Extracellular Matrix Interactome in Modulating Vascular Homeostasis and Remodeling.

The ECM (extracellular matrix) is a major component of the vascular microenvironment that modulates vascular homeostasis. ECM proteins include collagens, elastin, noncollagen glycoproteins, and proteoglycans/glycosaminoglycans. ECM proteins form complex matrix structures, such as the basal lamina and collagen and elastin fibers, through direct interactions or lysyl oxidase-mediated cross-linking. Moreover, ECM proteins directly interact with cell surface receptors or extracellular secreted molecules, exerting matricellular and matricrine modulation, respectively. In addition, extracellular proteases degrade or cleave matrix proteins, thereby contributing to ECM turnover. These interactions constitute the ECM interactome network, which is essential for maintaining vascular homeostasis and preventing pathological vascular remodeling. The current review mainly focuses on endogenous matrix proteins in blood vessels and discusses the interaction of these matrix proteins with other ECM proteins, cell surface receptors, cytokines, complement and coagulation factors, and their potential roles in maintaining vascular homeostasis and preventing pathological remodeling.

Heterogeneous integration of single-crystalline complex-oxide membranes.

Complex-oxide materials exhibit a vast range of functional properties desirable for next-generation electronic, spintronic, magnetoelectric, neuromorphic, and energy conversion storage devices1-4. Their physical functionalities can be coupled by stacking layers of such materials to create heterostructures and can be further boosted by applying strain5-7. The predominant method for heterogeneous integration and application of strain has been through heteroepitaxy, which drastically limits the possible material combinations and the ability to integrate complex oxides with mature semiconductor technologies. Moreover, key physical properties of complex-oxide thin films, such as piezoelectricity and magnetostriction, are severely reduced by the substrate clamping effect. Here we demonstrate a universal mechanical exfoliation method of producing freestanding single-crystalline membranes made from a wide range of complex-oxide materials including perovskite, spinel and garnet crystal structures with varying crystallographic orientations. In addition, we create artificial heterostructures and hybridize their physical properties by directly stacking such freestanding membranes with different crystal structures and orientations, which is not possible using conventional methods. Our results establish a platform for stacking and coupling three-dimensional structures, akin to two-dimensional material-based heterostructures, for enhancing device functionalities8,9.

Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

Multimodal data fusion based on IGERNNC algorithm for detecting pathogenic brain regions and genes in Alzheimer's disease.

At present, the study on the pathogenesis of Alzheimer's disease (AD) by multimodal data fusion analysis has been attracted wide attention. It often has the problems of small sample size and high dimension with the multimodal medical data. In view of the characteristics of multimodal medical data, the existing genetic evolution random neural network cluster (GERNNC) model combine genetic evolution algorithm and neural network for the classification of AD patients and the extraction of pathogenic factors. However, the model does not take into account the non-linear relationship between brain regions and genes and the problem that the genetic evolution algorithm can fall into local optimal solutions, which leads to the overall performance of the model is not satisfactory. In order to solve the above two problems, this paper made some improvements on the construction of fusion features and genetic evolution algorithm in GERNNC model, and proposed an improved genetic evolution random neural network cluster (IGERNNC) model. The IGERNNC model uses mutual information correlation analysis method to combine resting-state functional magnetic resonance imaging data with single nucleotide polymorphism data for the construction of fusion features. Based on the traditional genetic evolution algorithm, elite retention strategy and large variation genetic algorithm are added to avoid the model falling into the local optimal solution. Through multiple independent experimental comparisons, the IGERNNC model can more effectively identify AD patients and extract relevant pathogenic factors, which is expected to become an effective tool in the field of AD research.

Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane.

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1ß, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.

Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia.

BACKGROUND: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents. METHODS: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE-/- and LDLR-/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia. RESULTS: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE-/- and LDLR-/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7-mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization. CONCLUSIONS: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.

Enhancing Carrier Transport in 2D/3D Perovskite Heterostructures through Organic Cation Fluorination.

The interfacial 2D/3D perovskite heterostructures have attracted extensive attention due to their unique ability to combine the high stability of 2D perovskites with the remarkable efficiency of 3D perovskites. However, the carrier transport mechanism within the 2D/3D perovskite heterostructures remains unclear. In this study, the carrier transport dynamics in 2D/3D perovskite heterostructures through a variety of time-resolved spectroscopic measurements is systematically investigated. Time-resolved photoluminescence results reveal nanosecond hole transfer from the 3D to 2D perovskites, with enhanced efficiency through the introduction of fluorine atoms on the phenethylammonium (PEA) cation. Transient absorption measurements unveil the ultrafast picosecond electron and energy transfer from 2D to 3D perovskites. Furthermore, it is demonstrated that the positioning of fluorination on the PEA cations effectively regulates the efficiency of charge and energy transfer within the heterostructures. These insightful findings shed light on the underlying carrier transport mechanism and underscore the critical role of cation fluorination in optimizing carrier transport within 2D/3D perovskite heterostructure-based devices.

Development of a near-infrared single-photon 3D imaging LiDAR based on 64×64 InGaAs/InP array detector and Risley-prism scanner.

A near-infrared single-photon lidar system, equipped with a 64×64 resolution array and a Risley prism scanner, has been engineered for daytime long-range and high-resolution 3D imaging. The system's detector, leveraging Geiger-mode InGaAs/InP avalanche photodiode technology, attains a single-photon detection efficiency of over 15% at the lidar's 1064 nm wavelength. This efficiency, in tandem with a narrow pulsed laser that boasts a single-pulse energy of 0.5 mJ, facilitates 3D imaging capabilities for distances reaching approximately 6 kilometers. The Risley scanner, composing two counter-rotating wedge prisms, is designed to perform scanning measurements across a 6-degree circular field-of-view. Precision calibration of the scanning angle and the beam's absolute direction was achieved using a precision dual-axis turntable and a collimator, culminating in 3D imaging with an exceptional scanning resolution of 28 arcseconds. Additionally, this work has developed a novel spatial domain local statistical filtering framework, specifically designed to separate daytime background noise photons from the signal photons, enhancing the system's imaging efficacy in varied lighting conditions. This paper showcases the advantages of array-based single-photon lidar image-side scanning technology in simultaneously achieving high resolution, a wide field-of-view, and extended detection range.

Bmo-miR-6498-5p suppresses Bombyx mori nucleopolyhedrovirus infection by down-regulating BmPLPP2 to modulate pyridoxal phosphate content in B. mori.

The RNA interference pathway mediated by microRNAs (miRNAs) is one of the methods to defend against viruses in insects. Recent studies showed that miRNAs participate in viral infection by binding to target genes to regulate their expression. Here, we found that the Bombyx mori miRNA, miR-6498-5p was down-regulated, whereas its predicted target gene pyridoxal phosphate phosphatase PHOSPHO2 (BmPLPP2) was up-regulated upon Bombyx mori nucleopolyhedrovirus (BmNPV) infection. Both in vivo and in vitro experiments showed that miR-6498-5p targets BmPLPP2 and suppresses its expression. Furthermore, we found miR-6498-5p inhibits BmNPV genomic DNA (gDNA) replication, whereas BmPLPP2 promotes BmNPV gDNA replication. As a pyridoxal phosphate (PLP) phosphatase (PLPP), the overexpression of BmPLPP2 results in a reduction of PLP content, whereas the knockdown of BmPLPP2 leads to an increase in PLP content. In addition, exogenous PLP suppresses the replication of BmNPV gDNA; in contrast, the PLP inhibitor 4-deoxypyridoxine facilitates BmNPV gDNA replication. Taken together, we concluded that miR-6498-5p has a potential anti-BmNPV role by down-regulating BmPLPP2 to modulate PLP content, but BmNPV induces miR-6498-5p down-regulation to promote its proliferation. Our findings provide valuable insights into the role of host miRNA in B. mori-BmNPV interaction. Furthermore, the identification of the antiviral molecule PLP offers a novel perspective on strategies for preventing and managing viral infection in sericulture.

Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification.

BACKGROUND: Vascular calcification is closely related to the all-cause mortality of cardiovascular events. Basement membrane protein nidogen-2 is a key component of the vascular extracellular matrix microenvironment and we recently found it is pivotal for the maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). However, whether nidogen-2 is involved in VSMCs osteochondrogenic transition and vascular calcification remains unclear. METHODS: VSMCs was treated with high-phosphate to study VSMC calcification in vitro. Three different mice models (5/6 nephrectomy-induced chronic renal failure, cholecalciferol-overload, and periadventitially administered with CaCl2) were used to study vascular calcification in vivo. Membrane protein interactome, coimmunoprecipitation, flow cytometric binding assay, surface plasmon resonance, G protein signaling, VSMCs calcium assays were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Nidogen-2 protein levels were significantly reduced in calcified VSMCs and aortas from mice in different vascular calcification model. Nidogen-2 deficiency exacerbated high-phosphate-induced VSMC calcification, whereas the addition of purified nidogen-2 protein markedly alleviated VSMC calcification in vitro. Nidogen-2-/- mice exhibited aggravated aorta calcification compared to wild-type (WT) mice in response to 5/6 nephrectomy, cholecalciferol-overload, and CaCl2 administration. Further unbiased coimmunoprecipitation and interactome analysis of purified nidogen-2 and membrane protein in VSMCs revealed that nidogen-2 directly binds to LGR4 (leucine-rich repeat G-protein-coupled receptor 4) with KD value 26.77 nM. LGR4 deficiency in VSMCs in vitro or in vivo abolished the protective effect of nidogen-2 on vascular calcification. Of interest, nidogen-2 biased activated LGR4-Gαq-PKCα (protein kinase Cα)-AMPKα1 (AMP-activated protein kinase α1) signaling to counteract VSMCs osteogenic transition and mineralization. CONCLUSIONS: Nidogen-2 is a novel endogenous ligand of LGR4 that biased activated Gαq- PKCα-AMPKα1 signaling and inhibited vascular calcification.

Unspliced XBP1 Counteracts ß-Catenin to Inhibit Vascular Calcification.

BACKGROUND: Vascular calcification is a prevalent complication in chronic kidney disease and contributes to increased cardiovascular morbidity and mortality. XBP1 (X-box binding protein 1), existing as the XBP1u (unspliced XBP1) and XBP1s (spliced XBP1) forms, is a key component of the endoplasmic reticulum stress involved in vascular diseases. However, whether XBP1u participates in the development of vascular calcification remains unclear. METHODS: We aim to investigate the role of XBP1u in vascular calcification. XBP1u protein levels were reduced in high phosphate-induced calcified vascular smooth muscle cells, calcified aortas from mice with adenine diet-induced chronic renal failure, and calcified radial arteries from patients with chronic renal failure. RESULTS: Inhibition of XBP1u rather than XBP1s upregulated in the expression of the osteogenic markers Runx2 (runt-related transcription factor 2) and Msx2 (msh homeobox 2), and exacerbated high phosphate-induced vascular smooth muscle cell calcification, as verified by calcium deposition and Alizarin red S staining. In contrast, XBP1u overexpression in high phosphate-induced vascular smooth muscle cells significantly inhibited osteogenic differentiation and calcification. Consistently, smooth muscle cell-specific XBP1 deficiency in mice markedly aggravated the adenine diet- and 5/6 nephrectomy-induced vascular calcification compared with that in the control littermates. Further interactome analysis revealed that XBP1u is bound directly to ß-catenin, a key regulator of vascular calcification, via amino acid (aa) 205-230 in its C-terminal degradation domain. XBP1u interacted with ß-catenin to promote its ubiquitin-proteasomal degradation and thus inhibited ß-catenin/TCF (T-cell factor)-mediated Runx2 and Msx2 transcription. Knockdown of ß-catenin abolished the effect of XBP1u deficiency on vascular smooth muscle cell calcification, suggesting a ß-catenin-mediated mechanism. Moreover, the degradation of ß-catenin promoted by XBP1u was independent of GSK-3ß (glycogen synthase kinase 3ß)-involved destruction complex. CONCLUSIONS: Our study identified XBP1u as a novel endogenous inhibitor of vascular calcification by counteracting ß-catenin and promoting its ubiquitin-proteasomal degradation, which represents a new regulatory pathway of ß-catenin and a promising target for vascular calcification treatment.

PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing.

BACKGROUND: Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies indicate the metabolic reprogramming may be involved in VSMC phenotypic transition. However, the definite molecules that link energy metabolism to distinct VSMC phenotype remain elusive. METHODS: A carotid artery injury model was used to study postinjury neointima formation as well as VSMC phenotypic transition in vivo. RNA-seq analysis, cell migration assay, collagen gel contraction assay, wire myography assay, immunoblotting, protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: We collected cell energy-regulating genes by using Gene Ontology annotation and applied RNA-Seq analysis of transforming growth factor-ß or platelet-derived growth factor BB stimulated VSMCs. Six candidate genes were overlapped from energy metabolism-related genes and genes reciprocally upregulated by transforming growth factor-ß and downregulated by platelet-derived growth factor BB. Among them, prohibitin 2 has been reported to regulate mitochondrial oxidative phosphorylation. Indeed, prohibitin 2-deficient VSMCs lost the contractile phenotype as evidenced by reduced contractile proteins. Consistently, Phb2SMCKO mice were more susceptible to postinjury VSMC proliferation and neointima formation compared with Phb2flox/flox mice. Further protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay revealed that prohibitin 2, through its C-terminus, directly interacts with hnRNPA1, a key modulator of pyruvate kinase M1/2 (PKM) mRNA splicing that promotes PKM2 expression and glycolysis. Prohibitin 2 deficiency facilitated PKM1/2 mRNA splicing and reversion from PKM1 to PKM2, and enhanced glycolysis in VSMCs. Blocking prohibitin 2-hnRNPA1 interaction resulted in increased PKM2 expression, enhanced glycolysis, repressed contractile marker genes expression in VSMCs, as well as aggravated postinjury neointima formation in vivo. CONCLUSIONS: Prohibitin 2 maintains VSMC contractile phenotype by interacting with hnRNPA1 to counteract hnRNPA1-mediated PKM alternative splicing and glucose metabolic reprogramming.

Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice.

BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear. METHODS: Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet-induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed. RESULTS: We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a ß-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE-/- mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in ß-aminopropionitrile-treated mice, Fbn1C1041G/+ mice, and Ang II-infused ApoE-/- mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency. CONCLUSIONS: This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid-lowering drug may represent a promising therapeutic approach for TAAD.

Impact of visit characteristics on intention to recommend HPV vaccine: An experiment with US health care professionals.

OBJECTIVE: Presumptive recommendations that assume parents want to vaccinate can increase human papillomavirus (HPV) vaccine uptake. We sought to examine how visit characteristics affect health care professionals' (HCPs) intention to use this evidence-based recommendation style. METHODS: In 2022, we conducted an online experiment with 2527 HCPs who had a role in adolescent vaccination in the United States. Participants read 1 of 8 randomly assigned vignettes about a well-child visit. Using a 2 × 2 × 2 between-subjects factorial design, the vignettes varied the following visit characteristics: patient age (9 vs. 12-year-old), prior parental vaccine refusal (yes vs. no), and time pressure on the HCP (low vs. high). HCPs reported on their intention to use a presumptive HPV vaccine recommendation, as well as on related attitudes, subjective norms, and self-efficacy. Analyses used 3-way analysis of variance and parallel mediation. RESULTS: Participants were pediatricians (26%), family/general medicine physicians (22%), advanced practitioners (24%), and nursing staff (28%). Overall, about two-thirds of HCPs (64%) intended to use a presumptive recommendation. Intentions were higher for older children (b = 0.23) and parents without prior vaccine refusal (b = 0.39, both p < 0.001). Time pressure had no main effect or interactions. HCPs' attitudes and self-efficacy partially mediated effects of patient age and prior vaccine refusal (range of b = 0.04-0.28, all p < 0.05). CONCLUSION: To better support visits with younger children and parents who have refused vaccines, HCPs may need more training for making presumptive recommendations for HPV vaccine. Reinforcing positive attitudes and self-efficacy can help HCPs adopt this evidence-based recommendation style.

Conserved Role of mTORC1 Signaling in B Cell Immunity in Teleost Fish.

Mammalian studies have demonstrated that B cell immune responses are regulated by mechanistic target of rapamycin complex 1 (mTORC1) signaling. Teleost fish represent the oldest living bony vertebrates that contain bona fide B cells. So far, whether the regulatory mechanism of mTORC1 signaling in B cells occurred in teleost fish is still unknown. In this study, we developed a fish model by using rapamycin (RAPA) treatment to inhibit mTORC1 signaling and demonstrated the role of mTORC1 signaling in teleost B cells. In support, we found inhibition of mTORC1 signaling by RAPA decreased the phagocytic capacity, proliferation, and Ig production of B cells. Critically, Flavobacterium columnare induced specific IgM binding in serum, and these titers were significantly inhibited by RAPA treatment, thus decreasing Ab-mediated agglutination of F. columnare and significantly increasing the susceptibility of fish upon F. columnare reinfection. Collectively, our findings elucidated that the mTORC1 pathway is evolutionarily conserved in regulating B cell responses, thus providing a new point for understanding the B cells functions in teleost fish.

Kinetic energy distributions of atomic ions from disintegration of argon containing nanoclusters in moderately intense nanosecond laser fields: Coulomb explosion or hydrodynamic expansion.

We report kinetic energies (KE) of multiply charged atomic ions (MCAI) from interactions of moderately intense nanosecond lasers at 532 nm with argon containing clusters, including neat and doped clusters with a trace amount of trichlorobenzene. We develop a mathematical method to retrieve speed and thereby kinetic energy information from analyzing the time-of-flight profiles of the MCAI. This method should be generally applicable in detections of energetic charged particles with high velocities, a realm where velocity map imaging is inadequate. From this analysis, we discover that the KE of MCAI from doped clusters demonstrates a quadratic dependence on the charge of the atomic ions, while for neat clusters, the dependence is cubic. This result confirms the nature of the cluster disintegration process to be dominated by Coulomb explosion. This result bears more similarity to reports from extreme vacuum ultraviolet (EUV) fields with similar intensities, than to reports from near infrared (NIR) intense laser fields. However, the charge state distribution from our experiment is the opposite: we observe more higher charge state ions than reported in EUV fields, and our charge state distribution is actually similar to those reported in NIR fields. We also report a significant effect of the external electric field on the charge state distribution of the atomic ions: the presence of an electric field can significantly increase the charge from the atomic ions, as shown by a three-fold reduction in the average kinetic energy per charge. Although molecular dynamics simulations have been implemented for experiments in the EUV and NIR, our results allude to the need of a concerted effort in this regime of moderately intense nanosecond laser fields. The significant decrease in charge state distribution and the significant increase in KE from doped clusters, compared with neat clusters, is a telltale sign that the true interaction time between the laser field and the cluster may be substantially shorter than the duration of the laser, a welcome relief for molecular dynamics simulations.

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents.

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Nomogram for predicting venous thromboembolism after spinal surgery.

PURPOSE: This study aimed to establish a nomogram to predict the risk of venous thromboembolism (VTE), identifying potential risk factors, and providing theoretical basis for prevention of VTE after spinal surgery. METHODS: A retrospective analysis was conducted on 2754 patients who underwent spinal surgery. The general characteristics of the training group were initially screened using univariate logistic analysis, and the LASSO method was used for optimal prediction. Subsequently, multivariate logistic regression analysis was performed to identify independent risk factors for postoperative VTE in the training group, and a nomogram for predict risk of VTE was established. The discrimination, calibration, and clinical usefulness of the nomogram were separately evaluated using the C-index, receiver operating characteristic curve, calibration plot and clinical decision curve, and was validated using data from the validation group finally. RESULTS: Multivariate logistic regression analysis identified 10 independent risk factors for VTE after spinal surgery. A nomogram was established based on these independent risk factors. The C-index for the training and validation groups indicating high accuracy and stability of the model. The area under the receiver operating characteristic curve indicating excellent discrimination ability; the calibration curves showed outstanding calibration for both the training and validation groups. Decision curve analysis showed the clinical net benefit of using the nomogram could be maximized in the probability threshold range of 0.01-1. CONCLUSION: Patients undergoing spinal surgery with elevated D-dimer levels, prolonger surgical, and cervical surgery have higher risk of VTE. The nomogram can provide a theoretical basis for clinicians to prevent VTE.

ADAMTS7-Mediated Complement Factor H Degradation Potentiates Complement Activation to Contributing to Renal Injuries.

BACKGROUND: The dysfunction of complement factor H (CFH), the main soluble complement negative regulator, potentiates various complement-induced renal injuries. However, insights into the underlying mechanism of CFH dysfunction remain limited. In this study, we investigated whether extracellular protease-mediated degradation accounts for CFH dysfunction in complement-mediated renal injuries. METHODS: An unbiased interactome of lupus mice kidneys identified CFH-binding protease. In vitro cleavage assay clarified CFH degradation. Pristane-induced SLE or renal ischemia-reperfusion (I/R) injury models were used in wild-type and ADAMTS7-/- mice. RESULTS: We identified the metalloprotease ADAMTS7 as a CFH-binding protein in lupus kidneys. Moreover, the upregulation of ADAMTS7 correlated with CFH reduction in both lupus mice and patients. Mechanistically, ADAMTS7 is directly bound to CFH complement control protein (CCP) 1-4 domain and degraded CCP 1-7 domain through multiple cleavages. In mice with lupus nephritis or renal I/R injury, ADAMTS7 deficiency alleviated complement activation and related renal pathologies, but without affecting complement-mediated bactericidal activity. Adeno-associated virus-mediated CFH silencing compromised these protective effects of ADAMTS7 knockout against complement-mediated renal injuries in vivo. CONCLUSION: ADAMTS7-mediated CFH degradation potentiates complement activation and related renal injuries. ADAMTS7 would be a promising anticomplement therapeutic target that does not increase bacterial infection risk.

Effects of vaginal dilation therapy on vaginal condition and sexual function of endometrial cancer patients treated with radiotherapy after surgery.

OBJECTIVE: This study aimed to evaluate the effect of vaginal dilation therapy on vaginal length, vaginal stenosis, vaginal elasticity, and sexual function of endometrial cancer patients treated with radiotherapy after surgery. METHODS: A total of 117 women were enrolled in this study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal length, vaginal diameter, vaginal elasticity, and sexual function before radiotherapy, after radiotherapy, and after 6 months of vaginal dilation therapy. Their vaginal condition was assessed by customized vaginal dilating molds. Their sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyze all the data. RESULTS: According to multivariate analysis, vaginal diameter (ß = 0.300, 95% CI [0.217-1.446], p = 0.010) and sexual intercourse frequency before diagnosis (ß = 0.424, 95% CI [0.164-0.733], p = 0.006) were significantly correlated with female sexual function after radiotherapy. Vaginal dilation therapy helped increase vaginal length, improve vaginal stenosis and sexual function (p < 0.05), though most of the figures at the end of the intervention did not fully return to those before radiotherapy. Noticeably, vaginal dilation therapy was ineffective in improving vaginal elasticity and the incidence rate of female sexual dysfunction (p > 0.05). Moreover, patients with medium or good vaginal elasticity benefited more from vaginal dilation therapy than patients with poor vaginal elasticity (p < 0.05). CONCLUSION: Vaginal dilation therapy should be carried out timely and preventatively in endometrial cancer patients treated with radiotherapy after surgery to improve their vaginal condition and sexual function.