High-precision photoacoustic neural modulation uses a non-thermal mechanism.

Neuromodulation is a powerful tool for fundamental studies in neuroscience and potential treatments of neurological disorders. Both photoacoustic (PA) and photothermal (PT) effects have been harnessed for non-genetic high-precision neural stimulation. Using a fiber-based device excitable by a nanosecond pulsed laser and a continuous wave laser for PA and PT stimulation, respectively, we systematically investigated PA and PT neuromodulation at the single neuron level. Our results show that to achieve the same level of cell activation recorded by Ca2+ imaging the laser energy needed for PA neurostimulation is 1/40 of that needed for PT stimulation. The threshold energy for PA stimulation is found to be further reduced in neurons overexpressing mechano-sensitive channels, indicating direct involvement of mechano-sensitive channels in PA stimulation. Electrophysiology study of single neurons upon PA and PT stimulation was performed by patch clamp recordings. Electrophysiological features stimulated by PA are distinct from those induced by PT, confirming that PA and PT stimulations operate through distinct mechanisms. These insights offer a foundation for rational design of more efficient and safer non-genetic neural modulation approaches.

Tumor-associated microbiota in colorectal cancer with vascular tumor thrombus and neural invasion and association with clinical prognosis.

Neural invasion (NI) and vascular tumor thrombus (VT) are associated with poor prognosis in patients with colorectal cancer (CRC). In this study, we apply 16S rRNA amplicon sequencing to tumor tissues and adjacent normal tissues in patients with CRC to determine the microbial differences. A discovery cohort, including 30 patients with NI, 23 with VT, and 35 with double-negative CRC tissue, is utilized. Then, we analyze the relationship between the specific bacterial taxa and indicators of different dimensions in separate cohorts. In the discovery cohort, the diversity and composition of the gut microbiome distinctly differ between the tumor and nontumor tissues in the NI and VT groups. A high abundance of Cupriavidus is found to be related to a short survival time of NI CRC, while Herbaspirillum is a potential microbial biomarker predicting the prognosis of patients with CRC with NI or VT. Moreover, the abundance of Cupriavidus or Herbaspirillum is associated with some clinical patient characteristics and prognosis, respectively. In conclusion, this study is the first to comprehensively elaborate the differences in the gut microbiota of patients with CRC with different invasion statuses and to prove the relationship between some gut microbiota and clinical patient characteristics.

Living prosthetic breast for promoting tissue regeneration and inhibiting tumor recurrence.

Developing a living prosthetic breast to inhibit potential breast cancer recurrence and simultaneously promote breast reconstruction would be a promising strategy for clinical treatment of breast cancer after mastectomy. Here, a living prosthetic breast in the form of injectable gelatin methacryloyl microspheres is prepared, where they encapsulated zeolitic imidazolate framework (ZIF) nanoparticles loaded with small molecules urolithin C (Uro-C) and adipose-derived stem cells (ADSCs). Taking advantage of the acidic tumor microenvironment, the ZIF triggered a pH-sensitive drug release in situ so that Uro-C can induce tumor cell apoptosis via reactive oxygen species (ROS) generation. Meanwhile, the ADSCs proliferate in situ to promote tissue regeneration. Using such a design, our data showed that the ADSCs maintained viable and proliferate under the inhibitory effect of Uro-C in vitro. Through ROS generation, Uro-C also activated a suppressive tumor microenvironment in mice by both re-polarizing M2 macrophages to M1 macrophages for elevated inflammatory responses, and increasing the ratio between CD8 and CD4 T cells for tumor recurrence inhibition, significantly promoting new adipose tissue formation. Altogether, our results demonstrate that the prepared living prosthetic breast with bifunctional properties can be a promising candidate in clinic involving tumor treatment and tissue engineering in synergy.

New insights into inflammatory memory of epidermal stem cells.

Inflammatory memory, as one form of innate immune memory, has a wide range of manifestations, and its occurrence is related to cell epigenetic modification or metabolic transformation. When re-encountering similar stimuli, executing cells with inflammatory memory function show enhanced or tolerated inflammatory response. Studies have identified that not only hematopoietic stem cells and fibroblasts have immune memory effects, but also stem cells from various barrier epithelial tissues generate and maintain inflammatory memory. Epidermal stem cells, especially hair follicle stem cells, play an essential role in wound healing, immune-related skin diseases, and skin cancer development. In recent years, it has been found that epidermal stem cells from hair follicle can remember the inflammatory response and implement a more rapid response to subsequent stimuli. This review updates the advances of inflammatory memory and focuses on its mechanisms in epidermal stem cells. We are finally looking forward to further research on inflammatory memory, which will allow for the development of precise strategies to manipulate host responses to infection, injury, and inflammatory skin disease.

MicroRNA-19b-3p dysfunction of mesenchymal stem cell-derived exosomes from patients with abdominal aortic aneurysm impairs therapeutic efficacy.

Senescence of vascular smooth muscle cells (VSMCs) contributes to the formation of abdominal aortic aneurysm (AAA). Although mesenchymal stem cell exosomes (MSC-EXO) have been confirmed to restrict the development of AAA, their biological activity depends largely on the physiological state of the MSCs. This study aimed to compare the effects of adipose-derived MSC-EXO from healthy donors (HMEXO) and AAA patients (AMEXO) on senescence of VSMCs in AAA and explore the underlying mechanisms. An ApoE-/- mouse model of AAA was used to investigate the therapeutic effects of HMEXO, AMEXO or miR-19b-3p-AMEXO on AAA development. This in vitro model of AAA was established by treating VSMCs with Ang II (Angiotensin II). The senescence of VSMCs was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The morphology of mitochondria in VSMCs was examined by MitoTracker staining. HMEXO exhibited superior capacity compared with AMEXO to inhibit VSMC senescence and attenuate AAA formation in Ang II-treated ApoE-/- mice. In vitro, both AMEXO and HMEXO inhibited Ang II-induced VSMC senescence via downregulation of mitochondrial fission. Notably, compared with HMEXO, the ability of AMEXO to inhibit VSMC senescence was significantly decreased. miRNA sequencing and the expression of miR-19b-3p was significantly decreased in AMEXO compared with HMEXO. Luciferase assay suggested that MST4 (Mammalian sterile-20-like kinase 4) is a potential target of miR-19b-3p. Mechanistically, miR-19b-3p in HMEXO ameliorated VSMC senescence by inhibiting mitochondrial fission via regulation of the MST4/ERK/Drp1 signaling pathway. Overexpression of miR-19b-3p in AMEXO improved their beneficial effect on AAA formation. Our study reveals that MSC-exosomal miR-19b-3p exerts protective effects against Ang II-induced AAA and VSMC senescence via regulation of the MST4/ERK/Drp1 pathway. The pathological state of AAA patients alters the miRNA components of AMEXO and impairs their therapeutic benefits.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

CPSF4 promotes tumor-initiating phenotype by enhancing VEGF/NRP2/TAZ signaling in lung cancer.

Lung cancer is the leading cause of malignant tumor-related deaths worldwide. The presence of tumor-initiating cells in lung cancer leads to tumor recurrence, metastasis, and resistance to conventional treatment. Cleavage and polyadenylation specificity factor 4 (CPSF4) activation in tumor cells contributes to the poor prognosis of lung cancer. However, the precise biological functions and molecular mechanisms of CPSF4 in the regulation of tumor-initiating cells remain unclear. We demonstrated that CPSF4 promotes tumor-initiating phenotype and confers chemoresistance to paclitaxel both in vitro and in vivo. Mechanistically, we showed that CPSF4 binds to the promoters of vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) and activated their transcription. In addition, we showed that CPSF4/VEGF/NRP2-mediated tumor-initiating phenotype and chemoresistance through TAZ induction. Furthermore, analysis of clinical data revealed that lung cancer patients with high CPSF4 expression exhibit high expression levels of VEGF, NRP2, and TAZ and that expression of these proteins are positively correlated with poor prognosis. Importantly, selective inhibition of VEGF, NRP2, or TAZ markedly suppressed CPSF4-mediated tumor-initiating phenotype and chemoresistance. Our findings reveal the mechanism of CPSF4 modulating tumor-initiating phenotype and chemoresistance in lung cancer and indicate that the CPSF4-VEGF-NRP2-TAZ signaling pathway may be a prognosis marker and therapeutic target in lung cancer.

Optically-generated focused ultrasound for noninvasive brain stimulation with ultrahigh precision.

High precision neuromodulation is a powerful tool to decipher neurocircuits and treat neurological diseases. Current non-invasive neuromodulation methods offer limited precision at the millimeter level. Here, we report optically-generated focused ultrasound (OFUS) for non-invasive brain stimulation with ultrahigh precision. OFUS is generated by a soft optoacoustic pad (SOAP) fabricated through embedding candle soot nanoparticles in a curved polydimethylsiloxane film. SOAP generates a transcranial ultrasound focus at 15 MHz with an ultrahigh lateral resolution of 83 µm, which is two orders of magnitude smaller than that of conventional transcranial-focused ultrasound (tFUS). Here, we show effective OFUS neurostimulation in vitro with a single ultrasound cycle. We demonstrate submillimeter transcranial stimulation of the mouse motor cortex in vivo. An acoustic energy of 0.6 mJ/cm2, four orders of magnitude less than that of tFUS, is sufficient for successful OFUS neurostimulation. OFUS offers new capabilities for neuroscience studies and disease treatments by delivering a focus with ultrahigh precision non-invasively.

High-precision neural stimulation by a highly efficient candle soot fiber optoacoustic emitter.

Highly precise neuromodulation with a high efficacy poses great importance in neuroscience. Here we developed a candle soot fiber optoacoustic emitter (CSFOE), capable of generating a high pressure of over 10 MPa with a central frequency of 12.8 MHz, enabling highly efficient neuromodulation in vitro. The design of the fiber optoacoustic emitter, including the choice of the material and the thickness of the layered structure, was optimized in both simulations and experiments. The optoacoustic conversion efficiency of the optimized CSFOE was found to be 10 times higher than the other carbon-based fiber optoacoustic emitters. Driven by a single laser, the CSFOE can perform dual-site optoacoustic activation of neurons, confirmed by calcium (Ca2+) imaging. Our work opens potential avenues for more complex and programmed control in neural circuits using a simple design for multisite neuromodulation in vivo.

Gut microbiota distinct between colorectal cancers with deficient and proficient mismatch repair: A study of 230 CRC patients.

Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) exhibit heterogeneous tumor characteristics, distinct responses to immunotherapy, and different survival outcomes. However, it is unclear whether gut microbiota is distinct between CRCs with different MMR status. In this study, we used immunohistochemistry for four major MMR proteins to determine the MMR status in 230 CRC patients. The gut microbiota was profiled in cancerous and adjacent normal tissues by using bacterial 16S rRNA sequencing. The differences in microbiota diversity, composition and related metabolic pathways between patients with dMMR and pMMR CRCs were explored. Linear discriminant analysis effect size (LEfSe) analysis was further applied to validate the significant taxonomic differences at the genus level. In our study cohort, dMMR status was identified in 29 of 230 (12.61%) tumors. The richness (alpha-diversity) of gut microbiome in dMMR tumor tissue was higher compared with pMMR tumor tissues. The microbial community composition (beta-diversity) between the two groups was significantly different. The dMMR group was enriched considerably for some microbiota, including Fusobacteria, Firmicutes, Verrucomicrobia, and Actinobacteria at the phylum level and Fusobacterium, Akkermansia, Bifidobacterium, Faecalibacterium, Streptococcus, and Prevotella bacteria at the genus level. However, the pMMR group was dominated by Proteobacteria at the phylum level and Serratia, Cupriavidus and Sphingobium at the genus level. Moreover, a wide variety of microbiota associated functional pathways were observed with different MMR status. KEGG pathway analysis indicated a higher abundance of the biosynthesis and metabolic pathways of glycan and nucleotide, cell growth and death pathways, genetic replication and repair pathways in dMMR samples compared with the pMMR group. These findings demonstrate that CRC patients with different MMR status have distinct gut bacterial community richness, compositions and related metabolic pathways, suggesting basis that may explain the effectiveness of immunotherapy in dMMR tumors.

Apelin-13 Pretreatment Promotes the Cardioprotective Effect of Mesenchymal Stem Cells against Myocardial Infarction by Improving Their Survival.

Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.

High-precision neural stimulation through optoacoustic emitters.

Neuromodulation poses an invaluable role in deciphering neural circuits and exploring clinical treatment of neurological diseases. Optoacoustic neuromodulation is an emerging modality benefiting from the merits of ultrasound with high penetration depth as well as the merits of photons with high spatial precision. We summarize recent development in a variety of optoacoustic platforms for neural modulation, including fiber, film, and nanotransducer-based devices, highlighting the key advantages of each platform. The possible mechanisms and main barriers for optoacoustics as a viable neuromodulation tool are discussed. Future directions in fundamental and translational research are proposed.

The composition and functional profile of the microbial communities in human gastric cancer tissues and adjacent normal tissues.

(.) is known to be a major risk factor for the development of gastric cancer. In recent years, increasing attention is being paid to the role of non-. (NHPHs) in this disease and the role of microorganisms in local tumor microenvironment. In this study, we aimed to compare the microbial community composition and the predicted functional profile in paired cancer and adjacent normal tissues of gastric cancer patients. Cancer tissues and adjacent normal tissues were collected from 10 patients with gastric cancer under endoscopy, and genomic DNA was extracted. The V3-V4 region of the 16S rRNA gene was amplified by PCR and paired-end sequencing was performed on the Illumina MiSeq System. The data was analyzed using QIIME 2 software. The results showed that microbial richness and diversity as well as genetic diversity are significantly lower in cancer tissues compared with adjacent normal tissues. At the phylum level, the dominant taxa are , , , and in both groups. At the genus level, some taxa, such as and, are significantly enriched in cancer tissues, while other taxa, such as , are enriched in adjacent normal tissues. Moreover, those taxa enriched in cancer tissues are associated with the synthesis and degradation of ketone bodies. In conclusion, there is a significant difference in the composition of the mucosa-related microbial communities between cancer tissues and adjacent normal tissues in patients with gastric cancer.

Photoacoustic Carbon Nanotubes Embedded Silk Scaffolds for Neural Stimulation and Regeneration.

Neural interfaces using biocompatible scaffolds provide crucial properties, such as cell adhesion, structural support, and mass transport, for the functional repair of nerve injuries and neurodegenerative diseases. Neural stimulation has also been found to be effective in promoting neural regeneration. This work provides a generalized strategy to integrate photoacoustic (PA) neural stimulation into hydrogel scaffolds using a nanocomposite hydrogel approach. Specifically, polyethylene glycol (PEG)-functionalized carbon nanotubes (CNT), highly efficient photoacoustic agents, are embedded into silk fibroin to form biocompatible and soft photoacoustic materials. We show that these photoacoustic functional scaffolds enable nongenetic activation of neurons with a spatial precision defined by the area of light illumination, promoting neuron regeneration. These CNT/silk scaffolds offered reliable and repeatable photoacoustic neural stimulation, and 94% of photoacoustic-stimulated neurons exhibit a fluorescence change larger than 10% in calcium imaging in the light-illuminated area. The on-demand photoacoustic stimulation increased neurite outgrowth by 1.74-fold in a rat dorsal root ganglion model, when compared to the unstimulated group. We also confirmed that promoted neurite outgrowth by photoacoustic stimulation is associated with an increased concentration of neurotrophic factor (BDNF). As a multifunctional neural scaffold, CNT/silk scaffolds demonstrated nongenetic PA neural stimulation functions and promoted neurite outgrowth, providing an additional method for nonpharmacological neural regeneration.

Caulobacter and Novosphingobium in tumor tissues are associated with colorectal cancer outcomes.

Diversity and composition of the gut microbiome are associated with cancer patient outcomes including colorectal cancer (CRC). A growing number of evidence indicates that Fusobacterium nucleatum (Fn) in CRC tissue is associated with worse survival. However, few studies have further analyzed the differences in bacteria in tumor tissues of different patients depending on the survival time of CRC patients. Therefore, there is a need to further explore the bacterial differences in tumor tissues of patients with different prognoses and to identify key bacteria for analysis. Here, we sought to compare the differences in tumor microbiome between patients with long-term survival (LS) longer than 3 years or 4 and 5 years and patients with short-term survival (SS) in the present study cohort. We found that there were significant differences in tumor microbiome between the LS and SS and two bacteria-Caulobacter and Novosphingobium-that are present in all of the three groups. Furthermore, by analyzing bacteria in different clinical features, we also found that lower levels of microbiome (Caulobacter and Novosphingobium) have long-term survival and modulating microbiome in tumor tissue may provide an alternative way to predict the prognosis of CRC patients.

Fecal Streptococcus Alteration Is Associated with Gastric Cancer Occurrence and Liver Metastasis.

The gut microbiome plays an indispensable role in the occurrence and progression of various diseases. However, its ability to predict gastric cancer (GC) and liver metastasis (GCLM) has not been fully identified. Fecal samples were collected from 49 GC patients (cancer group [group C]) and 49 healthy people (normal group [group N]) between 4 July 2020 and 9 March 2021. Furthermore, 26 patients with metastatic GC were divided into a liver metastatic group (group L) (n = 13) and a non-liver-metastatic group (group M) (n = 13). DNA was extracted, and 16S rRNA gene sequencing was performed. SPSS was used for statistical analyses, and all bioinformatics analyses were based on QIIME2. P values of <0.05 were considered statistically significant. The microbial richness and diversity in group C were higher than those in group N, and there were significant differences in species compositions between the two groups. Streptococcus, enriched in groups C and L by linear discriminant analysis (LDA) effect size (LEfSe) and further identified by a random forest (RF) model, enhances its potential as a biomarker for GC and GCLM. Functional gene and metabolic pathway analyses showed that d-galacturonate degradation pathway II was of great importance in the occurrence and development of GC. Streptococcus has the potential ability to predict GC and GCLM, which is critical for the early diagnosis of GC and GCLM. IMPORTANCE The gut microbiome plays an indispensable role in the occurrence and progression of various diseases. However, its ability to predict gastric cancer (GC) and liver metastasis (GCLM) has not been fully identified. We retrospectively analyzed 49 untreated GC patients and 49 matched healthy people between 4 July 2020 and 9 March 2021. By extracting DNA from their fecal samples and sequencing the 16S rRNA gene, we found that Streptococcus alteration was strongly associated with GC occurrence and liver metastasis, which might be a potential biomarker in predicting GC and GCLM, and the results of this study are helpful in providing ideas for the early diagnosis and treatment of GC.

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence.

BACKGROUND: Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. METHODS: MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-ß-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence RESULTS: EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. CONCLUSION: Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction.

Non-genetic photoacoustic stimulation of single neurons by a tapered fiber optoacoustic emitter.

Neuromodulation at high spatial resolution poses great significance in advancing fundamental knowledge in the field of neuroscience and offering novel clinical treatments. Here, we developed a tapered fiber optoacoustic emitter (TFOE) generating an ultrasound field with a high spatial precision of 39.6 µm, enabling optoacoustic activation of single neurons or subcellular structures, such as axons and dendrites. Temporally, a single acoustic pulse of sub-microsecond converted by the TFOE from a single laser pulse of 3 ns is shown as the shortest acoustic stimuli so far for successful neuron activation. The precise ultrasound generated by the TFOE enabled the integration of the optoacoustic stimulation with highly stable patch-clamp recording on single neurons. Direct measurements of the electrical response of single neurons to acoustic stimulation, which is difficult for conventional ultrasound stimulation, have been demonstrated. By coupling TFOE with ex vivo brain slice electrophysiology, we unveil cell-type-specific responses of excitatory and inhibitory neurons to acoustic stimulation. These results demonstrate that TFOE is a non-genetic single-cell and sub-cellular modulation technology, which could shed new insights into the mechanism of ultrasound neurostimulation.

Apelin Rejuvenates Aged Human Mesenchymal Stem Cells by Regulating Autophagy and Improves Cardiac Protection After Infarction.

The protective effects of mesenchymal stem cell (MSC)-based therapy for myocardial infarction (MI) are largely hampered as they age. Apelin is an endogenous ligand of its receptor APJ and plays an essential role in regulating multiple biological activities including MSC proliferation and survival. In this study, we investigated whether Apelin regulates MSC senescence and whether its overexpression could rejuvenate aged MSCs (AMSCs) to improve cardiac protection following infarction in mice. MSC senescence was evaluated by senescence-associated ß-galactosidase assays. Apelin level was examined by western blotting. Autophagy was determined by transmission electron microscopy. The cardioprotective effect of AMSCs with Apelin overexpression (Apelin-AMSCs) was assessed in a mouse MI model. Apelin expression was dramatically reduced in AMSCs. Interestingly, knockdown of Apelin induced young MSCs (YMSC) senescence, whereas overexpression rescued AMSC senescence. Apelin overexpression also increased AMSC angiogenic capacity. Mechanistically, Apelin overexpression upregulated the autophagy level of AMSCs by activating AMP-activated protein kinase (AMPK) signaling, thereby rejuvenating AMSCs. Compared with AMSCs, transplantation of Apelin-AMSCs achieved better therapeutic efficacy for MI by enhancing cell survival and angiogenesis. In conclusion, our results reveal that Apelin activates AMPK to rejuvenate AMSCs by increasing autophagy and promotes cardioprotection following infarction in mice. This study identified a novel target to rejuvenate AMSCs and enhance their therapeutic efficacy.