Distraction force promotes the osteogenic differentiation of Gli1+ cells in facial sutures via primary cilia-mediated Hedgehog signaling pathway.

BACKGROUND: Trans-sutural distraction osteogenesis (TSDO) involves the application of distraction force to facial sutures to stimulate osteogenesis. Gli1+ cells in the cranial sutures play an important role in bone growth. However, whether Gli1+ cells in facial sutures differentiate into bone under distraction force is unknown. METHODS: 4-week-old Gli1ER/Td and C57BL/6 mice were used to establish a TSDO model to explore osteogenesis of zygomaticomaxillary sutures. A Gli1+ cell lineage tracing model was used to observe the distribution of Gli1+ cells and explore the role of Gli1+ cells in facial bone remodeling. RESULTS: Distraction force promoted bone remodeling during TSDO. Fluorescence and two-photon scanning images revealed the distribution of Gli1+ cells. Under distraction force, Gli1-lineage cells proliferated significantly and co-localized with Runx2+ cells. Hedgehog signaling was upregulated in Gli1+ cells. Inhibition of Hedgehog signaling suppresses the proliferation and osteogenesis of Gli1+ cells induced by distraction force. Subsequently, the stem cell characteristics of Gli1+ cells were identified. Cell-stretching experiments verified that mechanical force promoted the osteogenic differentiation of Gli1+ cells through Hh signaling. Furthermore, immunofluorescence staining and RT-qPCR experiments demonstrated that the primary cilia in Gli1+ cells exhibit Hedgehog-independent mechanosensitivity, which was required for the osteogenic differentiation induced by mechanical force. CONCLUSIONS: Our study indicates that the primary cilia of Gli1+ cells sense mechanical stimuli, mediate Hedgehog signaling activation, and promote the osteogenic differentiation of Gli1+ cells in zygomaticomaxillary sutures.

Multi-modal generative modeling for joint analysis of single-cell T cell receptor and gene expression data.

Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses.

Poloxamer 188 washing of lipoaspirate improves fat graft survival: A comparative study in nude mice.

BACKGROUND: Autologous fat transplantation is limited by the uncertainty of graft retention, impeding its application. Among the current strategies for processing lipoaspirates, high-density fat (HDF) is recommended owing to the enrichment of stem cells and washing before cotton concentration for simplicity of operation. Poloxamer 188 (P188) washing has been shown to repair the membranes of damaged cells. This study aimed to investigate the effect of P188-washing on fat graft survival and identify the best technique for processing lipoaspirates. METHODS: Lipoaspirates were prepared using centrifugation to obtain HDF, which was then washed with saline or P188 followed by cotton concentration. Tissue integrity, adipocytic activity, and viability of stromal vascular fraction (SVF) in the samples from the 3 groups were assessed. Samples were sequenced in vitro using high-throughput RNA-seq, and differentially expressed genes were validated using qPCR and western blotting (WB). After transplantation under the dorsum of nude mice for 8 weeks, the grafts were extracted and examined for residual volume, histologic characteristics, and vascularization. RESULTS: The HDF and P188 groups showed a higher survival rate of SVF, more Ki67-positive cells, intact tissue structure, and lesser fibrosis than the saline group. There were no significant differences in the density of SVF and residual volume of grafts. HDF showed significantly improved vascularization during 8 weeks. Through RNA-seq and bioinformatic analysis, notable changes in several related genes after transplantation were observed. CONCLUSIONS: P188 treatment can prevent cells from apoptosis and preserve tissue viability, thereby improving graft quality. HDF contains large amounts of SVF and can be regarded as an excellent grafting material.

Brain-Targeted Cas12a Ribonucleoprotein Nanocapsules Enable Synergetic Gene Co-Editing Leading to Potent Inhibition of Orthotopic Glioblastoma.

Gene-editing technology shows great potential in glioblastoma (GBM) therapy. Due to the complexity of GBM pathogenesis, a single gene-editing-based therapy is unlikely to be successful; therefore, a multi-gene knockout strategy is preferred for effective GBM inhibition. Here, a non-invasive, biodegradable brain-targeted CRISPR/Cas12a nanocapsule is used that simultaneously targeted dual oncogenes, EGFR and PLK1, for effective GBM therapy. This cargo nanoencapsulation technology enables the CRISPR/Cas12a system to achieve extended blood half-life, efficient blood-brain barrier (BBB) penetration, active tumor targeting, and selective release. In U87MG cells, the combinatorial gene editing system resulted in 61% and 33% knockout of EGFR and PLK1, respectively. Following systemic administration, the CRISPR/Cas12a system demonstrated promising brain tumor accumulation that led to extensive EGFR and PLK1 gene editing in both U87MG and patient-derived GSC xenograft mouse models with negligible off-target gene editing detected through NGS. Additionally, CRISPR/Cas12a nanocapsules that concurrently targeted the EGFR and PLK1 oncogenes showed superior tumor growth suppression and significantly improved the median survival time relative to nanocapsules containing single oncogene knockouts, signifying the potency of the multi-oncogene targeting strategy. The findings indicate that utilization of the CRISPR/Cas12a combinatorial gene editing technique presents a practical option for gene therapy in GBM.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Double Reinforcing Strategy with Perpendicular Plate of Ethmoid in Asian Secondary Unilateral Cleft Rhinoplasty: A Finite Element Analysis.

BACKGROUND: Deviation and asymmetry relapse after secondary unilateral cleft rhinoplasty with septal extension graft is a common yet serious problem especially among Asian patients. Therefore, finding an effective approach to reduce deformity relapse remains a great challenge to plastic surgeons. METHODS: In this study, authors established finite element models to simulate different nasal cartilage-corrected options and different reinforcing strategies in secondary unilateral cleft rhinoplasty. A load of 0.01N was given to the nasal tip to simulate the soft tissue pressure, while two loads of 0.5N were separately given to the anterior and posterior part of the septal extension graft to simulate the rhinoplasty condition. Maximum deformations were evaluated to make stability judgments. RESULTS: The maximum deformation of different cartilage correction models in ascending order was: UCL deformity with septum correction, normal nasal cartilage, UCL nasal deformity, and UCL nasal deformity with lower lateral cartilage correction. When applied L-strut reinforcement graft was harvested from the perpendicular plate of the ethmoid bone, the maximum deformation of the models decreased significantly, and strong fixation of the septum could further enhance this decreasing effect. CONCLUSIONS: Correcting the septum and lower lateral cartilage together could improve the structural stability and symmetry in secondary unilateral cleft rhinoplasty. To keep the corrected septum stable and thus reduce deformity relapse, reinforcing the L-strut with perpendicular plate of ethmoid graft while strongly anchoring the septal cartilage to the anterior nasal spine was proved to be effective in both finite element analysis and clinical observation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Analysis of the Efficacy of Psychological Intervention in 85 patients with New Coronavirus Pneumonia.

Objective: To investigate the effectiveness of strengthen psychological intervention in 85 clients who had pneumonia caused by a novel coronavirus. Methods: As the study's subjects, 162 new coronavirus pneumonia clients admitted to our hospital between January 2020 and September 2020 had their clinical records retrospectively examined. According to different nursing methods, 162 patients with new coronavirus pneumonia were separated into a control team (n=77) and an experimental team (n=85). The test group received the intense psychological intervention, whereas the controlling team only received standard nursing care. The two groups' treatment compliance and nursing satisfaction were observed, the self-rating symptom scale (SCL-90) scores and coping style (MCMQ) grades of the two teams prior to and after the interference was contrasted, and the nursing quality of the two teams was contrasted. Results: In terms of compliance, the overall treatment compliance rate of patients in the experimental group increased significantly. In terms of the psychological state of the experimental group, significant improvements were observed in all psychological dimensions of the patients in the experimental group, including a reduction in negative emotions and an increase in nursing satisfaction. In terms of self-coping, patients in the experimental group showed significant improvement in various dimensions. And the quality of nursing care in the experimental group has been significantly improved. Conclusion: This study highlights the importance of intensive psychological intervention in the overall care of COVID-19 patients and its role in improving patient treatment compliance, negative emotions, self-coping styles and patient health.

A multicrosslinked network composite hydrogel scaffold based on DLP photocuring printing for nasal cartilage repair.

Natural hydrogels are widely employed in tissue engineering and have excellent biodegradability and biocompatibility. Unfortunately, the utilization of such hydrogels in the field of three-dimensional (3D) printing nasal cartilage is constrained by their subpar mechanical characteristics. In this study, we provide a multicrosslinked network hybrid ink made of photocurable gelatin, hyaluronic acid, and acrylamide (AM). The ink may be processed into intricate 3D hydrogel structures with good biocompatibility and high stiffness properties using 3D printing technology based on digital light processing (DLP), including intricate shapes resembling noses. By varying the AM content, the mechanical behavior and biocompatibility of the hydrogels can be adjusted. In comparison to the gelatin methacryloyl (GelMA)/hyaluronic acid methacryloyl (HAMA) hydrogel, adding AM considerably enhances the hydrogel's mechanical properties while also enhancing printing quality. Meanwhile, the biocompatibility of the multicrosslinked network hydrogels and the development of cartilage were assessed using neonatal Sprague-Dawley (SD) rat chondrocytes (CChons). Cells sown on the hydrogels considerably multiplied after 7 days of culture and kept up the expression of particular proteins. Together, our findings point to GelMA/HAMA/polyacrylamide (PAM) hydrogel as a potential material for nasal cartilage restoration. The photocuring multicrosslinked network ink composed of appropriate proportions of GelMA/HAMA/PAM is very suitable for DLP 3D printing and will play an important role in the construction of nasal cartilage, ear cartilage, articular cartilage, and other tissues and organs in the future. Notably, previous studies have not explored the application of 3D-printed GelMA/HAMA/PAM hydrogels for nasal cartilage regeneration.

Efficacy of Lenvatinib in Combination With PD-1 Monoclonal Antibody and Interventional Treatment for Intermediate-Stage Hepatocellular Carcinoma: Impact on Serum Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9 Levels: A Retrospective Study.

Objectives: To scrutinize the therapeutic efficiency and safety profile of lenvatinib, accompanied by the programmed cell death protein-1 (PD-1) monoclonal antibody, and interventional treatment in managing intermediate-stage hepatocellular carcinoma. Methods: Retrospective analysis was performed on clinical data from 93 patients suffering from intermediate to advanced hepatocellular carcinoma, treated at our institution from May 2018 to April 2020. Patients were divided based on the therapeutic regimen: 43 cases constituted the control group receiving lenvatinib plus transhepatic artery chemoembolization (TACE), while the remaining 50 cases in the study group were managed with lenvatinib, PD-1 monoclonal antibody, and TACE. Outcome measures included therapeutic efficacy, tumor markers (carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], α-L-fucosidase [AFU], carbohydrate antigen 199 [CA199]), immune response indices (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), pertinent cytokine levels (vascular endothelial growth factor [VEGF], matrix metalloproteinase-9 [MMP-9], basic fibroblast growth factor [aFGF], acidic fibroblast growth factor [bFGF]), quality of life (as per Quality of Life Assessment Scale for Cancer Patients [QOL-LC] scores), adverse effects, and survival rates. Results: The study group exhibited a significantly enhanced total effective rate compared to the control group (74.00% vs 53.49%, P < .05). Post-treatment levels of CEA, AFP, AFU, CA199, CD8+, VEGF, MMP-9, aFGF, and bFGF were notably lower in both groups, particularly in the study group. Contrastingly, CD3+, CD4+, CD4+/CD8+ratios, and QOL-LC scores were substantially elevated in the study group (P < .05). Adverse reaction prevalence was analogous between 2 groups (27.91% vs 26.00%; P > .05). Moreover, the study group reported significantly higher 1-, 2-, and 3-year survival rates than the control group (P < .05). Conclusion: The combined use of lenvatinib, PD-1 monoclonal antibody, and interventional treatment for intermediate to advanced hepatocellular carcinoma may have a definitive therapeutic efficacy. This regimen is effective in reducing tumor marker levels, enhancing immune function, modulating VEGF, MMP-9, and other related cytokine levels, and improving patients' quality of life without significantly augmenting adverse effects. This treatment paradigm also contributes to increased survival rates and promises favorable prognosis.

The anti-tumor effect of extracellular vesicles derived from cytokine-activated CD8+ T cells.

Extracellular vesicles (EVs) are the nano-sized membrane particles secreted by various cell types, which are involved in many important cellular processes. Recently, EVs originating from immune cells, such as dendritic cells, chimeric antigen receptor T cells (CAR-T) and natural killer cells, have attracted much attention because of their known direct and indirect antitumor activity. Here, we report the EVs released by cytokine-activated CD8 + T cells (caCD8) and its cytotoxicity against cancer cells. CaCD8 cells can release EVs following stimulation of CD8+ T cells with an anti-CD3 antibody and a cytokines cocktail ex vivo. The isolated vesicles have typical EV characteristics, such as an oval shape and a size distribution between 30-200 nm, as well as CD81 expression. Notably, caCD8-EVs displayed cytotoxicity against various cancer cells in vitro. Furthermore, mechanism analysis demonstrates that caCD8-EVs not only contain typical cytotoxic proteins (i.e., granzyme B and perforin), but also significantly enrich IFNγ compared to caCD8 cells. The EVs-derived IFNγ participates in EVs-induced apoptosis in cancer cells. Therefore, our data reveal an antitumor effects of EVs secreted from caCD8 cells and the potential role of the EVs-derived IFNγ.

Differences in Daily Physical Activity by Alzheimer's Risk Markers Among Older Adults.

BACKGROUND: Daily physical activity patterns differ by Alzheimer's disease (AD) status and might signal cognitive risk. It is critical to understand whether patterns are disrupted early in the AD pathological process. Yet, whether established AD risk markers (ß-amyloid [Aß] or apolipoprotein E-ε4 [APOE-ε4]) are associated with differences in objectively measured activity patterns among cognitively unimpaired older adults is unclear. METHODS: Wrist accelerometry, brain Aß (+/-), and APOE-ε4 genotype were collected in 106 (Aß) and 472 (APOE-ε4) participants (mean age 76 [standard deviation{SD}: 8.5) or 75 [SD: 9.2] years, 60% or 58% women) in the Baltimore Longitudinal Study of Aging. Adjusted linear and function-on-scalar regression models examined whether Aß or APOE-ε4 status was cross-sectionally associated with activity patterns (amount, variability, or fragmentation) overall and by time of day, respectively. Differences in activity patterns by combinations of Aß and APOE-ε4 status were descriptively examined (n = 105). RESULTS: There were no differences in any activity pattern by Aß or APOE-ε4 status overall. Aß+ was associated with lower total amount and lower within-day variability of physical activity overnight and early evening, and APOE-ε4 carriers had higher total amount of activity in the evening and lower within-day variability of activity in the morning. Diurnal curves of activity were blunted among those with Aß+ regardless of APOE-ε4 status, but only when including older adults with mild cognitive impairment/dementia. CONCLUSIONS: Aß+ in cognitively unimpaired older adults might manifest as lower amount and variability of daily physical activity, particularly during overnight/evening hours. Future research is needed to examine changes in activity patterns in larger samples and by other AD biomarkers.

Dispersion-assisted high-dimensional photodetector.

Intensity, polarization and wavelength are intrinsic characteristics of light. Characterizing light with arbitrarily mixed information on polarization and spectrum is in high demand1-4. Despite the extensive efforts in the design of polarimeters5-18 and spectrometers19-27, concurrently yielding high-dimensional signatures of intensity, polarization and spectrum of the light fields is challenging and typically requires complicated integration of polarization- and/or wavelength-sensitive elements in the space or time domains. Here we demonstrate that simple thin-film interfaces with spatial and frequency dispersion can project and tailor polarization and spectrum responses in the wavevector domain. By this means, high-dimensional light information can be encoded into single-shot imaging and deciphered with the assistance of a deep residual network. To the best of our knowledge, our work not only enables full characterization of light with arbitrarily mixed full-Stokes polarization states across a broadband spectrum with a single device and a single measurement but also presents comparable, if not better, performance than state-of-the-art single-purpose miniaturized polarimeters or spectrometers. Our approach can be readily used as an alignment-free retrofit for the existing imaging platforms, opening up new paths to ultra-compact and high-dimensional photodetection and imaging.

Construction Form and Application of Three-Dimensional Bioprinting Ink Containing Hydroxyapatite.

With the increasing prevalence of bone tissue diseases, three-dimensional (3D) bioprinting applied to bone tissue engineering for treatment has received a lot of interests in recent years. The research and popularization of 3D bioprinting in bone tissue engineering require bioinks with good performance, which is closely related to ideal material and appropriate construction form. Hydroxyapatite (HAp) is the inorganic component of natural bone and has been widely used in bone tissue engineering and other fields due to its good biological and physicochemical properties. Previous studies have prepared different bioinks containing HAp and evaluated their properties in various aspects. Most bioinks showed significant improvement in terms of rheology and biocompatibility; however, not all of them had sufficiently favorable mechanical properties and antimicrobial activity. The deficiencies in properties of bioink and 3D bioprinting technology limited the applications of bioinks containing HAp in clinical trials. This review article summarizes the construction forms of bioinks containing HAp and its modifications in previous studies, as well as the 3D bioprinting techniques adopted to print bioink containing HAp. In addition, this article summarizes the advantages and underlying mechanisms of bioink containing HAp, as well as its limitations, and suggests possible improvement to facilitate the development of bone tissue engineering bioinks containing HAp in the future.

Challenges in Application: Gelation Strategies of DAT-Based Hydrogel Scaffolds.

Decellularized adipose tissue (DAT) has great clinical applicability, owing to its abundant source material, natural extracellular matrix microenvironment, and nonimmunogenic attributes, rendering it a versatile resource in the realm of tissue engineering. However, practical implementations are confronted with multifarious limitations. Among these, the selection of an appropriate gelation strategy serves as the foundation for adapting to diverse clinical contexts. The cross-linking strategies under varying physical or chemical conditions exert profound influences on the ultimate morphology and therapeutic efficacy of DAT. This review sums up the processes of DAT decellularization and subsequent gelation, with a specific emphasis on the diverse gelation strategies employed in recent experimental applications of DAT. The review expounds upon methodologies, underlying principles, and clinical implications of different gelation strategies, aiming to offer insights and inspiration for the application of DAT in tissue engineering and advance research for tissue engineering scaffold development.

Cross-sectional associations between multisensory impairment and brain volumes in older adults: Baltimore Longitudinal Study of Aging.

Sensory impairment and brain atrophy is common among older adults, increasing the risk of dementia. Yet, the degree to which multiple co-occurring sensory impairments (MSI across vision, proprioception, vestibular function, olfactory, and hearing) are associated with brain morphometry remain unexplored. Data were from 208 cognitively unimpaired participants (mean age 72 ± 10 years; 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Multiple linear regression models were used to estimate cross-sectional associations between MSI and regional brain imaging volumes. For each additional sensory impairment, there were associated lower orbitofrontal gyrus and entorhinal cortex volumes but higher caudate and putamen volumes. Participants with MSI had lower mean volumes in the superior frontal gyrus, orbitofrontal gyrus, superior parietal lobe, and precuneus compared to participants with < 2 impairments. While MSI was largely associated with lower brain volumes, our results suggest the possibility that MSI was associated with higher basal ganglia volumes. Longitudinal analyses are needed to evaluate the temporality and directionality of these associations.

Snake-shaped ePTFE nasal tip graft combined with conchal cartilage in Asian rhinoplasty: a retrospective cohort study.

BACKGROUND: Lacking a nasal tip projection is a common deformity of Asian nasals. Various commonly used nasal tip grafts require dissecting septal perichondrium, most of them are autologous cartilage with a nonintegrated design. A snake-shaped expanded polytetrafluoroethylene (ePTFE) nasal tip graft is an integrated, stable tip graft without any additional assembly and splicing, conforming to the nasal anatomy characteristics of Asians. METHOD: A retrospective study was performed on Asian patients who underwent rhinoplasty in the nasal tip at Peking University Third Hospital from 2015 to 2022. Nasal tip grafts were categorized into three groups: snake-shaped ePTFE combined with conchal cartilage (n = 15), only costal cartilage (n = 25), and only conchal cartilage (n = 17). Patients were excluded if their rhinoplasty did not involve any of the grafts above. Visual Analogue Scale, FACE-Q Nose, FACE-Q Nostril, Nasal Obstruction Symptom Evaluation scale, and Rhinoplasty Outcome Evaluation scale were used to evaluate the preoperative and postoperative results. RESULTS: Fifty-three (93.0%) cases had low nasal dorsum and 46 (80.7%) cases had short nose. There was no significant difference in complication rates among the three groups. The difference between preoperative and postoperative scale scores was statistically significant among the three groups (p < 0.05). Score improvements, including all scales, were the highest in the costal cartilage group and lowest in the conchal cartilage group. CONCLUSIONS: Snake-shaped ePTFE nasal tip grafts can be an effective integrated alternative that provides long-term safety and efficacy compared with traditional autogenous implants (conchal and costal cartilages).

Alzheimer's and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline.

BACKGROUND: Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer's disease (AD) pathology (amyloid-ß [Aß42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-ß status modified these associations. METHODS: Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. RESULTS: Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aß42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aß42/40 (higher Aß burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aß burden, as was the association of higher GFAP with memory decline. CONCLUSIONS: Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

Neuronal microstructural changes in the human brain are associated with neurocognitive aging.

Gray matter (GM) alterations play a role in aging-related disorders like Alzheimer's disease and related dementias, yet MRI studies mainly focus on macroscopic changes. Although reliable indicators of atrophy, morphological metrics like cortical thickness lack the sensitivity to detect early changes preceding visible atrophy. Our study aimed at exploring the potential of diffusion MRI in unveiling sensitive markers of cortical and subcortical age-related microstructural changes and assessing their associations with cognitive and behavioral deficits. We leveraged the Human Connectome Project-Aging cohort that included 707 participants (394 female; median age = 58, range = 36-90 years) and applied the powerful mean apparent diffusion propagator model to measure microstructural parameters, along with comprehensive behavioral and cognitive test scores. Both macro- and microstructural GM characteristics were strongly associated with age, with widespread significant microstructural correlations reflective of cellular morphological changes, reduced cellular density, increased extracellular volume, and increased membrane permeability. Importantly, when correlating MRI and cognitive test scores, our findings revealed no link between macrostructural volumetric changes and neurobehavioral performance. However, we found that cellular and extracellular alterations in cortical and subcortical GM regions were associated with neurobehavioral performance. Based on these findings, it is hypothesized that increased microstructural heterogeneity and decreased neurite orientation dispersion precede macrostructural changes, and that they play an important role in subsequent cognitive decline. These alterations are suggested to be early markers of neurocognitive performance that may distinctly aid in identifying the mechanisms underlying phenotypic aging and subsequent age-related functional decline.

Perfusable adipose decellularized extracellular matrix biological scaffold co-recellularized with adipose-derived stem cells and L6 promotes functional skeletal muscle regeneration following volumetric muscle loss.

Muscle tissue engineering is a promising therapeutic strategy for volumetric muscle loss (VML). Among them, decellularized extracellular matrix (dECM) biological scaffolds have shown certain effects in restoring muscle function. However, researchers have inconsistent or even contradictory results on whether dECM biological scaffolds can efficiently regenerate muscle fibers and restore muscle function. This suggests that therapeutic strategies based on dECM biological scaffolds need to be further optimized and developed. In this study, we used a recellularization method of perfusing adipose-derived stem cells (ASCs) and L6 into adipose dECM (adECM) through vascular pedicles. On one hand, this strategy ensures sufficient quantity and uniform distribution of seeded cells inside scaffold. On the other hand, auxiliary L6 cells addresses the issue of low myogenic differentiation efficiency of ASCs. Subsequently, the treatment of VML animal experiments showed that the combined recellularization strategy can improve muscle regeneration and angiogenesis than the single ASCs recellularization strategy, and the TA of former had greater muscle contraction strength. Further single-nucleus RNA sequencing (snRNA-seq) analysis found that L6 cells induced ASCs transform into a new subpopulation of cells highly expressing Mki67, CD34 and CDK1 genes, which had stronger ability of oriented myogenic differentiation. This study demonstrates that co-seeding ASCs and L6 cells through vascular pedicles is a promising recellularization strategy for adECM biological scaffolds, and the engineered muscle tissue constructed based on this has significant therapeutic effects on VML. Overall, this study provides a new paradigm for optimizing and developing dECM-based therapeutic strategies.