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.

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.

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.

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.

Difference analysis of the enzymatic hydrolysis performance of acid-catalyzed steam-exploded corn stover before and after washing with water.

The difference in the enzymatic hydrolysis yield of acid-catalyzed steam-exploded corn stover (ASC) before and after washing with water reached approximately 15 % under the same conditions. The reasons for the difference in the yield between ASC and washed ASC (wASC) were determined through the analysis of the composition of ASC prehydrolyzate and sugar concentration of enzymatic hydrolyzate. Salts produced by neutralization (CaSO4, Na2SO4, K2SO4, and (NH4)2SO4), sugars (polysaccharides, oligosaccharides, and monosaccharides), sugar-degradation products (weak acids and furans), and lignin-degradation products (ethyl acetate extracts and nine main lignin-degradation products) were back-added to wASC. Results showed that these products, except furans, exerted negative effect on enzymatic hydrolysis. According to the characteristics of acid-catalyzed steam explosion pretreatment, the five sugar-degradation products' mixture and salts [Na2SO4, (NH4)2SO4] showed minimal negative inhibition effect on enzymatic hydrolysis. By contrast, furans demonstrated a promotion effect. Moreover, soluble sugars, such as 13 g/L xylose (decreased by 6.38 %), 5 g/L cellobiose (5.36 %), 10 g/L glucose (3.67 %), as well as lignin-degradation products, and ethyl acetate extracts (4.87 %), exhibited evident inhibition effect on enzymatic hydrolysis. Therefore, removal of soluble sugars and lignin-degradation products could effectively promote the enzymatic hydrolysis performance.

Low frequency ultrasound elicits broad cortical responses inhibited by ketamine in mice.

The neuromodulatory effects of >250 kHz ultrasound have been well-demonstrated, but the impact of lower-frequency ultrasound, which can transmit better through air and the skull, on the brain is unclear. This study investigates the biological impact of 40 kHz pulsed ultrasound on the brain using calcium imaging and electrophysiology in mice. Our findings reveal burst duration-dependent neural responses in somatosensory and auditory cortices, resembling responses to 12 kHz audible tone, in vivo. In vitro brain slice experiments show no neural responses to 300 kPa 40 kHz ultrasound, implying indirect network effects. Ketamine fully blocks neural responses to ultrasound in both cortices but only partially affects 12 kHz audible tone responses in the somatosensory cortex and has no impact on auditory cortex 12 kHz responses. This suggests that low-frequency ultrasound's cortical effects rely heavily on NMDA receptors and may involve mechanisms beyond indirect auditory cortex activation. This research uncovers potential low-frequency ultrasound effects and mechanisms in the brain, offering a path for future neuromodulation.

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 are 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, PA and PT neuromodulation is systematically investigated at the single neuron level. These results show that to achieve the same level of neuron activation recorded by Ca2+ imaging, the laser energy needed for PA stimulation 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 is performed by patch clamp recordings. Electrophysiological features induced by PA are distinct from those by PT, confirming that PA and PT stimulation operate through different mechanisms. These insights offer a foundation for the rational design of more efficient and safer non-genetic neural modulation approaches.

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.

Ciprofloxacin Accelerates Angiotensin-II-Induced Vascular Smooth Muscle Cells Senescence Through Modulating AMPK/ROS pathway in Aortic Aneurysm and Dissection.

Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-ß-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular Reactive Oxygen Species (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular senescence-related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-ß-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-ß-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of AMPK signaling. This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate that Ciprofloxacin may accelerate AngII-induced VSMC senescence through modulating AMPK/ROS signaling and, subsequently, hasten the progression of AAD.

Gut Roseburia is a protective marker for peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC), particularly for advanced stage of GC, commonly undergoes peritoneal metastasis (PM), which is the leading cause of GC-related death. However, there currently has no reliable biomarker to predict the onset of GCPM. It is well known that the imbalance of gut microbiota contributes to the development and metastasis of gastrointestinal tumors. Unfortunately, little is known about how the alternation in gut microbiota is associated with the onset of GCPM. METHODS: Our current study analyzed structural characteristics and functional prediction of gut microbiota in GC patients with PM (PM group) and without PM (non-PM group). Fresh fecal samples were collected from a discovery cohort (PM = 38, non-PM = 54) and a validation cohort (PM = 15, non-PM = 21) of GC patients and their 16S ribosomal RNA (16s rRNA) gene amplicons were sequenced, followed by bioinformatics. RESULTS: The results indicated an increase in the biodiversity of gut microbiota in the non-PM group of the discovery cohort, compared with the PM group. Moreover, LEfSe analysis found 31 significantly different microorganisms, of which the Roseburia ranked the fifth in the random forest (RF) model. The characteristics of intestinal microbiota in GCPM patients were changed, and the abundance of Roseburia in gut microbiota from the GCPM patients was reduced and receiver operating characteristic (ROC) analysis revealed that the reduced abundance of gut Roseburia effectively predicted the onset of GCPM. CONCLUSION: This signature was also observed in the validation cohort. Therefore, Roseburia is a protective microbial marker and the reduced abundance of Roseburia in gut microbiota may help early diagnosis of GCPM.

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.

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.

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.

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.

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.

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.

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.

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.

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.