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CSF1R regulates monocyte subset differentiation and intracellular metabolism
Abstract Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6C high ) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6C low ) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL-34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6C low monocytes in part by blunting differentiation of Ly6C high monocytes. Based upon lineage-specific deletion of Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the hexosamine biosynthetic pathway (HBP) is identified as an important regulator of CSF1R expression and monocyte subsets. Inhibition of receptor tyrosine kinases CSF1R and FLT3 rewires and partially impairs metabolic activity in human monocytes. Our findings provide insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.
CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer
Glutamatergic signaling underlies brain structural organization for mathematical and reading abilities in children
Proton shuttling at electrochemical interfaces under alkaline hydrogen evolution
Specificity and exon target space of splicing modifying compounds
Abstract Modulation of splicing is an established therapeutic strategy with clinical applications and potential to target specific exons to influence gene expression. Small-molecule splicing modifiers such as Risdiplam and Branaplam induce inclusion of exons typically skipped due to weak $${5}^{{\prime} }$$ 5 ′ splice sites. Risdiplam preferentially induces exons with an N −3 G −2 A −1 sequence at the $${3}^{{\prime} }$$ 3 ′ exon end, whereas Branaplam favors A −3 G −2 A −1 -ending exons. However, determinants of specificity remain unclear, as many motif-matching exons are not induced. Here, we investigate the molecular basis of splicing-modulator specificity. Using biochemical assays, transcriptome analyses, and genetic perturbations, we identify sequence-dependent features that determine exon responsiveness to splicing-modulator induction. We further demonstrate that specificity can be reprogrammed through manipulation of U1 snRNA. These findings refine the determinants of splicing-modulator target space and may support identification of additional target exons and compounds.
Electric field tunable coupling strength and quantum metric hot spots in a moiré flatband superconductor
Closed-loop readout of anterior insula high-gamma activity steers value-based decisions
ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition
Programmable memtransistor array with temporal dynamics modulation for efficient time-series data processing
Cryo-EM structure of African horse sickness virus VP2 receptor-binding protein enables nanoparticle vaccine design
Ridge catalysis unlocking water oxidation activity of pentlandite
Personalized neoantigen-pulsed autologous dendritic cells in newly-diagnosed glioblastoma: a phase Ib trial
Abstract Newly-diagnosed glioblastoma (nGBM) remains a significant unmet need with limited therapeutic options. Here, we present the results of a single-arm, open-label phase 1b trial on neoantigen-pulsed autologous dendritic cells (ZSNeo-DC) as an adjuvant treatment for nGBM. The primary endpoint was safety, as assessed by the incidence and severity of adverse events (AEs). Eleven patients with nGBM received intradermal administration of ZSNeo-DC following surgery and standard radio-chemotherapy. Treatment was well tolerated, with AEs predominantly grade 1 or 2; only two grade-1/2 febrile AEs were recorded as treatment-related. Secondary endpoint analysis showed that median progression-free survival (PFS) was 16.2 months, median overall survival (OS) was not reached, and 12-month OS rate was 100% from surgery. A range of 1.9- to 284.7-fold (median: 7.2-fold) and 0.7- to 507.0-fold (median: 10.3-fold) increase of peripheral neoantigen-specific immune response (NSIR) was observed respectively after the 3 rd and 5 th vaccination. Following vaccination, both the activated-to-exhausted ratio of effector/central memory T cells and the clonal evenness of the T cell receptor repertoire increased significantly in peripheral blood; these parameters positively correlated with NSIR and PFS. Overall, ZSNeo-DC exhibits a favorable safety profile and preliminary efficacy signals in nGBM, supporting phase 2 evaluation in expanded cohorts. Trial number: NCT04968366.
Ectomesenchyme contributes to epidermal stem cell formation through mesenchymal-to-epithelial transition
Abstract Cutaneous development is initiated by crosstalk between non-neural ectodermal epithelium and underlying mesenchymal cells. Recent studies have shown that some mesenchymal cells contribute to keratinocyte regeneration in injured skin. However, whether mesenchymal cells contribute to keratinocyte formation in physiologically normal skin remains unclear. Here we show, using lineage tracing, single-cell transcriptome and epigenome analyses of mouse skin, that the interfollicular epidermis consists largely of mesenchymal-lineage cells. Further lineage-tracing and live-imaging analysis of mouse embryos indicate that these mesenchymal-lineage epidermal progenitor cells arise from ectomesenchyme and contribute to the surface ectoderm through a mesenchymal-to-epithelial transition-like process between embryonic days 8.5 and 9.5. We also establish human induced pluripotent stem cell-derived ectomesenchyme and demonstrate that it generates p63-expressing keratinocytes. These data reveal a previously unappreciated contribution of ectomesenchyme to cutaneous development and provide insight into skin diseases involving epidermal mosaicism.
Causal Dynamics of Social Gaze in Primate Prefrontal-Amygdala Networks Revealed by Dynamic Bayesian Modeling
Single twistable tendon-driven continuum robots
Abstract Tendon-driven continuum robots with spatial manipulability face fundamental challenges in miniaturization, stemming from the space required to accommodate multiple actuation tendons. Conventional multi-tendon designs create an inherent trade-off between miniaturization, 3D manipulability, and force output. Here, we introduce a class of continuum robots that achieves controllable body twist and full omnidirectional motion driven by pushing, pulling, and twisting a single tendon, breaking this long-standing design constraint. The resulting robot features an outer diameter of 2.0-3.5 mm and a circumferential hollow ratio exceeding 57%, nearly doubling spatial utilization efficiency over multi-tendon designs. Compared to conventional mechanisms, manipulability improves by over 1000-fold while retaining at least 70% of tip force across all directions. We derive the kinematics for this robot class and provide an open-source simulator. We demonstrate capabilities in teleoperation, navigation in tortuous environments, chopstick-like continuum grippers for in-gripper manipulation, and potential medical applications. Our design redefines actuation paradigms for tendon-driven continuum robots.
Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance
Abstract Brain maintenance – the preservation of brain structure or function relevant to cognitive performance – remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer’s cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.
A high-dexterity soft neuroprosthetic hand for daily activities
Abstract Robotic prostheses are the primary replacement for upper-limb amputees’ lost hands. Although various neuroprosthetic hands have been developed, featuring both rigid and soft mechanisms, they typically offer grasping-oriented functionality with fewer degrees of freedom (DOFs, ≤6). Herein, we report a dexterous soft neuroprosthetic hand with 11 active DOFs that restores common grasping and fine manipulation, validated by four amputee subjects (aged 38–70 years, male and female). The neuroprosthetic hand integrates soft fingers with thumb-palm articulations for dexterity and adaptivity via a 2-channel myoelectric interface with amplitude-speed decoding, enabling amputees to outperform current prostheses in standardized tests and maintain control robustness. Furthermore, the neuroprosthetic hand improves amputees’ participation in daily activities and interactions, such as hair braiding, pill taking, scissor manipulation, car steering, and continuous bulb screwing, while reducing compensatory body movements. These results demonstrate that the high-dexterity soft-robotic hand enhances both prosthesis versatility and compliant interaction.