Regulation of angiogenesis by signal sequence-derived peptides.

Background: The neuropilin-like, Discoidin, CUB and LCCL domain containing 2 (DCBLD2) is a transmembrane protein with an unusually long signal sequence (SS) composed of N-terminal (N) and C-terminal (C) subdomains, separated by a transition (tra) subdomain. DCBLD2 interacts with VEGFR-2 and regulates VEGF-induced endothelial cell signaling, proliferation and migration, as well as angiogenesis. The exact mechanisms by which DCBLD2 interacts with VEGFR2 to modulate VEGF signaling remain unclear. Methods: Searching for VEGFR2 interacting DCBLD2 domains, we generated various constructs containing different DCBLD2 domain combinations and conducted co-immunoprecipitation and signaling studies in HEK 293T and endothelial cells. Several peptides were synthesized based on the identified domain, and their effect on VEGF signaling was assessed in vitro in cell culture and in vivo using matrigel plug and corneal micropocket assays. The effect of the lead peptide was further evaluated using a murine hindlimb ischemia model. Results: DCBLD2 SS interacted with VEGFR2 and promoted VEGF signaling. SS was not cleaved in the mature DCBLD2 and its hydrophobic transmembrane 'traC' segment, but not the 'N' subdomain, was involved in DCBLD2-VEGFR2 interaction. The smallest unit in DCBLD2 SS that interacts with VEGFR2 was the L5VL5 sequence. Even after the central valine was removed, the L10 sequence mimicked the DCBLD2 SS traC's effect on VEGF-signaling, while shorter or longer poly-leucine sequences were less effective. Finally, a synthetic traC peptide enhanced VEGF signaling in vitro, promoted VEGF-induced angiogenesis in vivo, and improved blood flow recovery following hindlimb ischemia. Conclusion: DCBLD2 SS along with its derivative peptides can promote VEGFR2 signaling and angiogenesis. Synthetic peptides based on DCBLD2 SS hold promise as therapeutic agents for regulating angiogenesis. Importantly these findings refine the traditional view of signal sequences as mere targeting elements, revealing a role in cellular signaling. This opens new avenues for research and therapeutic strategies.

Highly Tunable Interlayer Coupling and Electronic Structures of Few-Layer Graphene with Pressure.

The interlayer electronic coupling is responsible for the electronic structure evolution from monolayer graphene to graphite and for the moiré potential in twisted bilayer graphene. Here we demonstrate that the interlayer transfer integral (hopping parameter) increases nearly 40% with a quite moderate pressure of ∼3.5 GPa, manifested by the resonance peak shift in the infrared spectra of all 2-10 L graphene. A simple model based on the Morse potential enabled us to establish the relationship between the transfer integral and pressure. Our work provides fundamental insights into the dependence of the electronic coupling on the interlayer distance.

The potential linkage between sediment oxygen demand and microbes and its contribution to the dissolved oxygen depletion in the Gan River.

The role of sediment oxygen demand (SOD) in causing dissolved oxygen (DO) depletion is widely acknowledged, with previous studies mainly focusing on chemical and biological SOD separately. However, the relationship between the putative functions of sediment microbes and SOD, and their impact on DO depletion in overlying water, remains unclear. In this study, DO depletion was observed in the downstream of the Gan River during the summer. Sediments were sampled from three downstream sites (YZ, Down1, and Down2) and one upstream site (CK) as a control. Aquatic physicochemical parameters and SOD levels were measured, and microbial functions were inferred from taxonomic genes through analyses of the 16S rRNA gene. The results showed that DO depletion sites exhibited a higher SOD rate compared to CK. The microbial community structure was influenced by the spatial variation of Proteobacteria, Chloroflexi, and Bacteroidota, with total organic carbon (TOC) content acting as a significant environmental driver. A negative correlation was observed between microbial diversity and DO concentration (p < 0.05). Aerobic microbes were more abundant in DO depletion sites, particularly Proteobacteria. Microbes involved in various biogeochemical cycles, such as carbon (methane oxidation, methanotrophs, and methylotrophs), nitrogen (nitrification and denitrification), sulfur (sulfide and sulfur compound oxidation), and manganese cycles (manganese oxidation), exhibited higher abundance in DO depletion sites, except for the iron cycle (iron oxidation). These processes were negatively correlated with DO concentration and positively with SOD (p < 0.05). Overall, the results highlight that aerobic bacteria's metabolic processes consume oxygen, increasing the SOD rate and contributing to DO depletion in the overlying water. Additionally, the study underscores the importance of targeting the removal of in situ microbial molecular mechanisms associated with toxic H2S and CH4 to support reoxygenation efforts in rehabilitating DO depletion sites in the Gan River, aiding in identifying factors controlling DO consumption and offering practical value for the river's restoration and management.

MPPT control of photovoltaic array based on improved marine predator algorithm under complex solar irradiance conditions.

In practical engineering applications, factors like dust adhesion and environmental changes can cause photovoltaic arrays to exhibit multiple peaks in output power. An optimization algorithm with global optimization capability is needed to track its maximum power. In this regard, this paper proposes an improved marine predator algorithm (IMPA) to extract the maximum power point of photovoltaic system under complex solar irradiation conditions. To overcome the issues in the traditional marine predator algorithm (MPA), the opposition-based learning(OBL) strategy is introduced in IMPA, and the sine cosine algorithm (SCA) is integrated into the iteration stage to enhance the search ability of the algorithm. Furthermore, the low-order converter in the traditional MPPT control system is replaced by the Zeta converter, which increases the operating voltage range. Ultimately, simulation results demonstrate that the MPPT based on IMPA has higher tracking efficiency and shorter response time.The experimental results also indicate the practical feasibility of this method, as well as its high level of stability and robustness.

A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling.

Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease.

The Renoprotective and Anti-Inflammatory Effects of Human Urine-Derived Stem Cells on Acute Kidney Injury Animals.

BACKGROUND: Acute Kidney Injury (AKI) is defined as a sudden loss of kidney function, which is often caused by drugs, toxins, and infections. The large spectrum of AKI implies diverse pathophysiological mechanisms. In many cases, AKI can be lethal, and kidney replacement therapy is frequently needed. However, current treatments are not satisfying. Developing novel therapies for AKI is essential. Adult stem cells possess regenerative ability and play an important role in medical research and disease treatment. METHODS: In this study, we isolated and characterized a distinct human urine-derived stem cell, which expressed both proximal tubular cell and mesenchymal stem cell genes as well as certain unique genes. RESULTS: It was found that these cells exhibited robust protective effects on tubular cells and anti- inflammatory effects on macrophages in vitro. In an ischemia-reperfusion-induced acute kidney injury NOD-SCID mouse model, transplantation of USCs significantly protected the kidney morphology and functions in vivo. CONCLUSION: In summary, our results highlighted the effectiveness of USCs in protecting from PTC injury and impeding macrophage polarization, as well as the secretion of pro-inflammatory interleukins, suggesting the potential of USCs as a novel cell therapy in AKI.

Tunable anisotropic van der Waals films of 2M-WS2 for plasmon canalization.

In-plane anisotropic van der Waals materials have emerged as a natural platform for anisotropic polaritons. Extreme anisotropic polaritons with in-situ broadband tunability are of great significance for on-chip photonics, yet their application remains challenging. In this work, we experimentally characterize through Fourier transform infrared spectroscopy measurements a van der Waals plasmonic material, 2M-WS2, capable of supporting intrinsic room-temperature in-plane anisotropic plasmons in the far and mid-infrared regimes. In contrast to the recently revealed natural hyperbolic plasmons in other anisotropic materials, 2M-WS2 supports canalized plasmons with flat isofrequency contours in the frequency range of ~ 3000-5000 cm-1. Furthermore, the anisotropic plasmons and the corresponding isofrequency contours can be reversibly tuned via in-situ ion-intercalation. The tunable anisotropic and canalization plasmons may open up further application perspectives in the field of uniaxial plasmonics, such as serving as active components in directional sensing, radiation manipulation, and polarization-dependent optical modulators.

Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice.

Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.

Influence of Transcutaneous Vagus Nerve Stimulation on Motor Planning: A Resting-State and Task-State EEG Study.

Transcutaneous vagus nerve stimulation (tVNS) shows a potential regulatory role for motor planning. Still, existing research mainly focuses on behavioral studies, and the neural modulation mechanism needs to be clarified. Therefore, we designed a multi-condition (active or sham, pre or under, difficult or easy, left-hand or right-hand) motor planning experiment to explore the effect of online tVNS (i.e., tVNS and tasks synchronized). Twenty-eight subjects were recruited and randomly assigned to active and sham groups. Both groups performed the same tasks in the experiment and separately collected task-state EEG and 5-min eye-open resting-state EEG. The results showed that the changes in event-related potential (ERP) and movement-related cortical potential (MRCP) amplitudes were more significant for the left-hand difficult task (LD) under active-tVNS. According to the power spectrum results, active-tVNS significantly modulated the activities of the contralateral motor cortex at beta and gamma bands in the resting state. The functional connectivity based on partial directed coherence (PDC) showed significant changes in the parietal lobe after active-tVNS. These findings suggest that tVNS is a promising way to improve motor planning ability.

Case Report: Snake Venom Ophthalmia Caused by Cobra Exposure: A Report of 26 Cases.

We report 26 cases of eye injuries resulting from cobra venom sprayed by Naja atra. This accounts for 14.5% of patients (26/173) treated for cobra injuries who presented to the emergency department of a snakebite treatment center in Guangzhou, South China. Pain, blurred vision, lacrimation, photophobia, and foreign body sensation were the most common symptoms, found in 24 patients. Ophthalmic examination revealed eyelid swelling and conjunctival congestion. Eye slit lamp examination showed obvious punctate corneal epithelial defects in four patients. Five patients received an intravenous infusion of antivenom. All patients' eyes were rinsed completely with normal saline after their arrival at the hospital. Prophylactic topical antibiotics were given to all patients. All eyes were cured without long-term sequelae.

Layer-dependent exciton polarizability and the brightening of dark excitons in few-layer black phosphorus.

The evolution of excitons from 2D to 3D is of great importance in photo-physics, yet the layer-dependent exciton polarizability hasn't been investigated in 2D semiconductors. Here, we determine the exciton polarizabilities for 3- to 11-layer black phosphorus-a direct bandgap semiconductor regardless of the thickness-through frequency-resolved photocurrent measurements on dual-gate devices and unveil the carrier screening effect in relatively thicker samples. By taking advantage of the broadband photocurrent spectra, we are also able to reveal the exciton response for higher-index subbands under the gate electrical field. Surprisingly, dark excitons are brightened with intensity even stronger than the allowed transitions above certain electrical field. Our study not only sheds light on the exciton evolution with sample thickness, but also paves a way for optoelectronic applications of few-layer BP in modulators, tunable photodetectors, emitters and lasers.

SINE-VNTR-Alu retrotransposon insertion as a novel mutational event underlying Glanzmann thrombasthenia.

BACKGROUND: Glanzmann thrombasthenia (GT) is an autosomal recessive platelet aggregation disorder caused by mutations in ITGA2B or ITGB3. OBJECTIVES: We aimed to assess the phenotype and investigate the genetic etiology of a GT pedigree. METHODS: A patient with bleeding manifestations and mild mental retardation was enrolled. Complete blood count, coagulation, and platelet aggregation tests were performed. Causal mutations were identified via whole exome and genome sequencing and subsequently confirmed through polymerase chain reaction and Sanger sequencing. The transcription of ITGB3 was characterized using RNA sequencing and reverse transcription polymerase chain reaction. The αⅡb and ß3 biosynthesis was investigated via whole blood flow cytometry and in vitro studies. RESULTS: GT was diagnosed in a patient with defective platelet aggregation. Novel compound heterozygous ITGB3 variants were identified, with a maternal nonsense mutation (c.2222G>A, p.Trp741∗) and a paternal SINE-VNTR-Alu (SVA) retrotransposon insertion. The 5' truncated SVA element was inserted in a sense orientation in intron 11 of ITGB3, resulting in aberrant splicing of ITGB3 and significantly reducing ß3 protein content. Meanwhile, both the expression and transportation of ß3 were damaged by the ITGB3 c.2222G>A. Almost no αⅡb and ß3 expressions were detected on the patient's platelets surface. CONCLUSION: Novel compound heterozygous ITGB3 mutations were identified in the GT pedigree, resulting in defects of αⅡbß3 biosynthesis. This is the first report of SVA retrotransposon insertion in the genetic pathogenesis of GT. Our study highlights the importance of combining multiple high-throughput sequencing technologies for the molecular diagnosis of genetic disorders.

Construction of a risk model based on N6 -methyladenosinerelated lncRNAs for predicting the prognosis of breast cancer.

N6-methyladenosine modification and lncRNAs are closely related to the prognosis and immunotherapy response of breast cancer patients. LncRNAs related to m6 A-associated genes were predicted based on coexpression analysis of the TCGA database. We established a novel 7-m6 A-associated lncRNA signature for predicting patient prognosis and validated it. The model was significantly correlated with survival time and survival status and was an independent predictor of overall survival (OS). Except for the M1 disease group, the model had good predictive value for OS in different subgroups. We constructed a prognostic model based on 7 m6 A-associated lncRNAs in breast cancer. This model could serve as an independent prognostic factor with tremendous predictive ability for breast cancer patients.

Tunable optical topological transitions of plasmon polaritons in WTe2 van der Waals films.

Naturally existing in-plane hyperbolic polaritons and the associated optical topological transitions, which avoid the nano-structuring to achieve hyperbolicity, can outperform their counterparts in artificial metasurfaces. Such plasmon polaritons are rare, but experimentally revealed recently in WTe2 van der Waals thin films. Different from phonon polaritons, hyperbolic plasmon polaritons originate from the interplay of free carrier Drude response and interband transitions, which promise good intrinsic tunability. However, tunable in-plane hyperbolic plasmon polariton and its optical topological transition of the isofrequency contours to the elliptic topology in a natural material have not been realized. Here we demonstrate the tuning of the optical topological transition through Mo doping and temperature. The optical topological transition energy is tuned over a wide range, with frequencies ranging from 429 cm-1 (23.3 microns) for pure WTe2 to 270 cm-1 (37.0 microns) at the 50% Mo-doping level at 10 K. Moreover, the temperature-induced blueshift of the optical topological transition energy is also revealed, enabling active and reversible tuning. Surprisingly, the localized surface plasmon resonance in skew ribbons shows unusual polarization dependence, accurately manifesting its topology, which renders a reliable means to track the topology with far-field techniques. Our results open an avenue for reconfigurable photonic devices capable of plasmon polariton steering, such as canaling, focusing, and routing, and pave the way for low-symmetry plasmonic nanophotonics based on anisotropic natural materials.

Twist-Angle and Thickness-Ratio Tuning of Plasmon Polaritons in Twisted Bilayer van der Waals Films.

Stacking bilayer structures is an efficient way to tune the topology of polaritons in in-plane anisotropic films, e.g., by leveraging the twist angle (TA). However, the effect of another geometric parameter, the film thickness ratio (TR), on manipulating the plasmon topology in bilayers is elusive. Here, we fabricate bilayer structures of WTe2 films, which naturally host in-plane hyperbolic plasmons in the terahertz range. Plasmon topology is successfully modified by changing the TR and TA synergistically, manifested by the extinction spectra of unpatterned films and the polarization dependence of the plasmon intensity measured in skew ribbon arrays. Such TR- and TA-tunable topological transitions can be well explained based on the effective sheet optical conductivity by adding up those of the two films. Our study demonstrates TR as another degree of freedom for the manipulation of plasmonic topology in nanophotonics, exhibiting promising applications in biosensing, heat transfer, and the enhancement of spontaneous emission.

Multimodality Imaging of Aortic Valve Calcification and Function in a Murine Model of Calcific Aortic Valve Disease and Bicuspid Aortic Valve.

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2-/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). 18F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate 18F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2-/- mice. Methods: Dcbld2-/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, 18F-NaF PET/CT (n = 34, or autoradiography (n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography (n = 12). The aortic valve signal was quantified as SUVmax on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve 18F-NaF signal on PET/CT was significantly higher at 18-24 mo (P < 0.0001) and 10-16 mo (P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher 18F-NaF signal than tricuspid aortic valves (P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher 18F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV (P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT (r = 0.55, P < 0.001) and autoradiography (r = 0.45, P < 0.01). Conclusion: 18F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2-/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, 18F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.

Discrete Element Study on Bending Resistance of Geogrid Reinforced Cement-Treated Sand.

Cement-treated sand reinforced with geogrids (CTSGs) has higher bending resistance and toughness than cement-treated sands (CTSs). To explore the reinforcement mechanism of geogrids with different stiffness and layers on CTSGs, three-point bending tests and numerical tests based on DEM are carried out on CTS specimens and CTSG specimens considering different reinforcement conditions. The results show that the geogrids and cement-treated sands have good cooperative working performance. Compared with CTSs, CTSG specimens show better ductility, flexural strength and toughness. The increase in geogrid stiffness and geogrid layers promote the reinforcement effect. On the meso-level, different geogrid stiffness and layers affect the crack propagation speed and distributions of cracks due to the anchorage action of geogrids, resulting in different reinforcement effects. In addition, the layers and stiffness of geogrids affect the evolution of the internal force chains of CTSG specimens. Both the increase in geogrid layers and decrease in geogrid stiffness reduce the average internal force of geogrids and weaken the anisotropy of the normal contact force of the specimens. The simulation results interpret the reinforcement mechanism of a CTSG specimen from crack development and internal force evolution, which can support a mesoscopic supplement to laboratory tests.

High-resolution visualization of pial surface vessels by flattened whole mount staining.

Understanding development of the cerebral vasculature is essential for the central nervous system (CNS) research and therapeutic developments. Here, we developed a simple, convenient, and fast method-the flattened cortex whole mount (FCWM) technique-for imaging of pial cerebral vessels. FCWM involves dissection of the whole cerebral cortex followed by flattening, sectioning and application of CLARITY technology. Compared to conventional methods, FCWM offers several advantages including (1) high-resolution visualization of the whole cortex pial surface vessel structures and distributions; (2) precise localization of a particular blood vessel, allowing observations of a desired blood vessel during normal development or in disease settings; (3) compatibility with confocal imaging. Application of FCWM for examination of cerebral vasculature during postnatal development or in stroke settings allowed us to demonstrate that cerebral blood vessels manifest type-specific maturation and remodeling which are linked to the rate of endothelial proliferation.

Study of platelet-rich plasma application for skin and plastic surgery in recent 20 years: A bibliometric analysis.

BACKGROUND: In recent years, platelet-rich plasma (PRP) has been used in plastic surgery, dermatology, and other treatment procedures worldwide. Since the number of scientific writings has been significantly increasing, it is challenging to generate a manual compilation and systematic review of PRP's therapeutic applications in dermatology and plastic surgeries. This study aimed to make a bibliometric analysis of the literature in the field and evaluate research hotspots and frontiers in this field in the past 20 years. METHODS: Using the Academic Search Premier and ScienceDirect defined search terms, we searched the Web of Science Core Collection (WoSCC) and Scopus databases. All data were analyzed using CiteSpace 5.8.R3 and VOSviewer, including countries, institutions, authors, keywords, cited authors, cited journals, cited references, discovered research hotspots, and frontiers. RESULTS: A total of 1931 studies were retrieved. The number of publications on PRP application in dermatology and plastic surgeries showed a yearly increase. The United States was the most significant contributor to this field, while Italy's contribution was noteworthy. The journal with the highest number of relevant articles in dermatology and plastic surgery included the Journal of Cosmetic Dermatology. However, the Wound Repair and Regeneration and International Journal of Molecular Sciences were the leading journals that should be paid attention to in the future. Author Anitua E from the Tor Vergata University of Rome published the most publications in this field. In the keyword co-occurrence analysis, all keywords were divided into six clusters, and the most common one in recent years was "PRP for facial beauty." Facial rejuvenation, scar, and alopecia were the main hotspots and research trends in this field. CONCLUSIONS: Based on the current global trends, the use of PRP in cosmetics and skin care is receiving increasing attention from researchers and clinicians. Recently, an increasing number of articles on PRP's application in skin tissue repair have been published in the United States and Italy. The number of studies on hair loss, facial rejuvenation, and scar management is increasing, suggesting that these subjects may become research hotspots for PRP in dermatology and cosmetic surgeries in recent years.

Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations.

Mutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn-/- mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn-/- mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal a previously unappreciated astroglial pathology as a potential key mechanism in neurodegeneration in FTLD-GRN.