Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes.

Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.

Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4.

Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and ß subunits1-3. A tethered agonism mediated by the 'Stachel sequence' of the ß subunit has been proposed to have central roles in aGPCR activation4-6. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the Gs heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-ß-Gs complex and the ADGRG4-ß-Gs complex (in which ß indicates the ß subunit of the aGPCR)-and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)-IP15-Gs). The Stachel sequences of both ADGRG2-ß and ADGRG4-ß assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-ß or ADGRG4-ß extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-Gs complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM-p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-ß structures. By converting the 'finger residues' to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs.

Memristor-Based Bionic Tactile Devices: Opening the Door for Next-Generation Artificial Intelligence.

Bioinspired tactile devices can effectively mimic and reproduce the functions of the human tactile system, presenting significant potential in the field of next-generation wearable electronics. In particular, memristor-based bionic tactile devices have attracted considerable attention due to their exceptional characteristics of high flexibility, low power consumption, and adaptability. These devices provide advanced wearability and high-precision tactile sensing capabilities, thus emerging as an important research area within bioinspired electronics. This paper delves into the integration of memristors with other sensing and controlling systems and offers a comprehensive analysis of the recent research advancements in memristor-based bionic tactile devices. These advancements incorporate artificial nociceptors and flexible electronic skin (e-skin) into the category of bio-inspired sensors equipped with capabilities for sensing, processing, and responding to stimuli, which are expected to catalyze revolutionary changes in human-computer interaction. Finally, this review discusses the challenges faced by memristor-based bionic tactile devices in terms of material selection, structural design, and sensor signal processing for the development of artificial intelligence. Additionally, it also outlines future research directions and application prospects of these devices, while proposing feasible solutions to address the identified challenges.

FURION: modeling of FEL pulses propagation in dispersive soft X-ray beamline systems.

Modern X-ray free-electron lasers (XFELs) can generate pulses with durations ranging from femtoseconds to attoseconds. The numerical evaluation of ultra-short XFEL pulses through beamline systems is a critical process of beamline system design. However, the bandwidth of such ultra-short XFEL pulses is often non-negligible, and the propagation cannot be simply approximated using the central wavelength, especially in dispersive beamline systems. We developed a numerical model which is called Fourier optics based Ultrashort x-Ray pulse propagatION tool (FURION). This model can not only be used to simulate dispersive beamline systems but also to evaluate non-dispersive beamline systems. The FURION model utilizes Fresnel integral and angular spectrum integral to perform ultra-short XFEL pulse propagation in free space. We also present the method for XFEL pulse propagation through different types of dispersive gratings, which are commonly used in soft X-ray beamline systems. By using FURION, a start-to-end simulation of the FEL-1 beamline system at Shenzhen superconducting soft X-ray free electron laser (S3FEL) is carried out. This model can also be used to evaluate gratings-based spectrometers, beam splitters, pulse compressors, and pulse stretchers. This work provides valuable insights into the start-to-end simulation of X-ray beamline systems.

BI-2865, a pan-KRAS inhibitor, reverses the P-glycoprotein induced multidrug resistance in vitro and in vivo.

BACKGROUND: Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. METHODS: The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. RESULTS: We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity. CONCLUSIONS: This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.

Chemical Proteomics and Morphological Profiling Revealing MYDGF as a Target for Synthetic Anticancer Macromolecules.

Biodegradable guanidinium-functionalized polycarbonates kill cancer cells via membrane translocation without causing resistance after repeated use, but the exact molecular targets of the polycarbonates are unknown. Here, we investigate the protein targets of the polycarbonates through affinity-based protein profiling and report myeloid-derived growth factor (MYDGF) as the main protein target. Direct binding of the polycarbonates to MYDGF protein is validated through biolayer interferometry. MYDGF is overexpressed in a range of cancer cells, and knockdown of MYDGF is shown to reduce cell proliferation in cancer cells. Through morphological profiling, we also identify similarities in phenotypic effects of the functionalized polycarbonates with topoisomerase I inhibitors, MDM2 inhibitors, and phosphatidylinositol 3kinase inhibitors against cancer cells, suggesting a common mechanism through the PIK3/AKT pathway leading to apoptosis. These findings present the first macromolecular compound targeting MYDGF and may serve as an example for MYDGF modulation as a potential new target for macromolecular chemotherapeutic development.

Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism.

Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.

Transvenous endocardial pacing with SelectSecure™ 3830 lead in pediatric patients: case series of two infants and a literature review.

BACKGROUND: The SelectSecure™ 3830 lead is an innovative, lumenless, and thin active fixed lead with a nonretractable screw-in tip and a diameter of 4.1 Fr, making it the thinnest pacing lead available. Its high anti-extrusion properties and durability have shown favorable outcomes in cardiac pacing, especially in pediatric patients. The superfine design and easy implantation of the lead have rendered it a preferred choice in children, particularly in cases of congenital heart disease. CASE PRESENTATION: This case series presents two infant patients who underwent transvenous endocardial pacing using the SelectSecure™ 3830 lead, along with a comprehensive literature review on the topic. The study followed the patients for 5 years and 3 years, respectively, and observed stable pacing parameters, indicating a positive therapeutic outcome and safety. This article discusses the optimal age and body shape for transvenous lead implantation in infants and highlights the advantages and disadvantages of endocardial and epicardial pacing approaches. Although endocardial pacing offers several benefits such as minimal trauma, short hospital stay, and longer battery life, it may not be suitable for intracardiac shunts, and venous occlusion remains a concern. On the other hand, epicardial pacing may be considered for children with challenging endocardial access but comes with higher risk of lead failure and coronary artery compression. This study emphasizes the importance of careful follow-up in pediatric patients with pacing, as lead failure can occur in young patients owing to growth and development, leading to syncope and battery depletion. The article also underscores the significance of selecting the appropriate pacing location to minimize the impact of cardiac function, with right ventricular septal pacing emerging as a preferable option. CONCLUSIONS: The SelectSecure™ 3830 lead presents a promising solution for transvenous endocardial pacing in pediatric patients with high degree atrioventricular block and bradycardia, ensuring safe and effective pacing as they grow and develop.

Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers in the world. The therapeutic outlook for HCC patients has significantly improved with the advent and development of systematic and targeted therapies such as sorafenib and lenvatinib; however, the rise of drug resistance and the high mortality rate necessitate the continuous discovery of effective targeting agents. To discover novel anti-HCC compounds, we first constructed a deep learning-based chemical representation model to screen more than 6 million compounds in the ZINC15 drug-like library. We successfully identified LGOd1 as a novel anticancer agent with a characteristic levoglucosenone (LGO) scaffold. The mechanistic studies revealed that LGOd1 treatment leads to HCC cell death by interfering with cellular copper homeostasis, which is similar to a recently reported copper-dependent cell death named cuproptosis. While the prototypical cuproptosis is brought on by copper ionophore-induced copper overload, mechanistic studies indicated that LGOd1 does not act as a copper ionophore, but most likely by interacting with the copper chaperone protein CCS, thus LGOd1 represents a potentially new class of compounds with unique cuproptosis-inducing property. In summary, our findings highlight the critical role of bioavailable copper in the regulation of cell death and represent a novel route of cuproptosis induction.

Addressing causal relationship between drinking behavior and metabolic syndrome: one-sample Mendelian randomization analysis.

AIMS: Alcohol drinking is associated with central obesity, hypertension, and hyperlipidemia, which further causes metabolic syndrome (MetS). However, prior epidemiological studies on such associations lack experimental evidence for a causal relationship. This study aims to explore the causal relationship between drinking behavior and MetS in Taiwan population by using Mendelian randomization (MR) analysis. METHODS: A cross-sectional study was conducted using the Taiwan Biobank database, which comprised 50 640 Han Chinese who were 30-70 years old without cancer from 2008 to 2020. In MR analysis, we constructed weighted and unweighted genetic risk scores by calculating SNP alleles significantly associated with alcohol drinking. We calculated odds ratios and 95% confidence interval (CI) by using a two-stage regression model. RESULTS: A total of 50 640 participants were included with a mean age of 49.5 years (SD: 1.67 years), 36.6% were men. The adjusted odds ratio (aOR) of MetS per 5% increase in the likelihood of genetic predisposition to drink based on weighted genetic risk score with adjustment was 1.11 (95% CI: 1.10, 1.12, P < .001). Analysis was also conducted by grouping the likelihood of genetic predisposition to drink based on quartiles with multivariate adjustment. Using Q1 as the reference group, the aORs of MetS for Q2, Q3, and Q4 were 1.19 (1.12, 1.27, p < .001), 1.31 (1.23, 1.40, p < .001), and 1.87 (1.75, 2.00, p < .001), respectively, for the weighted genetic risk score. CONCLUSIONS: This study shows a modest relationship between drinking behavior and MetS by using MR analysis.

Gold nanoparticles exhibit anti-osteoarthritic effects via modulating interaction of the "microbiota-gut-joint" axis.

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of "microbiota-gut-joint" axis, which might provide promising therapeutic strategies for OA.

Tolerance to decentration of biaspheric intraocular lenses with refractive phase-ring extended depth of focus and diffractive trifocal designs.

PURPOSE: This study aimed to investigate the in vitro tolerance to decentration of biaspheric intraocular lens (IOLs) with refractive phase-ring extended depth-of-focus (EDOF) and diffractive trifocal designs. METHODS: This experimental study was carried out at the Department of Optics and Optometry and Vision Science, University of Valencia, Spain. The modulation transfer function (MTF) of the ETLIO130C EDOF and the TFLIO130C trifocal IOLs (AST Products Inc., Billerica, MA, USA) were determined at different levels of decentration for a given wavelength and pupil diameter using the PMTF optical bench (Lambda-X Ophthalmics, Nivelles, Belgium). The modulation transfer function (MTF) curves, the through-focus MTF curves, and the Strehl ratios were measured at 3-mm pupil aperture for 0.25-, 0.50- and 0.75-mm decentration. RESULTS: The optical design of the trifocal TFLIO130C IOL is robust to small decentrations, with virtually no change in MTF response for 0.25 mm decentration. For greater decentration levels, the MTF response is slightly reduced with increasing decentration. The ETLIO130C EDOF design is robust to decentration, as the MTF response is only minimally affected when increasing the decentration up to 0.75 mm. CONCLUSIONS: MTF responses are slightly reduced with greater levels of decentration, but the range of focus provided by both trifocal and EDOF designs are preserved. The effects for average levels of decentration reported in the literature are minimum for both IOL designs.

Effectiveness of continuous home wound care on patients with diabetic foot ulcers.

AIMS: To explore the effectiveness of continuous home wound care on patients with diabetic foot ulcers (DFUs). DESIGN: A non-randomized parallel controlled non-inferiority trial. METHODS: Patients with Wagner grade I-III DFUs hospitalized in two distant campuses of the same hospital were included. All patients received infection treatment and wound bed preparation during hospitalization; after discharge, patients in one of the campuses received routine outpatient wound care, and those treated in the other received continuous home wound care. The per-protocol analysis was performed to compare ulcer healing indicators, knowledge, health belief, self-management behaviour and medical expenses of the two groups. RESULTS: Between October 2021 and December 2022, 116 patients were enrolled in the study; 107 completed. The home care was not inferior in terms of ulcer healing rate and demonstrated significant enhancements in the understanding of warning signs, health belief and self-management behaviour. Additionally, the home care saved 220.38 yuan (24.32 UK pounds) in direct medical expenses for each additional one square centimetre of ulcer healing. CONCLUSION: The continuous home wound care enhanced self-management behaviour of the patients and saved their medical expenses while not compromising ulcer healing. IMPACT: This is to date the first study to conduct continuous home wound care practice for patients with DFUs and confirmed its safety and non-inferiority in ulcer healing, and supported its superiority in improving self-management behaviour and saving medical expenses. REPORTING METHOD: We have adhered to the transparent reporting of evaluations with nonrandomized designs statements and the corresponding checklist was followed. PATIENT OR PUBLIC CONTRIBUTION: The patients and their primary caregivers were involved in intervention design, we received input from them about the factors that facilitate and hinder patient self-management behaviours to develop intervention strategies.

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles.

A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method enables a rapid access to heterocycles containing a trifluoromethyl group.

[A multicenter study of neonatal stroke in Shenzhen, China]. / 深圳市新生儿脑卒中多中心现况调查.

OBJECTIVES: To investigate the incidence rate, clinical characteristics, and prognosis of neonatal stroke in Shenzhen, China. METHODS: Led by Shenzhen Children's Hospital, the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022. The incidence, clinical characteristics, treatment, and prognosis of neonatal stroke in Shenzhen were analyzed. RESULTS: The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137, 1/6 060, and 1/7 704, respectively. Ischemic stroke accounted for 75% (27/36); boys accounted for 64% (23/36). Among the 36 neonates, 31 (86%) had disease onset within 3 days after birth, and 19 (53%) had convulsion as the initial presentation. Cerebral MRI showed that 22 neonates (61%) had left cerebral infarction and 13 (36%) had basal ganglia infarction. Magnetic resonance angiography was performed for 12 neonates, among whom 9 (75%) had involvement of the middle cerebral artery. Electroencephalography was performed for 29 neonates, with sharp waves in 21 neonates (72%) and seizures in 10 neonates (34%). Symptomatic/supportive treatment varied across different hospitals. Neonatal Behavioral Neurological Assessment was performed for 12 neonates (33%, 12/36), with a mean score of (32±4) points. The prognosis of 27 neonates was followed up to around 12 months of age, with 44% (12/27) of the neonates having a good prognosis. CONCLUSIONS: Ischemic stroke is the main type of neonatal stroke, often with convulsions as the initial presentation, involvement of the middle cerebral artery, sharp waves on electroencephalography, and a relatively low neurodevelopment score. Symptomatic/supportive treatment is the main treatment method, and some neonates tend to have a poor prognosis.

Fibroblast-Derived Extracellular Vesicle-Packaged Long Noncoding RNA Upregulated in Diabetic Skin Enhances Keratinocyte MMP-9 Expression and Delays Diabetic Wound Healing.

Accurate communication between fibroblasts and keratinocytes is crucial for diabetic wound healing. Extracellular vesicles are being explored as essential mediators of intercellular communication in the skin. However, the mechanisms underlying wound healing mediated by fibroblast-derived extracellular vesicles (Fib-EVs) remain unclear. The present study evaluated the role of long noncoding RNA upregulated in diabetic skin (lnc-URIDS) packed in Fib-EVs in the wound healing of streptozotocin-induced diabetes and the potential mechanisms of the effects. We demonstrated that high glucose induced the enrichment of lnc-URIDS in Fib-EVs, facilitated the transfer of lnc-URIDS to primary rat epidermal keratinocytes, and increased the expression of matrix metalloproteinase-9. Mechanistically, the binding of lnc-URIDS to YTH domain family protein-2 enhanced the degradation of YTH domain family protein-2 in the lysosomes, which increased the translational activity of the messenger RNA of matrix metalloproteinase-9 and ultimately induced the degradation of collagen for wound healing. The results provided an insight into the crosstalk and cooperation between fibroblasts and keratinocytes in collagen homeostasis in diabetic wounds and clarified the mechanism by which lnc-URIDS degrades collagen for diabetic wound healing.

The strategies to cure cancer patients by eradicating cancer stem-like cells.

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

Spatiotemporal response of concave VLS grating to ultra-short X-ray pulses.

In soft X-ray free-electron laser (FEL) beamlines, variable-line-spacing (VLS) gratings are often used as dispersive components of monochromators and spectrometers due to their combined dispersion and focusing properties. X-ray FEL pulses passing through the VLS grating can result in not only transverse focusing but also spatiotemporal coupling effects, such as pulse front tilt, pulse front rotation, and pulse stretching. In this paper, we present a theoretical study of the spatiotemporal response of concave VLS gratings to ultra-short X-ray pulses. The theoretical analysis indicates that the tilt angle of the non-zero diffraction orders varies with the propagation distance, and disappears at the focus, where the focal lengths and pulse stretching differ for different diffraction orders. The model demonstrates the pulse duration after the concave VLS grating is the convolution of the initial pulse duration and the stretching term induced by dispersion, while the beam size at the focus in x dimension is the convolution of the geometric scaling beam size and the dispersion term. This work provides a mathematical explanation for the spatiotemporal response of concave VLS grating to ultra-short X-ray pulses and offers valuable insights into the design of FEL grating monochromators, spectrometers, pulse compressors, and pulse stretchers.