Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis.

Nerves play important roles in organ development and tissue homeostasis. Stem/progenitor cells differentiate into different cell lineages responsible for building the craniofacial organs. The mechanism by which nerves regulate stem/progenitor cell behavior in organ morphogenesis has not yet been comprehensively explored. Here, we use tooth root development in mouse as a model to investigate how sensory nerves regulate organogenesis. We show that sensory nerve fibers are enriched in the dental papilla at the initiation of tooth root development. Through single cell RNA-sequencing analysis of the trigeminal ganglion and developing molar, we reveal several signaling pathways that connect the sensory nerve with the developing molar, of which FGF signaling appears to be one of the important regulators. Fgfr2 is expressed in the progenitor cells during tooth root development. Loss of FGF signaling leads to shortened roots with compromised proliferation and differentiation of progenitor cells. Furthermore, Hh signaling is impaired in Gli1-CreER;Fgfr2fl/fl mice. Modulation of Hh signaling rescues the tooth root defects in these mice. Collectively, our findings elucidate the nerve-progenitor crosstalk and reveal the molecular mechanism of the FGF-SHH signaling cascade during tooth root morphogenesis.

Enhanced quantitation of pathological α-synuclein in patient biospecimens by RT-QuIC seed amplification assays.

Disease associated pathological aggregates of alpha-synuclein (αSynD) exhibit prion-like spreading in synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Seed amplification assays (SAAs) such as real-time quaking-induced conversion (RT-QuIC) have shown high diagnostic sensitivity and specificity for detecting proteopathic αSynD seeds in a variety of biospecimens from PD and DLB patients. However, the extent to which relative proteopathic seed concentrations are useful as indices of a patient's disease stage or prognosis remains unresolved. One feature of current SAAs that complicates attempts to correlate SAA results with patients' clinical and other laboratory findings is their quantitative imprecision, which has typically been limited to discriminating large differences (e.g. 5-10 fold) in seed concentration. We used end-point dilution (ED) RT-QuIC assays to determine αSynD seed concentrations in patient biospecimens and tested the influence of various assay variables such as serial dilution factor, replicate number and data processing methods. The use of 2-fold versus 10-fold dilution factors and 12 versus 4 replicate reactions per dilution reduced ED-RT-QuIC assay error by as much as 70%. This enhanced assay format discriminated as little as 2-fold differences in αSynD seed concentration besides detecting ~2-16-fold seed reductions caused by inactivation treatments. In some scenarios, analysis of the data using Poisson and midSIN algorithms provided more consistent and statistically significant discrimination of different seed concentrations. We applied our improved assay strategies to multiple diagnostically relevant PD and DLB antemortem patient biospecimens, including cerebrospinal fluid, skin, and brushings of the olfactory mucosa. Using ED αSyn RT-QuIC as a model SAA, we show how to markedly improve the inter-assay reproducibility and quantitative accuracy. Enhanced quantitative SAA accuracy should facilitate assessments of pathological seeding activities as biomarkers in proteinopathy diagnostics and prognostics, as well as in patient cohort selection and assessments of pharmacodynamics and target engagement in drug trials.

Porous Flow Field for Next-Generation Proton Exchange Membrane Fuel Cells: Materials, Characterization, Design, and Challenges.

Porous flow fields distribute fuel and oxygen for the electrochemical reactions of proton exchange membrane (PEM) fuel cells through their pore network instead of conventional flow channels. This type of flow fields has showed great promises in enhancing reactant supply, heat removal, and electrical conduction, reducing the concentration performance loss and improving operational stability for fuel cells. This review presents the research and development progress of porous flow fields with insights for next-generation PEM fuel cells of high power density (e.g., ∼9.0 kW L-1). Materials, fabrication methods, fundamentals, and fuel cell performance associated with porous flow fields are discussed in depth. Major challenges are described and explained, along with several future directions, including separated gas/liquid flow configurations, integrated porous structure, full morphology modeling, data-driven methods, and artificial intelligence-assisted design/optimization.

Y225A induces long-range conformational changes in human prion protein that are protective in Drosophila.

Prion protein (PrP) misfolding is the key trigger in the devastating prion diseases. Yet the sequence and structural determinants of PrP conformation and toxicity are not known in detail. Here, we describe the impact of replacing Y225 in human PrP with A225 from rabbit PrP, an animal highly resistant to prion diseases. We first examined human PrP-Y225A by molecular dynamics simulations. We next introduced human PrP in Drosophila and compared the toxicity of human PrP-WT and Y225A in the eye and in brain neurons. Y225A stabilizes the ß2-α2 loop into a 310-helix from six different conformations identified in WT and lowers hydrophobic exposure. Transgenic flies expressing PrP-Y225A exhibit less toxicity in the eye and in brain neurons and less accumulation of insoluble PrP. Overall, we determined that Y225A lowers toxicity in Drosophila assays by promoting a structured loop conformation that increases the stability of the globular domain. These findings are significant because they shed light on the key role of distal α-helix 3 on the dynamics of the loop and the entire globular domain.

Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease.

OBJECTIVES: To elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. METHODS: The genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. RESULTS: A total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27-30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. CONCLUSION: This study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.

Genetic insights into drug targets for sporadic Creutzfeldt-Jakob disease: Integrative multi-omics analysis.

OBJECTIVE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data. METHODS: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets. RESULTS: Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD. CONCLUSIONS: Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.

Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during tooth root development.

The control of size and shape is an important part of regulatory process during organogenesis. Tooth formation is a highly complex process that fine-tunes the size and shape of the tooth, which are crucial for its physiological functions. Each tooth consists of a crown and one or more roots. Despite comprehensive knowledge of the mechanism that regulates early tooth crown development, we have limited understanding of the mechanism regulating root patterning and size during development. Here, we show that Ror2-mediated non-canonical Wnt signaling in the dental mesenchyme plays a crucial role in cell proliferation, and thereby regulates root development size in mouse molars. Furthermore, Cdc42 acts as a potential downstream mediator of Ror2 signaling in root formation. Importantly, activation of Cdc42 can restore cell proliferation and partially rescue the root development size defects in Ror2 mutant mice. Collectively, our findings provide novel insights into the function of Ror2-mediated non-canonical Wnt signaling in regulating tooth morphogenesis, and suggest potential avenues for dental tissue engineering.

Microwave Ablation versus Surgical Resection for US-detected Multifocal T1N0M0 Papillary Thyroid Carcinoma: A 10-Center Study.

Background Microwave ablation (MWA) is currently under preliminary investigation for the treatment of multifocal papillary thyroid carcinoma (PTC) and has shown promising treatment efficacy. Compared with surgical resection (SR), MWA is minimally invasive and could preserve thyroid function. However, a comparative analysis between MWA and SR is warranted to draw definitive conclusions. Purpose To compare MWA and SR for preoperative US-detected T1N0M0 multifocal PTC in terms of overall and 1-, 3-, and 5-year progression-free survival rates and complication rates. Materials and Methods In this retrospective study, 775 patients with preoperative US-detected T1N0M0 multifocal PTC treated with MWA or SR across 10 centers between May 2015 and December 2021 were included. Propensity score matching (PSM) was performed for patients in the MWA and SR groups, followed by comparisons between the two groups. The primary outcomes were overall and 1-, 3-, and 5-year progression-free survival (PFS) rates and complication rates. Results After PSM, 229 patients (median age, 44 years [IQR 36.5-50.5 years]; 179 female) in the MWA group and 453 patients (median age, 45 years [IQR 37-53 years]; 367 female) in the SR group were observed for a median of 20 months (range, 12-74 months) and 26 months (range, 12-64 months), respectively. MWA resulted in less blood loss, shorter incision length, and shorter procedure and hospitalization durations (all P < .001). There was no evidence of differences in overall and 1-, 3-, or 5-year PFS rates (all P > .05) between MWA and SR (5-year rate, 77.2% vs 83.1%; P = .36) groups. Permanent hoarseness (2.2%, P = .05) and hypoparathyroidism (4.0%, P = .005) were encountered only in the SR group. Conclusion There was no evidence of a significant difference in PFS rates between MWA and SR for US-detected multifocal T1N0M0 PTC, and MWA resulted in fewer complications. Therefore, MWA is a feasible option for selected patients with multifocal T1N0M0 PTC. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Visualization of Multiphase Reactive Flow and Mass Transfer in Functionalized Microfluidic Porous Media.

Multiphase reactive flow in porous media is an important research topic in many natural and industrial processes. In the present work, photolithography is adopted to fabricate multicomponent mineral porous media in a microchannel, microfluidics experiments are conducted to capture the multiphase reactive flow, methyl violet 2B is employed to visualize the real-time concentration field of the acid solution and a sophisticated image processing method is developed to obtain the quantitative results of the distribution of different phases. With the advanced methods, experiments are conducted with different acid concentration and inlet velocity in different porous structures with different phenomena captured. Under a low acid concentration, the reaction will be single phase. In the gaseous cases with higher acid concentration, preferential flow paths with faster flow and reaction are formed by the multiphase hydrodynamic instabilities. In the experiments with different inlet velocities, it is observed that a higher inlet velocity will lead to a faster reaction but less gas bubbles generated. In contrast, more gas bubbles would be generated and block the flow and reaction under a lower inlet velocity. Finally, in heterogeneous structures, fractures or cavities would significantly redirect the flow and promote the formation of preferential flow path nearby.

Quantum nonlinear effect in a dissipatively coupled optomechanical system.

A full-quantum approach is used to study the quantum nonlinear properties of a compound Michelson-Sagnac interferometer optomechanical system. By deriving the effective Hamiltonian, we find that the reduced system exhibits a Kerr nonlinear term with a complex coefficient, entirely induced by the dissipative and dispersive couplings. Unexpectedly, the nonlinearities resulting from the dissipative coupling possess non-Hermitian Hamiltonian-like properties preserving the quantum nature of the dispersive coupling beyond the traditional system dissipation. This protective mechanism allows the system to exhibit strong quantum nonlinear effects when the detuning (the compound cavity detuning Δc and the auxiliary cavity detuning Δe) and the tunneling coupling strength (J) of two cavities satisfy the relation J2 = ΔcΔe. Moreover, the additive effects of dispersive and dissipative couplings can produce strong anti-bunching effects, which exist in both strong and weak coupling conditions. Our work may provide a new way to study and produce strong quantum nonlinear effects in dissipatively coupled optomechanical systems.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Skin α-Synuclein Seeding Activity in Patients with Type 1 Gaucher Disease.

BACKGROUND: Patients with type 1 Gaucher disease (GD1) have a significantly increased risk of developing Parkinson's disease (PD). OBJECTIVE: The objective of this study was to evaluate skin α-synuclein (αSyn) seeding activity as a biomarker for GD1-related PD (GD1-PD). METHODS: This single-center study administered motor and cognitive examinations and questionnaires of nonmotor symptoms to adult patients with GD1. Optional skin biopsy was performed for skin αSyn seed amplification assay (αSyn SAA) using real-time quaking-induced conversion assay. RESULTS: Forty-nine patients were enrolled, and 36 underwent skin biopsy. Two study participants had PD. Ten participants were αSyn SAA positive (27.8%), 7 (19.4%) were intermediate, and 19 (52.8%) were negative. Positive αSyn seeding activity was observed in the single GD1-PD case who consented to biopsy. αSyn SAA positivity was associated with older age (p = 0.043), although αSyn SAA positivity was more prevalent in patients with GD1 than historic controls. CONCLUSIONS: Longitudinal follow-up is required to determine whether skin αSyn seeding activity can be an early biomarker for GD1-PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Washed microbiota transplantation improved the level of serum vitamin D in ulcerative colitis.

BACKGROUND AND AIM: Vitamin D (VD) deficiency was reported to correlate with ulcerative colitis (UC) activity, which might be closely related to gut microbiota dysbiosis. This study aims to investigate the effects of washed microbiota transplantation (WMT) on VD metabolism in UC. METHODS: The serum levels of 25-hdroxyvitamin D [25(OH)D] in 121 patients with UC and 53 healthy controls (HC) were detected. Subsequently, a non-randomized control trial (non-RCT) was conducted. Patients with UC were non-randomly assigned to undergo WMT (n = 28) vs. conventional treatment (5-aminosalicylic acid, 5-ASA, n = 10). Serum levels of 25(OH)D, fecal microbiota, and the expression of vitamin D receptor (VDR) in patients with UC were evaluated with a 3-month follow-up. RESULTS: Serum VD levels collected in the clinic practice indicated that patients with UC had significantly lower VD levels than HC (P < 0.001). In the non-RCT, serum 25(OH)D level and VDR expression significantly increased (P = 0.011, 0.026, respectively) in the WMT group, while no noticeable changes were observed in the non-WMT group. Microbiome profiling revealed that the increase in VD levels after WMT was positively associated with the abundances of Adlercreutzia_equolifaciens, Ruminococcus_obeum, and Dorea but negatively correlated with Escherichia. CONCLUSIONS: The study suggested that WMT increases the levels of VD with characteristic changes of specific microbiota, which indicated the association between the VD and the activity of UC might be regulated by gut microbiota.

Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation.

Various neuromodulation approaches have been employed to alter neuronal spiking activity and thus regulate brain functions and alleviate neurological disorders. Infrared neural stimulation (INS) could be a potential approach for neuromodulation because it requires no tissue contact and possesses a high spatial resolution. However, the risk of overheating and an unclear mechanism hamper its application. Here we show that midinfrared stimulation (MIRS) with a specific wavelength exerts nonthermal, long-distance, and reversible modulatory effects on ion channel activity, neuronal signaling, and sensorimotor behavior. Patch-clamp recording from mouse neocortical pyramidal cells revealed that MIRS readily provides gain control over spiking activities, inhibiting spiking responses to weak inputs but enhancing those to strong inputs. MIRS also shortens action potential (AP) waveforms by accelerating its repolarization, through an increase in voltage-gated K+ (but not Na+) currents. Molecular dynamics simulations further revealed that MIRS-induced resonance vibration of -C=O bonds at the K+ channel ion selectivity filter contributes to the K+ current increase. Importantly, these effects are readily reversible and independent of temperature increase. At the behavioral level in larval zebrafish, MIRS modulates startle responses by sharply increasing the slope of the sensorimotor input-output curve. Therefore, MIRS represents a promising neuromodulation approach suitable for clinical application.

Outcomes of partial pulpotomy in permanent molars of children with irreversible pulpitis: A prospective cohort study.

BACKGROUND: Vital pulp therapy is gaining traction in dental practice, especially for young patients. AIM: To evaluate the outcomes of partial pulpotomy in permanent molars of children diagnosed with irreversible pulpitis (IP) using iRoot BP Plus. DESIGN: A total of 94 permanent molars in 88 patients, aged 6-15 years, with symptoms of IP, were treated with partial pulpotomy, using iRoot BP Plus as the pulp capping agent. The treated teeth underwent clinical and radiographic assessments at 1, 6, 12, 18, and 24 months postoperative. The outcomes were determined based on clinical and radiographic criteria by calibrated examiners. RESULTS: The success rates were 98.4% (63/64), 93.2% (41/44), and 89.7% (26/29) at the 6-month, 12-month, and 24-month follow-up. By the end of this study, the median follow-up period was 15.1 months, and the estimated survival rate was 95.2% at 24 months. Gender, root maturity, and number of missing walls had no significant effect on success rates. Six molars were failed, and root canal therapy (RCT) was applied. CONCLUSIONS: Partial pulpotomy for permanent molars with IP in young patients using iRoot BP Plus as pulp capping material achieved high success. This method presents a viable alternative to apexification and RCT for treating vital, inflamed molars with IP in children.

Prevalence and risk factors of training-related abdominal injuries: A multicenter survey study.

PURPOSE: This study aims to identify the prevalence and risk factors of military training-related abdominal injuries and help plan and conduct training properly. METHODS: This questionnaire survey study was conducted from October 2021 to May 2022 among military personnel from 6 military units and 8 military medical centers and participants' medical records were consulted to identify the training-related abdominal injuries. All the military personnel who ever participated in military training were included. Those who refused to participate in this study or provided an incomplete questionnaire were excluded. The questionnaire collected demographic information, type of abdominal injury, frequency, training subjects, triggers, treatment, and training disturbance. Chi-square test and t-test were used to compare baseline information. Univariate and multivariate regression analyses were used to explore the risk factors associated with military training-related abdominal injuries. RESULTS: A total of 3058 participants were involved in this study, among which 1797 (58.8%) had suffered training-related abdominal injuries (the mean age was 24.3 years and the service time was 5.6 years), while 1261 (41.2%) had no training-related abdominal injuries (the mean age was 23.1 years and the service time was 4.3 years). There were 546 injured patients (30.4%) suspended the training and 84 (4.6%) needed to be referred to higher-level hospitals. The most common triggers included inadequate warm-up, fatigue, and intense training. The training subjects with the most abdominal injuries were long-distance running (589, 32.8%). Civil servants had the highest rate of abdominal trauma (17.1%). Age ≥ 25 years, military service ≥ 3 years, poor sleep status, and previous abdominal history were independent risk factors for training-related abdominal injury. CONCLUSION: More than half of the military personnel have suffered military training-related abdominal injuries. Inadequate warm-up, fatigue, and high training intensity are the most common inducing factors. Scientific and proper training should be conducted according to the factors causing abdominal injuries.

[Application of bioactive ceramics iRoot BP Plus® in pulpotomy for complicated crown fracture of immature permanent anterior teeth in children].

OBJECTIVE: To analyze the clinical and radiographic effectiveness of a calcium silicate-based bioactive ceramic iRoot BP Plus® pulpotomy of immature permanent teeth with complicated crown fracture and to evaluate the factors influencing its long-term success rate. METHODS: The digital medical records of patients under 13 years old who had undergone iRoot BP Plus® pulpotomy in the Department of Oral Emergency or the First Clinical Division, Peking University School and Hospital of Stomatology from March 2017 to September 2022 due to complicated crown fracture of anterior teeth, and had taken at least one post-operation apical radiograph were reviewed. The clinical and radiographic information at the initial examination and follow-up period were obtained, including crown color, mobility, percussion, cold test (partial pulpotomy teeth), dental restoration, fistula, swelling or inflammation of the gingival tissue, the formation of apical foramen, pathologic radiolucency and calcification of pulp chamber or root canal obliteration. Data were tested by Fisher exact test and a multiple comparison. RESULTS: In the study, 64 patients including 37 males (57.8%) and 27 females (42.2%) with a mean age of 9.1 years : ere finally enrolled. The total number of permanent teeth that received pulpotomy was 75, and the average follow-up time was 19.3 months. The success rate was 93.1% with the time interval between dental injury and treatment in 24 h, while the success rate dropped to 88.2% with the time intervals beyond 24 h. The time intervals did not significantly affect the pulp survival rate (P=0.61) after pulpotomy (partial or coronal). The success rate 6 months after pulpotomy was 96. 0%, and one-year success rate was 94. 7%. A total of 23 cases were reviewed for more than 2 years after pulpotomy, and 6 cases failed. The mobility had no significant effect on the success rate (P=0.28). Pulp chamber calcification and pulp canal obli-teration were not observed in all the post-operative radiographs. CONCLUSION: The one year clinical and radiographic success rates obtained in this study indicate that iRoot BP Plus® is an appropriate pulp capping material option for pulpotomy treatment of complicated crown fracture in immature permanent teeth without displacement injuries. This technique has broad promotional value.

Paeonol inhibits melanoma growth by targeting PD1 through upregulation of miR-139-5p.

The abnormal immune response mediated by malignant melanoma is related to PD1. Paeonol has pharmacological antitumor activity. Previous studies have indicated that paeonol induces tumor cell apoptosis, but its underlying mechanism in tumor immunity remains unknown. In this study, malignant melanoma was established in normal and thymectomized mice to determine the important role of the thymus in the antitumor effects of paeonol. Paeonol-treated thymocytes were cocultured with melanoma cell spheres to further evaluate the regulatory role of thymocytes in tumor immune dysfunction. Studies have shown that PD1 may be targeted by miR-139-5p. Our results revealed that tumor-induced thymic atrophy was significantly accompanied by high PD1 expression and low miR-139-5p expression. Interestingly, paeonol significantly reversed thymic atrophy and largely protected thymocytes against low PD1 expression and high miR-139-5p expression. Dual-luciferase assays indicated that miR-139-5p interacted with the 3' untranslated region (3'-UTR) of PD1. These results showed that paeonol alleviates PD1-mediated antitumor immunity by reducing miR-139-5p expression and demonstrated a novel mechanism for melanoma immunotherapy.

Wavelength sensitivity reconfigurable SPR photodetector with a blazed grating profile.

Surface plasmonic detectors based on one-dimensional half-wavelength gratings have attracted attention due to their wavelength- or polarization-specific photodetection. Although the effect of a grating period and a grating depth on the photoelectric conversion of 1D half-wavelength grating-based surface plasmon resonance (SPR) detectors has been discussed thoroughly in recent years, the effect of different grating profiles on device performance is still limited to the rectangular shape. In this article, we proposed a wavelength sensitivity reconfigurable photodetector enhanced by SPR with a blazed grating profile. The gold layer was fabricated on a silicon-based blazed grating to form a Schottky barrier and act as an SPR coupler. By measuring the photocurrent in the range of -58° to -48°of an incident angle, the peak shifts of a photocurrent signal waveform are found to depend on the wavelength over 800-1000 nm.

Tumor-derived small extracellular vesicles promote breast cancer progression by upregulating PD-L1 expression in macrophages.

BACKGROUND: The metastasis of breast cancer (BC) is a complex multi-step pathological process, strictly dependent on the intrinsic characteristics of BC cells and promoted by a predisposing microenvironment. Although immunotherapy has made important progress in metastasis BC, the heterogeneity of PD-L1 in tumor associated macrophages (TAMs) in BC and the underlying mechanisms in the metastasis development of BC are still not completely elucidated. Small extracellular vesicles (sEVs) represent essential interaction mediators between BC cells and TAMs. It is worth noting to explore the underlying mechanisms typical of sEVs and their role in the metastasis development of BC. METHODS: The structure of sEVs was identified by TEM, while the particle size and amounts of sEVs were detected by BCA and NTA analysis. The specific PD-L1 + CD163 + TAM subpopulation in metastasis BC was identified by scRNA-seq data of GEO datasets and verified by IHC and IF. The function of TAMs and sEVs in metastasis BC was explored by RT-qPCR, WB, IF, flow cytometry and in vivo experiment. The expression profiles of plasma sEVs-miRNA in relation to BC metastasis was analyzed using next-generation sequencing. Further detailed mechanisms of sEVs in the metastasis development of BC were explored by bioinformatics analysis, RT-qPCR, WB and luciferase reporter assay. RESULTS: In this study, we identified that the immunosuppressive molecule PD-L1 was more abundant in TAMs than in BC cells, and a specific PD-L1 + CD163 + TAM subpopulation was found to be associated with metastasis BC. Additionally, we found that BC cells-derived sEVs can upregulate the PD-L1 expression and induce the M2 polarization, enhancing the metastasis development both in vitro and in vivo. Also, Clinical data showed that sEV-miR-106b-5p and sEV-miR-18a-5p was in relation to BC metastasis development and poor prognosis of BC patients. Further mechanistic experiments revealed that BC-derived sEV-miR-106b-5p and sEV-miR-18a-5p could synergistically promoted the PD-L1 expression in M2 TAMs by modulating the PTEN/AKT and PIAS3/STAT3 pathways, resulting in the enhancement of the BC cells invasion and metastasis. CONCLUSIONS: Our study demonstrated that BC-derived sEVs can induce metastasis in BC through miR-106b-5p/PTEN/AKT/PD-L1 and miR-18a-5p/PIAS3/STAT3/PD-L1 pathways in TAMs. Therefore, the inhibition of these specific interactions of signaling pathways would represent a promising target for future therapeutic strategies for treatment of BC.