARS-CoV-2 and increased colon tumorigenesis. Conversely, increasing arginine availability via dietary supplementation or myeloid-specific arginase 1 deletion enhanced MHC class I protein levels, suppressed colon tumorigenesis, and improved viral infection outcomes. These disease-modulating effects were abolished in β2-microglobulin (B2m)-deficient mice. Thus, dietary modulation of a single amino acid critically influences codon-biased translation and MHC class I-mediated immunity to respiratory viral infections and cancer, revealing an unexpected mechanism and disease hazard for arginine deficiency and highlighting potential for amino acid-based translation modulation therapy.

Wu Q
Seydlitz LM
Iakimov V
Hsu DJ
Habibzadeh P
Hoffmann HH
Paty PB
Rice CM
Tavazoie SF


Basement membrane turnover controls cell shape

Abstract: The regulation of 3D cell shape is a fundamental problem of life. In multicellular tissues, cell shape emerges through the balance of forces inside and outside the cell. In epithelia, the basement membrane (BM) is the first extracellular barrier that cells sense biochemically and mechanically. Despite this, little is known about how BM mechanical properties are regulated and how they impact cell shape. Through mathematical modeling, we show that the stress relaxation time of the BM can regulate cell shape. Using molecular dynamics simulations, we show that the stress relaxation time of a collagen IV network can be inferred from the lifetime of collagen IV molecules. To measure collagen IV lifetime in vivo, we develop a fluorescent timer reporter for collagen IV and show that perlecan modifies collagen IV lifetime. This cross-disciplinary approach establishes a multiscale framework to probe matrix turnover, and its regulation and function in cell shape control.

Barrientos R
Meadowcroft B
Sánchez-Sánchez BJ
Stramer BM
Paluch EK
Charras G
Banerjee S
Šarić A
Mao Y


Gasdermin E couples viral pyroptosis to lethal hepatic lipid accumulation

Abstract: Tick-borne orthonairoviruses, including the emerging wetland virus (WELV), pose a growing public health concern as cases increase, yet their pathogenesis remains unclear. Here, we show that WELV infection causes fatal liver dysfunction in patients, characterized by elevated hepatic enzymes, triacylglycerol accumulation, and hyperinflammation. WELV induces gasdermin E (GSDME)-dependent pyroptosis in hepatocytes through mitochondrial and Fas-mediated apoptotic pathways. Viral RNA activates RIG-I/CASP3-mediated GSDME cleavage, while viral nucleoprotein undergoes CASP3-dependent processing, forming a negative regulatory feedback loop. GSDME directly interacts with fatty acid synthase (FASN) and blocks K48-linked ubiquitination to inhibit FASN degradation, driving lipid metabolic reprogramming and lethal hepatic steatosis. GSDME knockout abolishes pyroptosis and metabolic dysregulation, conferring complete protection against WELV infection. Clinically approved caspase and FASN inhibitors mitigate liver pathology and improve survival in WELV-infected mice. These findings establish a pyroptosis-metabolism axis driving orthonairovirus pathogenesis, highlighting GSDME as a critical determinant of liver injury and a promising target for antiviral therapy.

Wang C
Zheng X
Zhang Y
Shang X
Qu Q
Li C
Zhang X
Jin N
Liu W
Li H


CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer

Abstract: Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8+ T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8+ T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.

Chen ACY
Ji KY
Yerinde C
Knudsen NH
Bi K
Hao S
Zhabotynsky V
Martinez D
Carmona-LaSalle TJ
Taguchi K
Xu KH
Seider EM
Schwartz MA
Zschummel M
Nieman LT
Yates KB
Gazzaniga FS
Miller BC
Mempel TR
Manguso RT
Hacohen N
Sen DR


Why machines don't speak biology: Toward native biological language models

Abstract: Recent advances in AI inspire visions of universal models of biology. Yet living systems are evolved, emergent processes whose behaviors cannot be inferred from their parts alone. We propose grounding AI in canonical biological processes, constructing data-driven world models with explicit mechanistic links across molecules, cells, and their dynamics in space and time.


Coordinated RNA- and protein-templated synthesis of double-stranded DNA by a dual reverse transcriptase immune system

Abstract: Defense-associated reverse transcriptase (DRT) systems mediate antiviral immunity through distinct modes of cDNA synthesis: class 1 DRTs catalyze untemplated synthesis, whereas class 2 DRTs polymerize non-coding RNA-templated products. However, how these distinct modes drive defense remains unclear. Here, we report that DRT3 immunity arises when class 1 and class 2 RT activities cooperate to produce self-complementary double-stranded DNA (dsDNA). DRT3a uses a 5'-ACACAC-3' RNA template to synthesize poly-(dTdG) repeats, whereas DRT3b synthesizes poly-(dCdA) repeats without any nucleic acid template. Cryo-electron microscopy reveals that DRT3b forms a hexamer and uses active-site-adjacent residues as deoxyadenosine and deoxycytidine gates to enforce alternating nucleotide addition, representing a unique example of amino-acid-templated DNA polymerization. DRT3 is toxic in cells lacking RecBCD, implicating host recombination machinery in limiting dsDNA accumulation, and the phage-encoded RecBCD inhibitor Gam triggers DRT3-mediated abortive infection. These findings reveal how two polymerases with distinct templating strategies generate complementary DNA for antiviral defense.

Wang M
Yoneyama K
Žedaveinytė R
Ishikawa J
Tang S
Le HC
Wiegand T
Ramirez JL
Nagahata N
Ma Y
Zhang DJ
Helmeczi E
Berisa M
Jovanovic M
Hiraizumi M
Yamashita K
Nishimasu H
Sternberg SH


Advancing cancer detection and treatment using longitudinal routine clinical data

Abstract: Cancer management remains fragmented across its continuum, from late-stage diagnosis and salvage therapies to non-personalized surveillance. Here, we present Oncoformer, a unified multimodal transformer model trained on the China Oncology Multimodal Prediction and Surveillance Study (COMPASS) cohort (3.67 million individuals, 17.7 million clinical visits) and validated on independent external cohorts, including the UK Biobank. Oncoformer integrates longitudinal electronic health records with chest X-ray imaging to address multiple clinical tasks: pan-cancer diagnosis (area under the receiver operating characteristic curve [AUROC] = 0.956), future cancer prediction up to 1 year before diagnosis (AUROC = 0.869), tumor stage inference (mean AUROC > 0.90), patient-specific treatment-response forecasting, and recurrence-free survival stratification across ten cancer types (all p < 0.01). Staging predictions were independently validated against postoperative pathological endpoints and shown to converge on core cancer genomic pathways. By translating routine clinical data into a dynamic view of cancer evolution, Oncoformer provides a framework for risk-informed cancer prediction and treatment stratification using routine clinical data.

International Consortium of Digital Twins in Healthcare and Medicine


UniPert-G2CP bridges genetic and chemical screens from molecular representation to phenotype modeling

Abstract: Systematically simulating and predicting phenotypic effects of diverse interventions across heterogeneous cellular environments is central to the vision of artificial intelligence virtual cell (AIVC). However, disparities in perturbagen modalities, assay formats, and data production efficiency hinder unified modeling and analysis of genetic and chemical screens. This study presents UniPert-G2CP, a two-stage deep learning framework that bridges genetic and chemical screens by unifying multimodal molecular perturbagen (cause) representations and enabling genetic-to-chemical perturbation phenotype (effect) transfer learning. Validated on large-scale genetic and chemical screening datasets, UniPert-G2CP enables more efficient, accurate, robust, interpretable, and generalizable simulation of multicellular and multidomain perturbation cause-effect spaces. Further joint analysis of these spaces reveals cellular heterogeneity underlying drug responses, providing mechanistic insights into drug action and resistance. Collectively, UniPert-G2CP advances universal biological causal modeling, accelerates AIVC realization, and expands the potential of AI-powered precision medicine.

Li Y
Zeng M
Zhu J
Liu L
Wang F
Huang L
Yang F
Li M
Yao J


Dynamic dimer-of-dimers architecture defines Mg(2+) transport in human CNNM4

Abstract: Mg2+ is essential for all living organisms, yet its transport across mammalian membranes remains poorly understood. Here, we present cryoelectron microscopy (cryo-EM) structures of a full-length mammalian Mg2+ transporter on the plasma membrane, human CNNM4, in outward-facing and occluded states, revealing an unexpected tetrameric assembly organized as a dimer of asymmetric dimers-distinct from the symmetric dimers in prokaryotic homologs and long assumed for eukaryotic CNNMs. We show that Mg2+/ATP binding stabilizes the dynamic intracellular domains and promotes tetramerization, while an acidic patch binds additional Mg2+, potentially acting as a sensor to couple cytoplasmic Mg2+ levels to transport activity. Within the transmembrane domain, a key glutamate flips upon Na+ binding and destabilizes the Mg2+-binding site in the outward-facing state, thereby promoting Mg2+/Na+ exchange. Together, these findings establish a mechanistic framework for CNNM transport and regulation that diverges from prokaryotic models and links CNNM function to human physiology and disease.


An Oryza orphan gene confers trans-species drought tolerance

Abstract: Drought threatens crop productivity, yet enhancing tolerance often compromises yield. Abscisic acid (ABA) signaling is central to drought response, but its deep conservation can constrain adaptive flexibility. Here, we identify ROAD1 (rice orphan gene adapted for drought 1), an Oryza-specific orphan gene that confers robust drought tolerance without obvious growth defects under normal conditions. ROAD1 originated from Oryza meridionalis, and its functional allele, ROAD1C, was selected during japonica domestication. In field trials, elite rice lines carrying ROAD1C exhibited up to 34.75% higher grain yield than corresponding controls under drought. Mechanistically, ROAD1 bypasses the canonical ABA receptor-ligand complex by binding the phosphatase OsPP2C68, preventing sucrose non-fermenting 1-related protein kinases 2 (SnRK2) dephosphorylation and activating downstream responses. ROAD1 also interacts with protein phosphatase 2C (PP2C) orthologs from maize, wheat, and Arabidopsis, and heterologous expression of ROAD1C enhances drought tolerance in Arabidopsis, rapeseed, maize, wheat, and poplar. These findings reveal that an Oryza-specific orphan gene can co-opt conserved signaling for potential trans-species drought tolerance.

Tu H
Liu Q
Ye T
Ye Y
Feng X
Shen L
Li S
Bai S
Liu X
Liu X
Wang H
Li X
Lin J
Wang H
Chen Y
Feng Z
Ji B
Ding J
Li W
Zhang J
Dai M
Dong F
Hu H
Tang N
Lai X
Xiong H
Xiong L


Trichoderma swollenin activates AtABCB5-dependent auxin efflux to promote plant development

Abstract: The beneficial fungus Trichoderma enhances plant growth and stress tolerance through poorly understood mechanisms. Here, we show that Trichoderma harzianum swollenin ThSWO contributes to efficient root colonization and plant growth promotion. ThSWO traverses the plant cell wall and localizes to the plasma membrane, where it interacts with ABC transporter AtABCB5, which we establish as a bona fide auxin efflux carrier. ThSWO binding to NBD2 and R-domain faces of AtABCB5 prosmotes phosphorylation at Ser640 and Ser644, enhancing indole-3-acetic acid (IAA) efflux and triggering auxin-associated responses, including cell wall acidification, membrane potential transitions, and accelerated cytoplasmic streaming. Structure-guided substitutions at the AtABCB5-ThSWO interface differentially affected transporter binding and lateral root promotion, supporting the conclusion that host auxin transport is a primary effector target. These findings reveal a molecular mechanism by which a fungal effector co-opts host auxin transport machinery to promote plant development, with implications for microbe-assisted crop improvement.

Lu J
Liu J
Jiang S
Xu Y
Yan Z
Li L
Zhang F
Chen W
Xu D
Li Y
Liu B
Raza W
Xuan W
Liu D
Shen Q


Bacteriophage genome-wide transposon mutagenesis

Abstract: Bacteriophage genomes are densely packed with coding sequences and frequently encode genes of unknown function. Unbiased phage functional genomics approaches are therefore needed, particularly for large lytic phages. Here, we harness the mariner transposase to develop phage transposon mutagenesis and sequencing (phage TnSeq), which enables pooled sequencing to identify both fitness-conferring and dispensable genes. Using the Pseudomonas aeruginosa-infecting nucleus-forming jumbo phage ΦKZ (280,334 bp; 371 predicted genes), we show that ∼110 genes are fitness-conferring via phage TnSeq, identifying many known and previously unknown essential genes. Moreover, this phage harbors ∼261 non-essential genes, including some capsid and tail proteins, many of which are important for fitness across different clinical isolates or conditions. Phage TnSeq was also extended to a base-modified phage. Together, phage TnSeq is a scalable technology that can identify essential phage genes, generate knockouts in all non-essential genes, and sensitively assign the quantitative fitness contributions of every gene in parallel.

Chan A
Yee WX
Mozumdar D
Kokontis C
Rojas-Montero M
Liu M
Yang Y
Yuping L
Bondy-Denomy J

DNA Transposable Elements
Genome, Viral
Bacteriophages
Pseudomonas aeruginosa
Mutagenesis


Auxin signaling

Abstract: Following its discovery nearly a century ago, the signaling molecule auxin has captured the interest of plant scientists. Mostly through genetics, key components of the auxin response were identified, and these were rapidly connected in a topologically simple nuclear auxin pathway (NAP). While the identification of the NAP established a coherent framework for transcriptional auxin response, recent years have seen a remarkable series of advances in the evolution, mechanisms, and regulation of NAP components that shed new light on auxin response. Furthermore, it has long been known that auxin triggers both rapid and slow responses, but success in NAP characterization has eclipsed insights into rapid responses. Recently, a paradigm for rapid responses has emerged. This involves widespread protein phosphorylation, new roles for NAP components, and a set of contentious, yet resurrected, extracellular auxin-binding proteins. Here, we present recent progress in auxin responses, reflect on their historical context, and formulate a set of pertinent questions for the field.

Chu J
Ang ACH
de Roij M
Strader L
Xu T
Weijers D

Indoleacetic Acids
Signal Transduction
Phosphorylation
Plant Proteins
Gene Expression Regulation, Plant
Plant Growth Regulators
Arabidopsis
Arabidopsis Proteins


Do autoantibodies shape cancer immunosurveillance?

Abstract: Why cancer arises, progresses, or proves fatal in some people but not others remains largely unresolved. Antibody repertoires, including autoantibodies targeting immune pathways, may shape cancer immunosurveillance. Mapping antibody landscapes across cancer-free, at-risk, and cancer-affected individuals could clarify their roles in cancer susceptibility and disease outcome.

Bastard P
Hulett T
Smith-Byrne K
Landegren N
Mogensen TH
Fellay J
Travis RC
Casanova JL
Dang CV
Lu X

Humans
Neoplasms
Autoantibodies
Animals
Immunologic Surveillance


The silicon citizen naturalist

Abstract: Smartphone-wielding citizen scientists and an AI called FLORIST are transforming ecology at the continental scale. In this issue of Cell, when Tibbs-Cortes et al. pair the crowdsourced data with controlled genetics, they discover how switchgrass times its flowering to outwit both frost and heat, depending on latitude.


UTR-ly unexpected: RNA chaperones tame intrinsically disordered proteins

Abstract: How do cells ensure that complex, multidomain proteins fold correctly? Luo et al. reveal a self-contained solution. The 3' UTR of an mRNA co-translationally chaperones the protein it encodes, preventing intrinsically disordered regions from making inappropriate contacts. This functionality, localized to mesh-like condensates, challenges Anfinsen's dogma and opens therapeutic possibilities.

Molecular Chaperones
Intrinsically Disordered Proteins
3' Untranslated Regions
Humans
Animals
Protein Folding
RNA, Messenger


The intrinsic cardiac nervous system is essential for cardiac function and survival

Abstract: The intrinsic cardiac nervous system (ICNS) is a key node in heart-brain communication and an emerging target for cardiac therapy, yet its physiological importance and functional organization remain poorly understood. Here, we show that the ICNS is essential for cardiac performance and survival across conditions. Using integrated genetic and imaging approaches in mice, we identify two molecularly distinct intrinsic cardiac neuron (ICN) subtypes that differ in extrinsic inputs, projection architectures, and physiological roles. Npy⁺ ICNs preferentially receive vagal input and mediate parasympathetic control of heart rate and coronary perfusion, and their ablation leads to fatal cardiac failure. By contrast, Ddah1⁺ ICNs receive sympathetic input and are required to preserve electrical stability and prevent sudden cardiac arrest under extreme physiological or psychological stress, with their activation providing cardioprotection. Together, these findings establish the ICNS as a critical regulator of cardiac function, providing a framework for precise, cell-type-targeted neuromodulatory therapies.

Xu QJ
Applegate MC
Hsu IY
Kogan RP
Hafez OA
Wang RL
Rios Coronado PE
Young LH
Zeng X
Zhang L
Chang RB


Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development

Abstract: Genes that define cell identity are often highly transcribed, but how their activity is regulated to prevent pathological dysregulation remains elusive. Using a two-tiered genetic screen, we identify a network of genes regulating hypertranscribed loci, which is notably enriched for genes mutated in developmental disorders. Among these, ANKRD11, a chromatin regulator haploinsufficient in KBG syndrome, exerts progressively stronger repression on more highly transcribed genes. ANKRD11 enriches around hypertranscribed loci and forms biomolecular condensates via charge-block-patterned intrinsically disordered regions. These condensates spatially sequester elongation factors away from RNA polymerase II, thereby restricting transcription elongation. In mice, Ankrd11 loss abrogates this restriction, causing aberrant developmental gene activation, disrupted organogenesis, and embryonic lethality. Critically, KBG patient cells with ANKRD11 mutations show defective condensate formation and consequent overactivation of hypertranscribed genes. These results uncover a condensate-mediated mechanism that restricts hypertranscribed genes and suggest its disruption underlies developmental disorders such as KBG syndrome.

Zhang T
Li X
Zhou W
Li ZL
Bi J
Ma X
Li X
Fan Y
Hong Y
Wang S
Wang Y
Yang L
Chen Y
Qin W
Wang H
Xi Q
Shi S
Liu N


Expanding the scope of protein language modeling to protein-protein interactions with MSA Pairformer

Abstract: Protein-protein interactions underlie biological complexity, and modeling their coevolution is essential for characterizing and engineering molecular assemblies. While protein and genomic language models have excelled at modeling individual proteins, extending these capabilities to protein complexes remains challenging. We present multiple sequence alignment (MSA) Pairformer, a protein language model that builds on AlphaFold2/3's bidirectional refinement between sequence and pairwise residue representations to accurately model the evolution of protein-protein interactions, despite training exclusively on individual chains. MSA Pairformer achieves nearly 3-fold improvement over existing methods in predicting protein-protein interface contacts and better distinguishes binding from non-binding sequences. A learned attention mechanism selectively weights sequences by their inferred evolutionary relevance, enabling discovery of subfamily-specific contacts. On single-protein benchmarks, it achieves state-of-the-art contact prediction and strong variant effect prediction using only 111 million parameters, over two orders of magnitude smaller than frontier models. These results offer an evolutionarily grounded, computationally efficient alternative to the scaling paradigm.

Akiyama Y
Zhang Z
Tang O
Kim RS
Mirdita M
Steinegger M
Ovchinnikov S


Localized PD-1 CAR T therapy reprograms neuroinflammation

Abstract: B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

Shalita R
Ben Yehuda M
Gur C
Frid Y
McGrath S
Suhler R
Bolokan L
Eisenberg V
Eshed RS
Shlomi-Loubaton S
Tofield A
Vardy K
Zada M
Kurilovich A
David E
Jaitin D
Mazuz K
Avellino R
Tzemach R
Kuznetsov Y
Fellus-Alyagor L
Levy-Barda A
Mundt S
Rosenzweig R
Schreiner B
Peters A
Stadelmann C
Zwicky P
Yarkoni AW
Ingelfinger F
Amit I


CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics

Abstract: Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid space (SAS) to the nasal mucosa and identified a discrete arachnoid region surrounding the olfactory bulbs with abundant fenestrations. Similar arachnoid fenestrations were found in cynomolgus monkeys. Fluorescent tracers in the SAS passed through arachnoid fenestrations into dural lymphatics, which traversed the cribriform plate foramina, joined the nasal lymphatics, and drained to the cervical lymph nodes. In aged mice, the known reduction in CSF outflow was accompanied by lymphatic atrophy in the olfactory dura and nasal mucosa and by fewer arachnoid fenestrations and smaller cribriform plate foramina. Importantly, the lymphatics and CSF clearance were restored to normal by intranasal delivery of vascular endothelial growth factor-C (VEGF-C), thereby documenting the reversibility of the aging-related impairment in CSF clearance.

Hong SP
Jin C
Yang MJ
Jin H
Yoon JH
Choi DR
Jung J
Yuk CM
Antila S
Seo SJ
Admasu LA
Seo J
Lim KS
Chung WS
Alitalo K
McDonald DM
Koh GY


A domestication-selected enhancer coordinates source-sink balance to improve harvest index and yield in maize

Abstract: Crop yield is fundamentally determined by the harvest index, the proportion of photosynthates allocated to grain. However, its genetic and evolutionary basis remains elusive. Here, we show that the maize harvest index increased by 81% during domestication. A major locus, Harvest Index1 (HI1), contributes to this divergence and is controlled by a 9.1-kb presence/absence variation. This insertion acts as a distant enhancer to boost the expression of the downstream B-type response regulator BRR1 and was fixed by selection. Mechanistically, the transcription factor CONZ1 binds to both the HI1 enhancer and the BRR1 promoter, recruiting the acetyltransferase General Control Nonrepressed 5 (GCN5) to form a chromatin loop that enhances BRR1 expression. BRR1 directly activates genes involved in carbon and nitrogen metabolism and transport, promoting source-to-sink allocation to increase harvest index and grain yield even under nitrogen-limiting conditions. Our findings elucidate a key domestication-selected regulatory module that coordinates resource allocation, providing a strategic target for sustainable crop improvement.

Guo L
Xia J
Tang J
Zhang M
Chen T
Han X
Liu S
Wang X
Wu L
Tian F


Viral protease-initiated lytic cell death as a universal antiviral mRNA therapy

Abstract: While gasdermin (GSDM)-mediated pyroptosis is a potent immune effector, its antiviral potential remains largely untapped. Here, we introduce viral protease-initiated lytic cell death (VID), a universal mRNA therapeutic platform inspired by the modular architecture of GSDM and the clinical success of mRNA vaccines. By engineering gasdermin-D (GSDMD) to harbor viral protease-specific cleavage motifs, we generated VID activators (VIDAs) that selectively trigger lytic cell death in virus-infected cells. Using hepatitis A virus (HAV) as a model, lipid nanoparticle (LNP)-encapsulated VIDA mRNA abolished viral replication and shedding in vivo and mitigated liver injury through a coordinated "kill-and-alert" mechanism that primes bystander immunity. The platform's versatility was further demonstrated against Zika virus (ZIKV) and SARS-CoV-2. Leveraging a generative artificial intelligence (AI) framework, we designed de novo cleavage motifs for the SARS-CoV-2 main protease, yielding optimized VIDAs with superior antiviral potency. Collectively, our study establishes VIDA mRNA as a versatile, broadly applicable strategy for combating diverse viral threats.

Li L
Yan XL
Wang HY
Zhou HY
Li YY
Ma W
Li J
Zhang RR
Lv L
Huang XY
Du H
Cao TS
Ye Q
Zhao H
Fu Y
Kang BH
Ding Q
Wu A
Huang YJ
Qin CF


A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death

Abstract: Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

Nix MN
Gourisankar S
Bowman KJ
Nettles SA
Yang H
Dwyer BG
Sarott RC
Abuzaid H
Martinez MM
Phillips N
Cabaud V
Hakobyan A
Arakelov V
Petrosyan G
Davtyan A
Wang Y
Simanauskaite JM
Romero BA
Jones HM
Krokhotin A
Lowensohn TN
Chen L
Low C
Vogel H
Davis MM
Fernandez D
Zhang T
Green MR
Hinshaw SM
Gray NS
Crabtree GR


Robust regulatory interplay of enhancers, facilitators, and promoters in a native chromatin context

Abstract: Enhancers are abundant and critical gene-distal cis-regulatory elements with distinct architectural features; however, a mechanistic understanding of their interactions within endogenous chromatin contexts remains challenging. Here, we developed a recombinase-mediated genome-rewriting platform to explore how a long-range human enhancer, eNMU, confers a remarkable 10,000-fold activation of its target gene, Neuromedin U (NMU), at its native locus. Our systematic dissection reveals two functionally distinct sub-elements of eNMU: the canonical autonomous enhancer e1 and the intrinsically inactive facilitator e2, which dramatically augments e1's activity. The autonomous enhancer e1 is functionally hierarchical to e2, additional facilitators, and the NMU promoter across the ∼100-kb NMU-eNMU region, and it orchestrates the formation of a 3D regulatory hub. e1 also harbors a bipartite structure: a divergently transcribed retroviral long terminal repeat (LTR) enhancer and an adjacent LTR promoter that dampens NMU expression. We explore and discuss the broader implications of our focused study for understanding enhancer regulatory mechanisms genome-wide.

Zhou Z
Cheng Y
Lieberth J
Zhang J
Jin Y
Li A
Yu H
Ozer A
Lis JT


Skin-innervating glutamatergic neurons modulate aging

Abstract: Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2+) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen, frequently contact Nefh+ nerve fibers. Moreover, Nefh deletion in Vglut2+ glutamatergic neurons drives skin fibroblast senescence and collagen loss, whereas additional glutamate improves skin aging phenotypes. Mechanistically, cyclin-dependent kinase 5 (Cdk5) interacts with both Nefh and Vglut2 and maintains glutamate release and collagen homeostasis. Additionally, in skin fibroblasts, solute carrier family 1 member 3 (Slc1a3) governs the collagen-promoting and anti-senescence functions of glutamate. Together, these findings reveal Nefh-mediated glutamatergic neuromodulation of skin aging and provide therapeutic targets for aging-related skin disorders.

Wang Z
Jin X
Wu Y
Ding W
Zhang F
Sun Y
Lou F
Bai J
Yang X
Zhou H
Liang J
Cai X
Li Y
Zheng X
Han J
Tong F
Yang Q
Fang Z
Zhao L
Shen Q
Xu Z
Deng S
Fan L
Tong J
Tong L
Wang J
Gao M
Fang Z
Li Q
Chen R
Huang L
Li Z
Yang Y
Zou J
Wu Y
Zhang X
Wang H


Boron-bridged GIPCs stabilize cell wall anchoring and PIN polar domains

Abstract: Boron (B) is an essential plant micronutrient whose deficiency impairs global crop yields. Glycosylinositol phosphorylceramides (GIPCs) are major lipids in the plasma membrane (PM), and PIN-FORMED (PIN) proteins mediate polar auxin transport (PAT) via asymmetric PM localization. This study demonstrates that these components are functionally linked: B cross-links nearly all GIPC series, forming physical PM-cell wall attachments visualized as Hechtian strands. B-mediated cross-linking also restricts PIN2 lateral diffusion and endocytosis, stabilizing its polar domain formation via direct GIPC-PIN2 interaction. Phenotypic evidence supports this mechanism, as both B deficiency and impaired GIPC biosynthesis phenocopy high-order pin mutants, showing defective PIN localization and diminished auxin maxima. Thus, the B-dependent, GIPC-mediated PM-cell wall continuum immobilizes PIN polar domains, enabling PAT and ensuring proper plant development and environmental adaptation.


Whole-transcriptome-scale isoform-resolved spatial imaging of single cells in tissues

Abstract: Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved transcriptomic analysis of single cells with high spatial resolution. Here, we introduce an in situ RNA amplification method and its integration with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to detect short RNA sequences and enable whole-transcriptome-scale, isoform-resolved spatial transcriptomics of individual cells in intact tissues. Using this approach, we imaged ∼33,000 distinct RNAs-including ∼23,000 genes and ∼10,000 isoforms-in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed rich spatial diversity and cell-type specificity in isoform usage across numerous genes, as well as brain structures particularly rich in isoform specificity. We anticipate broad application of this method for characterizing the molecular and cellular basis of tissue functions, unlocking previously inaccessible discoveries in cell and organismal biology.

Cohen L
Halpern AR
Blosser TR
Che ZP
Pan X
Zhuang X


Spatial proximity sequencing maps developmental dynamics in the germinal center

Abstract: Spatial profiling of proteins and protein interactions facilitates understanding of cell functions within tissues and is essential for studies in signaling, immunity, and cancer. We present spatial proximity sequencing (Sprox-seq) for simultaneous profiling of surface proteins, protein complexes, and mRNAs, recording the tissue location of each molecule. Sprox-seq profiled 32 proteins, 528 pairwise interactions, and thousands of mRNAs with spatial resolution across human tonsils and germinal centers. Mapping tissue-wide protein interactions recapitulated RNA-defined tissue architecture but also revealed higher interaction complexity in the light zone. Protein-interaction trajectories uncovered a B cell state transition distinct from that inferred by RNA. Integrated protein-complex and mRNA analysis related spatially enriched complexes with mitotic pathways. Sprox-seq captured cell-cell interactions, such as B cell-follicular dendritic cell interactions mediated by the receptor complex VLA-4-VCAM1. Sprox-seq provides a spatially resolved multi-modal view of cell states and an integrated study of protein and cellular interactions across tissues.

Wang H
Xia J
Rahman PMSM
Keisham B
Padhi A
Deng Y
Li Y
Vistain L
Kim S
Mercado-Vásquez G
Khan AA
Clark MR
Tay S


A spliceosome-independent eukaryote generated by complete intron removal

Abstract: Spliceosomal introns impose a universal processing burden on eukaryotes and obstruct genome minimization because their essentiality remains unresolved. By exploiting Spo11-independent meiosis in synthetic single-chromosome Saccharomyces cerevisiae, the complete deletion of all 300 spliceosomal introns was achieved, generating an intron-free strain, SYNE27α. Whole-genome sequencing confirmed precise excision. Unexpectedly, spliceosomal components (all five small nuclear RNAs [snRNAs], Prp8, Prp9, Prp19, Yhc1, and Luc7) were no longer required for viability, demonstrating that a eukaryotic cell can exist independently of spliceosomal function. U3 small nucleolar RNA (snoRNA) splicing bypassed the requirements for Yhc1, Luc7, Prp9, and Prp19, revealing a mechanistic divergence from pre-mRNA splicing. Cumulative intron loss caused slow growth via ribosomal dysregulation, yet SYNE27α maintained genetic stability. Fitness costs were fully recessive in diploids, confirming intron loss as the primary driver. These findings establish an intron-free, spliceosome-independent eukaryote, resolving the essential function of the spliceosome and enabling minimal-system studies of genome evolution.

Man X
Zhang WT
Zhang YD
Li QX
Dai P
Jiang W
Zhou JQ

Introns
Spliceosomes
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
RNA Splicing
Meiosis


Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies

Abstract: Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.

Alzheimer Disease
Humans
Animals
Apolipoproteins E
Plaque, Amyloid
Amyloid beta-Peptides


Bridging omics and physiology to build multimodal clocks of human aging

Abstract: Human aging is a heterogeneous, multi-system process that spans molecular, tissue, and physiological decline. In this issue of Cell, Li et al. integrate clinical data, multi-omics, and organ-associated signatures to construct a multi-layer framework for quantifying biological aging across scales.


Rewriting Duchenne muscular dystrophy therapy

Abstract: In this issue of Cell, Guo et al. report the development of a new exon-skipping, RNA-editing-based therapy for Duchenne muscular dystrophy. The dual mechanism of action through both ADAR-dependent and -independent pathways has the potential to be more effective and require a lower dosing frequency than currently available ASO-based exon-skipping treatments.

Muscular Dystrophy, Duchenne
Humans
Exons
RNA Editing
Animals
Adenosine Deaminase
Genetic Therapy
RNA-Binding Proteins
Oligonucleotides, Antisense


Photosynthetic medicine: Engineering a plant-derived nanofoundry to power mammalian cells

Abstract: Mammalian eyes receive constant visible light yet lack photosynthesis. Xing et al. engineer an intact thylakoid grana nanoparticle enabling light-driven NADPH production within corneal cells, restoring antioxidant defenses and interrupting inflammatory cycles in dry eye disease. This work positions borrowed photosynthesis as a therapeutic strategy for oxidative, light-exposed tissue pathologies.

Photosynthesis Animals Humans Thylakoids NADP Nanoparticles


Map of spiking activity underlying change detection in the mouse visual system

Abstract: Visual behavior requires coordinated activity across hierarchically organized brain circuits. Understanding this complexity demands datasets that are both large-scale (sampling many areas) and dense (recording many neurons in each area). Here, we present a database of spiking activity across the mouse visual system-including the cortex, thalamus, and midbrain-while mice perform an image change detection task. Using Neuropixels probes, we record from >75,000 high-quality units in 54 mice, mapping area-, cortical-layer-, and cell-type-specific coding of sensory and motor information. Modulation by task engagement increased across the thalamocortical hierarchy but was strongest in the midbrain. Novel images recruited an expanded cortical population and modulated late cortical (but not thalamic) responses. Population decoding and optogenetics identified a critical time window for change detection and were consistent with mice using an adaptation-based rather than image-comparison strategy. This comprehensive resource provides a valuable substrate for understanding sensorimotor computations in neural networks.

Bennett C
Gale SD
Heller G
Ramirez TK
Belski H
Piet A
Zobeiri O
Amster A
Arkhipov A
Cahoon A
Caldejon S
Carlson M
Casal L
Daniel SF
Farrell C
Garrett M
Gillis R
Grasso C
Hardcastle BJ
Hytnen R
Johnson T
Ledochowitsch P
L'Heureux Q
Mastrovito D
McBride EG
Mihalas S
Mochizuki C
Morrison CB
Nayan C
Ngo NK
North K
Ollerenshaw DR
Ouellette B
Rhoads P
Ronellenfitch K
Schroedter M
Siegle JH
Slaughterbeck C
Sullivan D
Swapp J
Taormina M
Wakeman W
Waughman X
Williford A
Phillips JW
Groblewski PA
Durand S
Koch C
Olsen SR

Animals
Mice
Visual Cortex
Neurons
Optogenetics
Mice, Inbred C57BL
Action Potentials
Thalamus
Brain Mapping
Male
Mesencephalon
Visual Perception
Female
Photic Stimulation


A viral ORFeome library for systems-level genetic dissection of host-pathogen interactions

Abstract: Virological research has traditionally focused on individual viruses or viral families. Advances in DNA synthesis now allow large-scale construction of individual gene products, enabling systematic exploration of the virome. Here, we developed a barcoded library of ∼12,000 viral open reading frames (vORFs) from 513 viral species, which we leveraged to identify hundreds of viral regulators of cellular proliferation, MHC class I antigen presentation, and interferon signaling. Integrating results across these screens revealed unique phenotypic profiles and functional vORF modules, allowing the in-depth characterization of two previously uncharacterized viral proteins, MC162R and Yaba-like disease virus (YLDV) 151R, which impair MHC class I antigen presentation and interferon (IFN)-β signaling, respectively. Together, the viral ORFeome provides a scalable framework for dissecting viral protein function across the breadth of the virome.

Fujimura E
O'Leary CN
Li MZ
Roberts RA
Glassman CR
Paulo JA
Jiang H
Abdelfattah NS
Wooten EC
Mirman Z
Harper JW
Cole PA
Elledge SJ


Co-option of lysosomal machinery shapes the evolution of the intracellular photosymbiosis supporting coral reefs

Abstract: Endosymbiosis has spurred the evolution of new organelles across life. Corals and other cnidarians have repeatedly evolved an organelle, called the symbiosome, which houses intracellular algal symbionts. However, the molecular mechanisms enabling this repeated evolution remain unclear. Using the sea anemone Aiptasia, we generated a high-quality proteome of the symbiosome, revealing protein trafficking mechanisms and the types of biomolecules exchanged during symbiosis. Symbiosomal enrichment of lysosomal proteins, visualization of lysosomal fusion, and reduced symbiosis following knockdown of lysosomal genes indicate that the symbiosome functions through extensive co-option of lysosomal proteins. We identified a symbiosomal bicarbonate/sulfate transporter, SLC26A11, and showed through CRISPR/Cas9 mutagenesis that this lysosomal transporter is required for symbiosis in Aiptasia and a reef-building coral. Together, these findings reveal that corals and anemones have repeatedly co-opted lysosomal proteins to concentrate carbon and shuttle metabolites to support photosymbiosis, providing a relatively simple path for the repeated evolution of new photosymbioses.

Maruyama S
Henderson CF
Swinhoe N
Kowalewski GP
Meier EK
Engelke TR
Cleves PA


LEF1 and niche factors determine T cell stemness across chronic diseases

Abstract: In settings of persistent (self or foreign) antigen, such as autoimmunity and chronic infection, immune responses are sustained by stem-like T cells. Although TCF1 has emerged as a key transcription factor (TF) associated with stemness, the TCF1hi population is heterogeneous, raising the question of whether TCF1 exclusively defines the stem T cell (TSC) pool. Using preclinical models of autoimmune type 1 diabetes and chronic infection, we discover that a small subset of TCF1hi T cells express the TF LEF1. LEF1+ TCF1hi T cells define a true self-renewing TSC pool. TSC give rise to LEF1- TCF1hi progenitor T cells (TPRO), which lack stem functions and generate terminally differentiated TCF1lo T cells (TDIFF) (TSC→TPRO→TDIFF). We show that LEF1 is essential for T cell stemness. Autoimmune and exhausted LEF1+ TSC share a unique epigenetically encoded core program enriched for genes and pathways characteristic of embryonic and adult stem cells, including WNT/β-catenin and Notch signaling. Spatial positioning, niche signals, and migration regulate stem-cell fate; accordingly, targeting integrins or Notch signaling impairs T cell stemness and prevents disease. Our studies identify LEF1 and niche-derived factors as fundamental regulators of T cell stemness across chronic diseases.

Miakicheva S
Hawley KM
Zumbo P
Gearty SV
Grassmann S
Naizir B
Chiu E
Carson S
Kissner M
Owyong M
Zhang Y
Washburn R
Sun JC
Chaligné R
Reiner SL
Maillard I
Betel D
Schietinger A

Lymphoid Enhancer-Binding Factor 1
Animals
Mice
Diabetes Mellitus, Type 1
Chronic Disease
Stem Cell Niche
T-Lymphocytes
Hepatocyte Nuclear Factor 1-alpha
Cell Differentiation
Stem Cells
Humans


Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders

Abstract: Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.

Zhou Z
Luquette LJ
Dong G
Kim J
Ku J
Kim K
Ramesh N
Bae M
Caplin A
Shao DD
Sahile B
Essuman K
Goodman E
Miller MB
Huang AY
Nathan WJ
Nussenzweig A
Park PJ
Lagier-Tourenne C
Lee EA
Walsh CA


Four-dimensional molecular mapping from a spatial snapshot reveals the dynamics of hair follicle organogenesis

Abstract: Understanding organ formation requires capturing molecular information simultaneously in three-dimensional (3D) space and across developmental time. To this end, we developed 3D DNase-Enhanced Expression Profiling (3DEEP), a tissue-clearing approach that removes genomic DNA to extend spatial transcriptomic profiling hundreds of microns into intact tissues. We applied 3DEEP to neonatal mouse skin, capturing hundreds of developing hair follicles across their organogenesis trajectory. Ordering follicles by molecularly inferred developmental age transformed this single spatial snapshot into a four-dimensional (3D + time) molecular map of organogenesis. This map revealed developmental dynamics spanning stem cell compartment stratification, emergence of new cell subtypes within the follicle, and cascading structural transformations leading to hair canal formation. Comparative analysis of Foxn1-deficient nude mice, a hairlessness model, revealed organ-wide changes in developmental dynamics, including delayed molecular progression, reduced coordination, and increased developmental instability, preceding overt structural defects. This work demonstrates how deep-tissue spatial transcriptomics can uncover hidden dynamics of organ formation.


Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data

Abstract: We introduce a whole-cell digital twin framework that integrates four-dimensional (4D) (x, y, z, and t) lattice light-sheet microscopy with particle-based reaction-diffusion simulations in ReaDDy to model mesoscale intracellular organelle dynamics. Using fluorescence microscopy data from live Cal27 cells, we construct spatially resolved digital twins incorporating mitochondrial networks, microtubule networks, dynein and kinesin motors, the plasma membrane, and the nucleus. Mitochondrial dynamics include fusion/fission remodeling, diffusion, and motor-driven active transport along microtubules. Our simulations reproduce experimental trends in mitochondrial dynamics across control and two microtubule-perturbed conditions, demonstrating predictive capability without reparameterization. We then use stress-mimicking to predict emergent perinuclear mitochondrial clustering. Crucially, these simulations reveal that microtubule topology acts as a structural gate for this reorganization, demonstrating that upregulated retrograde motor kinetics alone are insufficient to drive clustering without permissive filament connectivity. This digital twin framework provides an approach for investigating intracellular dynamics and perturbation effects in an interpretable and biologically grounded manner.

Arkfeld E
Wang Z
Hakozaki H
Schöneberg J

Humans
Cell Membrane
Cell Nucleus
Computer Simulation
Dyneins
Kinesins
Microscopy, Fluorescence
Microtubules
Mitochondria
Mitochondrial Dynamics


Systematic discovery of pathogen effector functions across human pathogens and pathways

Abstract: Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor κB (NF-κB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo-evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways.

Pachano T
Leng H
Dugied G
Tribble T
Loubiere V
Lee Y
Rauh F
Manon V
Yuan K
Nurtanto J
Schleiffer A
Young V
Weller B
Lyons EA
Hass MR
Kottyan LC
Weirauch MT
Fuxman Bass JI
Newton HJ
Ensminger AW
Falter-Braun P
Chen J
Schramek D
Stark A
Taipale M


Structural basis for host membrane binding and remodeling by invading malaria parasites

Abstract: The Plasmodium moving junction is central to malarial host-cell invasion, and yet its function remains unclear. Here, we determine the endogenous structure of the basic repeating unit of the moving junction, purified directly from invasion-stalled Plasmodium falciparum parasites, revealing a sailboat-shaped 1:1:1:1 assembly of apical membrane antigen 1 (PfAMA1) and rhoptry neck proteins 2, 4, and 5 (PfRON2, PfRON4, and PfRON5). We observe two PfRON2 transmembrane helices that anchor the complex in the red blood cell (RBC) membrane and display an extracellular handle for PfAMA1 binding. PfAMA1 directly contacts the RBC membrane, strengthening the connection. PfRON2/4/5 form a large, basic platform inside the RBC that electrostatically engages the RBC membrane and wedges seven amphipathic helices deep into the bilayer, suggesting an active role in host-membrane remodeling. We then leverage the native membrane context revealed by our structure, along with recent advances in computational protein design, to enable the rational design of a small protein binder that inhibits invasion.

Haile MT
Kaxiras DA
Zhen J
Lee CL
Jiang B
Small-Saunders JL
Ho CM


Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning

Abstract: Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet how such heterogeneities are integrated with the mechanochemical state of the tissue and stabilized at the chromatin level into stable, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (YAP1). We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable and self-organized tissue architecture.

Schwayer C
Barbiero S
Brückner DB
Oost KC
Baader C
Repina NA
Kim J
Diaz OE
Uccelli I
Capolupo L
Meylan LC
Kalck V
Moos F
Suppinger S
Yang Q
Schnabl J
Kilik U
Bourdon M
Camp JG
Stockinger B
Ferrari A
Bühler M
Stadler MB
Hannezo E
Liberali P


Arc mediates intercellular tau transmission via extracellular vesicles

Abstract: Tau pathology spreads cell to cell, but the mechanisms of intercellular tau transmission remain unclear. We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain EVs purified from transgenic rTg4510 mutant tau mice (rTgWT) crossed with Arc knockout mice (rTgArc KO) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTgArc KO mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.

Tyagi M
de Hoog E
Grega M
Sullivan KR
Walker AC
Chadha R
Northrop A
Fábián B
Hummer G
Fuxreiter M
Hyman BT
Shepherd JD

Animals
tau Proteins
Extracellular Vesicles
Humans
Mice
Cytoskeletal Proteins
Mice, Knockout
Alzheimer Disease
Brain
Nerve Tissue Proteins
Neurons
Phosphorylation
Mice, Transgenic


Electromagnetic field-inducible in vivo gene switch for remote spatiotemporal control of gene expression

Kim J
Hwang Y
Kim S
Kwon D
Park J
Cho B
An S
Kang S
Kim Y
Kim S
Lengner CJ
Kim S
Kwon Y
Sung JS
Kim J


Geometric constraints on the architecture of mammalian cortical connectomes

Abstract: The intricate network of axonal fibers forming the mammalian cortical connectome exhibits a complex topology, being neither completely regular nor random. It also has a characteristic topography in which distinct regions have specific connectivity profiles. How such properties arise remains a mystery. Here, we formulate a simple analytical model derived from neural field theory that prioritizes physical constraints on connectome architecture, assuming that connectivity is preferentially concentrated between cortical locations that facilitate the excitation of resonant geometric modes of the cortex. Our model outperforms existing approaches in reproducing topological and topographical properties of cortical connectomes mapped via either non-invasive diffusion magnetic resonance imaging (MRI) or invasive viral tract tracing at spatial scales spanning multiple orders of magnitude in humans, chimpanzees, macaques, marmosets, and mice. Our findings point to a fundamental role of geometry in shaping the multiscale architecture of cortical connectomes that has been conserved across 90 million years of evolution.

Normand F
Gajwani M
Cao T
Cruddas J
Sangchooli A
Oldham S
Holmes A
Robinson PA
Pang JC
Fornito A


Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases

Abstract: Gasdermin D (GSDMD)-mediated interleukin (IL)-33 secretion by lung epithelial cells initiates airway inflammation upon allergen challenge. How environmental allergens activate GSDMD remains elusive. Here, we demonstrate that exposing epithelial cells to allergens triggers protease-activated receptor 1 (PAR1)-dependent ferritinophagy, elevating intracellular labile iron. This iron pool is essential for noncanonical, protease-independent GSDMD activation. The iron chaperone poly(rC)-binding protein 2 (PCBP2) delivers iron directly to GSDMD, initiating a highly localized Fenton reaction. This generates constrained hydroxyl radicals that cleave GSDMD, releasing the active N-terminal p40 fragment to form pores for IL-33 release. Blocking any step of this iron-GSDMD pathway, via iron chelation or genetic ablation, abolishes IL-33 secretion, prevents group 2 innate lymphoid cell (ILC2) activation, and mitigates allergic airway inflammation and tissue damage in mice. Our findings reveal an unconventional, iron-catalyzed, and protease-independent mechanism for GSDMD activation, offering potential new therapeutic targets for allergic inflammatory diseases.

Chen S
Deng F
Peng B
Liu L
Wang J
Jin F
Xu J
Lin D
Chen W
Zhang D
Yi C
Zhang J
Zhong S
Zhu L
Huang Y
Yang J
Wang R
Sun X
Zhang Y
Ling Z
Ma L
Liu X
Sun B


Excessive epithelial mechanosensation drives nociceptive innervation and chronic bladder pain via the PIEZO1-SLC7A11-glutamate axis

Abstract: Epithelial mechanosensation maintains tissue homeostasis by sensing mechanical stimuli. Dysregulated mechanotransduction has been implicated in chronic pain, yet the molecular link between epithelial stress and persistent sensory dysfunction remains unclear. Here, we report that the mechanosensitive ion channel PIEZO1 is markedly upregulated in bladder epithelial cells under recurrent uropathogenic E. coli infection through interleukin-6 (IL-6)-dependent signaling. PIEZO1 overexpression amplifies mechanotransduction-induced reactive oxygen species (ROS) generation, triggering a homeostatic antioxidant response via the cystine-glutamate antiporter system Xc⁻ (SLC7A11). This protective mechanism inadvertently promotes extracellular glutamate accumulation, driving aberrant sprouting and hyperinnervation of peptidergic nociceptive C fibers into the epithelial layer. This neuroepithelial remodeling sensitizes bladder afferents and induces persistent pain-like states resembling chronic visceral pain and organ dysfunction. Our findings reveal a paradoxical role of epithelial antioxidant defense in promoting pain through the PIEZO1-SLC7A11-glutamate axis and highlight the neuroepithelial interface as a key therapeutic target for infection-induced chronic pain syndromes.

Kim MJ
Noh JH
Lee HY
Lee B
Park AD
Oh H
Kim GD
Lee HS
Oh Y
Hwang H
Kim C
Lee H
Li X
Oh MM
Lim D
Abraham SN
Cho Y
Chi SW
Choi HW


Learning from routine health system data builds better neuroimaging AI models


End-to-end multimodal pathology foundation model with clinical dialogue

Abstract: Recent rapid progress in the field of computational pathology has been enabled by foundation models. These models are beginning to move beyond encoding image patches toward whole-slide understanding, but their clinical utility remains limited. Here we present PRISM2, a multimodal slide-level foundation model trained on 2.3 million whole-slide images and 14 million question-answer pairs derived from 700,000 pathology reports. Through clinical dialogue supervision, PRISM2 aligns histomorphology with diagnostic reasoning, yielding representations that support both prompt-based inference and transferable embeddings for downstream tasks. With prompt-based inference, PRISM2 achieves or exceeds (P < 0.05) the balanced accuracy of clinical-grade products calibrated for cancer detection in the prostate, breast and breast lymph node. Additionally, across comprehensive diagnostic, biomarker and survival benchmarks, PRISM2 embeddings never statistically underperform previous foundation models via linear probing (P < 0.05). Furthermore, task-specific fine-tuning on survival prediction outperforms training from scratch on the same large survival dataset. PRISM2 demonstrates how language-supervised pretraining provides a scalable, clinically grounded signal for generalizable pathology representations, bridging human diagnostic reasoning and foundation model performance.

Vorontsov E
Shaikovski G
Casson A
Viret J
Zimmermann E
Tenenholtz N
Wang YK
Bernhard JH
Godrich RA
Retamero JA
Shia J
Gonen M
Weiser MR
Klimstra DS
Yousfi R
Fusi N
Fuchs TJ
Severson K
Liu S


'Heading' the ball linked to spikes in neural damage biomarkers


Humanoid robots perform successful surgery in animals


Deciphering the role of histidine in cancer


Integrated care pathway in individuals with Long COVID: STIMULATE-ICP, a cluster-randomized, phase 3 trial

Abstract: Combining multidisciplinary care plans into integrated care pathways (ICPs) is scalable, generalizable and effective for several long-term conditions, but not evaluated in Long COVID (LC). Our phase 3, cluster-randomized, multicenter clinical trial investigated the effectiveness of ICP interventions for LC. Recruitment of adults ≥18 years with LC was conducted in 6 National Health Service LC clinics in England with specialist ICPs. The intervention arms were (i) multi-organ magnetic resonance imaging (MRI; Coverscan), (ii) digital rehabilitation (Living with COVID Recovery), (iii) both multi-organ MRI and digital rehabilitation, and (iv) neither multi-organ MRI nor digital rehabilitation (usual care); cluster randomizing at primary care network (PCN) level to deliver interventions as 'standard of care' in that area. The primary endpoint was mean Fatigue Assessment Scale (FAS) at 12 weeks. Secondary endpoints included FAS at 24 weeks and EQ-5D-5L visual assessment scale at 12 and 24 weeks. A total of 1,152 participants from allocated PCNs consented to data collection, and 122 PCN clusters were allocated to the multi-organ MRI (33 PCNs), digital rehabilitation (32 PCNs), 'both' (27 PCNs) and 'neither' (30 PCNs) arms. Baseline FAS was equivalent across groups (mean 35.8, s.d. 8.21, 66.4% female). Overall, the primary outcome was achieved in all arms, with scores improving by 4.5 points to 31.3 (s.d. 9.31) at 12 weeks. Compared with usual care, effects on 12-week FAS were -0.18 (95% confidence interval -0.72, 1.09; P = 0.69) with multi-organ MRI; -0.53 (-1.42, 0.36; P = 0.25) with digital rehabilitation; and -0.17 (-1.06, 0.72; P = 0.71) with their interaction. Absolute differences for other interventions from usual care were modest. There were no serious adverse events related to ICP interventions. Multidisciplinary holistic clinical care is associated with fatigue reduction in LC, irrespective of multi-organ MRI. Digital rehabilitation could be useful in longer-term LC management. Large, multi-site trials of optimal ICP interventions are feasible, but further trials are required. ISRCTN identifier: ISRCTN10665760 .


Maternal 6-valent group B Streptococcus vaccine in non-pregnant and pregnant females: a randomized phase 1/2 trial

Abstract: Group B Streptococcus (GBS) disease is a major cause of infant morbidity and mortality. Capsular polysaccharide conjugate GBS vaccines have been evaluated for decades; however, none is licensed. This phase 1/2 trial evaluated an investigational maternal hexavalent polysaccharide-protein conjugate GBS vaccine (GBS6) in non-pregnant females and pregnant participants and their infants. In stage 1 (conducted in South Africa), healthy non-pregnant participants received GBS6, GBS6 + aluminum phosphate (AlPO4) or placebo; a subset received GBS6 + AlPO4 booster approximately 2 years later. Stage 2 (conducted in South Africa) maternal dose-finding data were reported previously and are not presented here. In stage 3, healthy pregnant participants from South Africa, the United States and the United Kingdom received GBS6 or placebo (24-36 weeks' gestation). In stage 1, 66 non-pregnant participants received GBS6, GBS6 + AlPO4 or placebo (n = 22 each); 26 also received GBS6 + AlPO4 booster. In stage 3, 216 pregnant participants were included (GBS6, n = 108; placebo, n = 108); 209 infants were born to maternal participants (GBS6, n = 104; placebo, n = 105). Primary objectives described GBS6 safety/tolerability profiles. Nearly all reactogenicity events were mild or moderate. Among non-pregnant participants, no serious adverse events (SAEs) or adverse event (AE)-associated withdrawals were reported after vaccination; medically attended adverse events (MAEs) were reported in similar percentages across primary vaccination groups (GBS6 groups = 41-45%; placebo = 41%). Rates of AEs (GBS6 = 75/108 (69%); placebo = 70/108 (65%)), SAEs (GBS6 = 21/108 (19%); placebo = 23/108 (21%)) and delivery outcome frequencies were similar in GBS6 and placebo maternal participants. Most infants were born full-term. Infant AE (GBS6 = 87/104 (84%); placebo = 86/105 (82%)), SAE (GBS6 = 45/104 (43%); placebo = 46/105 (44%)) and MAE (GBS6 = 65/104 (63%); placebo = 66/105 (63%)) frequencies were similar across groups. Two neonatal sepsis-associated deaths occurred (GBS6 = 1; placebo = 1); neither was considered vaccine related. Secondary objectives described immune responses. GBS6 elicited robust immune responses in non-pregnant and pregnant individuals; additionally, serotype-specific quantitative and functional antibody responses were observed in infants whose parent received GBS6. These data support continuing clinical investigation of maternal GBS6 vaccination. ClinicalTrials.gov identifier: NCT03765073 .

Madhi SA
Snaggs H
Skogeby Z
Feng Y
Barnabas S
Baker J
Fairlie L
Beeslaar J
Radley D
Jiang HQ
Silmon de Monerri NC
Simon R
McLaughlin L
Gaylord M
Skinner J
Munjal I
Anderson AS
Gurtman A


Reducing the diagnostic odyssey in rare disease: why screening is not the only answer

Wright CF
Phillips A
Wynn SL
Meade N
Baple EL
Lucassen AM
Jackson L


Global economic burden of depression in 154 countries from 2025 to 2050

Abstract: Depression is a major contributor to the global burden of diseases with substantial socioeconomic consequences. Here, to estimate the economic effects of depression, we developed a macroeconomic model using data from the World Bank and Global Burden of Disease Study 2021. The model estimated the impact of depression on labor force participation, educational attainment and work experience, adjusted for age and sex. The projected global economic burden from 2025 to 2050 is estimated at US$12 trillion (2024 US dollars), representing 0.460% of annual global gross domestic product. When suicide-related deaths attributable to depression are accounted for, based on an assumed 60% attribution rate representing the upper bound of estimates in the literature, the overall economic burden increases to US$14 trillion. The highest economic burdens are observed in the United States and China. Relative to regional gross domestic product, the impact is greatest in North America. Reduced labor force participation and productivity were identified as the predominant drivers of this cost. The macroeconomic burden of depression is substantial and inequitably distributed globally. These findings underscore the importance of addressing depression as a public health and economic concern. Reducing the health burden of depression could yield economic returns by supporting productivity and capital accumulation.

Cao Z
Luo Y
Jiao L
Chen W
Prettner K
Kuhn M
Bloom DE
Jamison DT
Bärnighausen TW
Chen S


The genetic architecture of fibromyalgia across 2.5 million individuals

Abstract: Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including DCC, DRD2/NCAM1, MDGA2 and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. This study provides robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

Kerrebijn I
Bjornsdottir G
Arbabi K
Urpa L
Haapaniemi H
Thorleifsson G
Stefansdottir L
Frangakis S
Valliere J
Kunorozva L
Abner E
Ji C
Kangur M
Aagaard B
Bliddal H
Brunak S
Bruun MT
Didriksen M
Erikstrup C
Finer S
Geirsson AJ
Gudbjartsson DF
Hansen TF
van Heel D
Jonsdottir I
Knight S
Knowlton KU
Mikkelsen C
Nadauld LD
Olafsdottir TA
Ostrowski SR
Pedersen OBV
Saevarsdottir S
Skuladottir AT
Sørensen E
Stefansson H
Sulem P
Sveinsson OA
Thorlacius GE
Thorsteinsdottir U
Ullum H
Vikingsson A
Werge TM
Chronic Pain Genomics Consortium
FinnGen
DBDS Genomic Consortium
Estonian Biobank Research Team
Genes & Health Research Team
Saxena R
Stefansson K
Brummett CM
Glintborg B
Clauw DJ
Thorgeirsson TE
Williams FMK
Sinnott-Armstrong N
Ollila HM
Wainberg M


Toward a test of medical AI superintelligence

Goh E
Wu D
Walton C
McCoy LG
Perez A
Wegner L
Nateghi Haredasht F
Luo L
Lacar K
Buckley T
Schoeffler A
Brodeur P
Black KC
Havlik J
Liu Y
Chen PC
Schaekermann M
Rumsfeld J
Lopez-Martinez D
Maeder-York P
Singhal K
Gunning D
Ku B
Warraich H
Nundy S
Ravi V
Milstein A
Hom J
Schulman K
Rajpurkar P
Manrai AK
Wachter R
Topol E
Horvitz E
Rodman A
Chen JH


Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS

Abstract: The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6 years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.

Ran X
Wuu J
Qin ZS
McDermott MP
Cooper-Knock J
Li Y
Granit V
Grignon AL
Lin E
Fernandez MC
Colato D
Carberry N
Lill CM
Piazza P
Malaspina A
Benatar M


AI-based clinician decision support system for diagnosis of inherited retinal diseases: a multicenter, randomized trial

Abstract: The accurate and timely diagnosis of inherited retinal diseases (IRDs) represents an unmet clinical need in ophthalmology, as the current pathways rely on resource-intensive phenotyping, multidisciplinary expertise and genetic testing. Here we developed Retina4IRD, an artificial intelligence (AI)-based clinician decision support system (CDSS) that predicts 17 genotype categories from retina images. Retina4IRD uses a Vision Transformer model pretrained with RETFound. We then trained and validated Retina4IRD using multimodal data with color fundus photographs and optical coherence tomography scans from 1,843 genetically confirmed patients (3,376 eyes) across China, South Korea and Poland. The top-5 prediction accuracy was 0.904 (95% confidence interval (CI): 0.896-0.912) and 0.856 (95% CI: 0.850-0.863) for internal and external validation, respectively. We conducted a randomized controlled trial with 300 participants with suspected IRD randomized 1:1 to either Retina4IRD-assisted specialist arm or specialist-only arm. Of these, 295 participants (median age 33 years, 114 (38.6%) females) with available next-generation sequencing reports were included in the final analysis. The primary outcome was met: top-5 genetic accuracy was significantly higher in the Retina4IRD-assisted specialist arm versus the specialist-only arm (88.5% versus 67.3%, P < 0.001). For secondary endpoints, top-1 to top-4 accuracies all favored the Retina4IRD-assisted specialist arm, with top-1 accuracy of 37.8% versus 22.4% and top-4 accuracy of 81.8% versus 53.1%, respectively. Post hoc analyses demonstrated that, with Retina4IRD assistance, clinicians made better management decisions, and the composite downstream management score indicated significantly higher scores relative to the control group (37.7 versus 28.5, P < 0.001). Our study shows that Retina4IRD is a CDSS tool prior to genetic testing and aligns with clinical workflow for patients with suspected IRDs. ClinicalTrials.gov identifier: NCT06839170 .

Jia H
Qian B
Qu Y
Wang J
Chen J
Li T
Zheng C
Han J
Zhang G
Jin Y
Lee S
Chen X
Chen H
Xu J
Xu K
Rong Y
Jiang Y
Yang Y
Li W
Guo Q
Li Y
Li Y
Wu J
Zhang Q
Lu F
Zhuang W
Lei B
Byeon SH
Lee J
Smedowski A
Swierczynska M
Zhang D
Rim TH
Grzybowski A
Sheng B
Wong TY
Sun X


Prospective validation of imaging and serum diagnostic biomarkers of steatohepatitis and fibrosis in MASLD: the LITMUS Imaging Study

Abstract: There is a need for robust evaluations of noninvasive biomarkers for metabolic dysfunction-associated steatotic liver disease. This prospective multicenter study assessed the diagnostic accuracy of imaging (including liver stiffness measurement (LSM) using magnetic resonance elastography (MRE) and FibroScan (vibration-controlled transient elastography (VCTE)), serum biomarkers (including NIS2+) and composite scores (including Agile 3+ and Agile 4) for centrally read steatohepatitis and fibrosis. For cirrhosis, several biomarkers exceeded the minimum acceptable performance criterion (MAC), including MRE (area under the receiver operating curve (AUC) 0.91; P < 0.01), VCTE-LSM (AUC 0.87; P < 0.01), Agile 3+ (AUC 0.89; P < 0.01) and Agile 4 (AUC 0.88; P < 0.01). Among 357 participants, fibrosis stages F0-F4 were present in 12%, 16%, 25%, 32% and 15%, respectively. NIS2+ had the highest diagnostic accuracy among serum biomarkers for metabolic dysfunction-associated steatohepatitis (MASH; AUC 0.83) and at-risk MASH (MASH with at least stage 2 fibrosis; AUC 0.82), although neither significantly exceeded the MAC (P = 0.15 and P = 0.19). Among imaging biomarkers, MRE showed the highest performance for MASH (AUC 0.71) and at-risk MASH (AUC 0.75), but these remained below the MAC. For fibrosis staging, performance was stronger: MRE met the MAC for advanced fibrosis (AUC 0.91; P < 0.01), as did Agile 3+ (AUC 0.84; P = 0.03). For cirrhosis, several biomarkers exceeded the MAC, including MRE (AUC 0.91; P < 0.01), VCTE-LSM (AUC 0.87; P < 0.01), Agile 3+ (AUC 0.89; P < 0.01) and Agile 4 (AUC 0.88; P < 0.01). Serum biomarkers tended to outperform imaging for identifying at-risk MASH, whereas elastography and composite scores showed excellent accuracy for staging advanced fibrosis and cirrhosis.

Pavlides M
Vali Y
Mózes FE
Wonders K
Akhtar S
Hockings PD
Shumbayawonda E
Pepin K
Fernandez-Lizaranzu I
Leeming DJ
Cobbold JF
Allison MED
Aithal GP
Romero-Gomez M
Aller R
Pericàs JM
Boursier J
Petta S
Schattenberg JM
Ekstedt M
Berzigotti A
Yki-Järvinen H
Martic M
Tuthill T
Brass CA
Kalutkiewicz M
Banerjee R
Ehman RL
Schneider MJ
Tiniakos D
Karsdal M
Magnanensi J
Fournier-Poizat C
Ratziu V
Yunis C
Bugianesi E
Harrison SA
LITMUS Consortium Investigators
Bossuyt PM
Anstee QM


Early detection of Alzheimer's disease with circular RNA from blood


Povorcitinib for hidradenitis suppurativa: the randomized, double-blind, placebo-controlled STOP-HS1 and STOP-HS2 phase 3 trials

Abstract: Although therapeutic options for hidradenitis suppurativa (HS) continue to expand, unmet needs remain substantial. We evaluated the efficacy and safety of povorcitinib (an oral, highly selective Janus kinase 1 (JAK1) inhibitor) in patients with moderate to severe HS in two randomized trials. STOP-HS1 and STOP-HS2 were identically designed, randomized, double-blind, placebo-controlled phase 3 trials. Adults with moderate to severe HS were randomized 2:2:1:1 to once-daily treatment through week 54: povorcitinib 45 mg; povorcitinib 75 mg; placebo with crossover at week 12 to povorcitinib 45 mg; or placebo with crossover at week 12 to povorcitinib 75 mg. The primary endpoint was HiSCR50 (≥50% decrease in total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count) at week 12. STOP-HS1/STOP-HS2 enrolled 608/619 patients, respectively. In both studies, both povorcitinib doses met the primary endpoint; in STOP-HS1, 82/204 (40%) patients in the povorcitinib 45-mg group and 82/202 (41%) in the 75-mg group versus 60/202 (30%) in the placebo group achieved HiSCR50 (OR (95% CI) 45 mg: 1.6 (1.1-2.5), P = 0.0240; 75 mg: 1.6 (1.1-2.4), P = 0.0214); corresponding values for STOP-HS2 were 88/208 (42%) and 88/208 (42%) versus 58/203 (29%; OR (95% CI) 45 mg: 1.8 (1.2-2.8), P = 0.0035; 75 mg: 1.9 (1.2-2.8); P = 0.0033). Through week 12, across STOP-HS1/STOP-HS2, serious treatment-emergent adverse events (AEs) occurred in 1-2% of patients across povorcitinib doses and in 2-3% with placebo; through week 54, serious AEs occurred in 5%/6% of patients receiving 45-mg/75-mg povorcitinib, respectively. The most frequent AEs among patients treated with 45-mg/75-mg povorcitinib were acne (17%/20%), nasopharyngitis (10%/12%) and upper respiratory tract infection (11%/10%). One death of undetermined etiology was reported and deemed unrelated to treatment. No new or unexpected safety findings were identified. Oral povorcitinib demonstrated significant improvements in HiSCR50 versus placebo and a favorable safety profile in patients with moderate to severe HS. ClinicalTrials.gov registration: NCT05620823 and NCT05620836 .

Porter ML
Martorell A
Sayed CJ
Bechara FG
Lev-Tov H
Hsiao JL
Frew JW
Reguiaï Z
Gooderham MJ
Goldfarb N
van der Zee HH
Del Marmol V
Marzano AV
Ehst BD
Ackerman LS
Hayama K
Tian C
Kelley J
Zhen H
Kirby JS
Brown K
Santos LL
Zouboulis CC


Author Correction: Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial

Gomez S
DiCioccio RA
Geiger AE
Grant ML
Reynolds E
Datar A
McCann CD
Tanna J
Kukadiya D
Hoq F
Zhang A
Hanley PJ
Webb JL
Kilburn LB
Rood BR
Fonseca A
Meany HJ
Vézina LG
Packer RJ
Cruz CRY
Bollard CM
Hwang EI


FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial

Abstract: Fc receptor-homolog 5 (FcRH5) is a membrane protein that is ubiquitously expressed on myeloma cells. Cevostamab is a first-in-class, FcRH5×CD3 bispecific antibody. GO39775 is a phase 1 dose-escalation and dose-expansion study evaluating fixed-duration cevostamab in relapsed or refractory multiple myeloma. Cevostamab was initiated with step-up dosing and continued at the target dose (TD) once every 3 weeks for 17 cycles (~12 months) unless disease progression or unacceptable toxicity occurred. Primary objectives were to evaluate safety, including determination of the maximum tolerated dose (MTD), and to identify a recommended phase 2 dose and schedule (RP2D) for cevostamab monotherapy. Secondary objectives included determining the rate of response and the duration of response (DOR). As of 24 February 2025, 324 patients had been enrolled; most were heavily pretreated (median prior lines, 6; triple-class refractory, 89.5% (290/324); prior B-cell maturation antigen (BCMA)-targeted therapy, 47.5% (154/324)). The MTD was not reached. Across all TD levels (0.15-252 mg), grade 3 or 4 adverse events (AEs) and serious AEs occurred in 59.6% (193/324) and 60.2% (195/324), respectively. Grade 5 AEs excluding disease progression occurred in 4.6% (15/324); 0.9% (3/324) were considered treatment related (hemophagocytic lymphohistiocytosis, n = 2; disseminated intravascular coagulation in the context of pseudomonal sepsis, n = 1). Objective response and very good partial response or better rates were 42.1% (136/323) and 25.1% (81/323), respectively. Median DOR was 11.2 months (95% confidence interval, 8.3, 15.6). A total of 167 patients received treatment at the 160 mg TD level (RP2D). Objective response and very good partial response or better rates were 44.3% (74/167) and 25.7% (43/167) in all patients and 60.6% (43/71) and 39.4% (28/71) in the BCMA naive, respectively. Median DOR was 10.4 months in all patients and 19.7 months in the BCMA naive, with durable responses maintained after the completion of treatment. Cytokine release syndrome was grade 1 or 2 in the 0.3/1.2/3.6/160 mg triple step-up cohort (RP2D). Cevostamab had manageable safety and induced durable remissions in late-line relapsed or refractory multiple myeloma. ClinicalTrials.gov registration: NCT03275103 .

Cohen AD
Richter J
Trudel S
Lesokhin A
Laubach JP
Thomas SK
Harrison SJ
Costa LJ
Spencer A
Fonseca R
Forsberg PA
Berdeja JG
Kaedbey R
Bahlis NJ
Rodriguez-Otero P
Mateos MV
Tyagi T
Samineni D
Liu W
Nakamura R
Choeurng V
Wong C
Cooper J
Krishnan A


Governing the social production of care: the hidden foundation of health systems

Occhipinti JA
Prodan A
Buchanan J
Martin M
Khalatbari-Soltani S
Swieboda P
Eyre H
Crosland P
Hosseini SH
van Zwieten A
Samtani S
Sawan M
Cobos Muñoz D
Okamoto S
Robinson J
Norris D
Jeste DV
Destrebecq F
Heffernan M
Tanner M
Miranda JJ


Genomas Brasil program: building precision public health within Brazil's Unified Health System

Araújo de França GV
Lupatini EO
Rocha RT
Toledo RCP
Figueiredo GSF
Gonçalves CEI
Machado ILO
Anzolin AP
Gontijo CC
Vidal JFD
Ramos PIP
Carreiro RP
Freitas MS
De Negri F


A new additive in the opioid supply is causing disastrous complications


Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy

Abstract: SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient's phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

Kim-McManus O
Mignon L
Douville J
Pu H
Parisien C
Glass S
Bennett CF
Celso J
Robbins K
Ung H
Olson H
Kingsmore SF
Petrou S
Crooke ST
Gleeson JG
Berry-Kravis E


An AI co-scientist to accelerate biomedical research


A neuroprosthesis for restoring hand movement and sensation in a person with complete tetraplegia

Abstract: Millions of people worldwide are living with movement and sensory impairments owing to spinal cord injury, stroke and other neurological conditions. Here we report a double neural bypass (DNB), a hybrid neuroprosthetic system designed to restore both immediate and lasting gains in movement and sensation after a severe, complete spinal cord injury. The DNB links an intracortical brain-computer interface with targeted and patterned neuromodulation of the spinal cord and cortex. This allows brain signals associated with movement intention to directly control the movement of the user's own hand in real time while also promoting long-term sensorimotor recovery-even after the system is turned off. The DNB system uses recurrent artificial neural networks and reinforcement learning for fine grasp control, together with patterned spinal cord stimulation and activity-informed intracortical microstimulation ('cortical mirroring') to promote neuroplasticity and durable recovery of function. In a participant with chronic C4 sensory/C5 motor complete tetraplegia, this hybrid approach enabled recovery of functional abilities including self-feeding and manipulation of delicate objects, while also producing significant and persistent improvements in elbow flexion and wrist tactile sensation. These findings demonstrate the potential of combining a sensorimotor neuroprosthesis with targeted brain and spinal neuromodulation to restore clinically relevant function in severe paralysis.

Chandrasekaran S
Wandelt SK
Jangam A
Elias Z
Ibroci E
Maffei C
Rosenthal IA
Ramdeo R
Kim JW
Xu J
Glasser MF
Neuwirth A
Goldstein TA
Crone NE
Fifer MS
Tostaeva G
Bickel S
Griffin D
Funaro M
Carras NG
Pruitt R
Ben-Shalom N
Stein AB
Mehta AD
Bouton CE

Humans
Quadriplegia
Hand
Movement
Spinal Cord Injuries
Brain-Computer Interfaces
Recovery of Function
Neural Prostheses
Sensation
Male
Adult


Author Correction: Integrated community-based HIV and sexual and reproductive health services for youth: a cluster-randomized trial

Ferrand RA
Dauya E
Chikwari CD
Bandason T
Bernays S
Mackworth-Young C
Doyle AM
Grundy C
Indravudh P
Terris-Prestholt F
Mavodza CV
Mugurungi O
Apollo T
Ncube G
Larsson L
McCarthy O
Simms V
Tembo M
Kranzer K
Hayes RJ


Author Correction: Evolution of claudin18.2 therapies in gastroesophageal cancers


Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial

Abstract: There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19-4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00 ; ClinicalTrials.gov identifier: NCT04077723 .

Hutchings M
Dickinson M
Gritti G
Carlo-Stella C
Townsend W
Bosch F
Bartlett NL
Cartron G
Ghesquieres H
Houot R
Walter H
Offner F
Dimier N
Jamois C
Herter S
Keelara A
Wilson S
Gallien J
Hinton H
Gonzalez-Albo IP
Korfi K
Kazantzidis G
Wasmer MH
Lechner K
Morschhauser F


Mining antigens for a universal malaria vaccine


A turning point for gene editing in severe blood disorders


Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial

Abstract: While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with Fc-effector silencing and reduced FcRn binding (IBC-Ab002) was engineered. Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1-30 mg kg-1), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg kg-1 dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD. ClinicalTrials.gov registration: NCT05551741 .

Croese T
Mummery CJ
Bregman N
Bracha D
Baruch K
Kertser A
Raveh S
Shochat E
Schwartz M


Multi-omics maps human-pig interactions in extracorporeal liver cross-circulation


Fertilizer scarcity as a failure of global health governance

Nasari A
Nasari A
Marzouk S
Prasad T
Fanzo J


Studying vanishing dietary diversity before it is lost: the World Diet Initiative

de Mast Q
Brown CV
Mwakasungura F
Nakanjako D
Temba GS
Kumar V
Pramono A
Crișan TO
Riza A
de Jonge MI
Wagner N
Hoentjen F
Ferreira AVM
Chakraborty A
Teixeira M
Fekadu A
Xavier RJ
Sunguya B
Netea MG


When caution becomes harm