E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors.

INTRODUCTION: Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial. OBJECTIVES: To elucidate the function and mechanism of RNF128 in colitis and CRC. METHODS: Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling. RESULTS: RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis. CONCLUSION: RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition.

Two new compounds isolated from the aerial parts of gastrodia elata blume.

Two new aromatic compounds, namely gastupdin A (1), and gastupdin B (2), together with three known compounds, arundin(3), phomosines B (4) and monocillin IV (5), were isolated from the aerial parts of Gastrodia elata Blume. The structures of the new compounds were confirmed through spectral analyses including NMR, HR-ESI-MS, ECD, UV, and IR. All isolated compounds were evaluated for their neuroprotective effects against 6-hydroxydopamine-induced cell death in Human Neuroblastoma Cells, with curcumin as the positive control, however, the activity of all compounds was weaker than the positive control, showing no significant activity.

Urchin-like covalent organic frameworks templated Au@Ag composites for SERS detection of emerging contaminants.

Au@Ag core-shell composites were successfully fabricated on urchin-like covalent organic frameworks (COFs), providing a platform with numerous hot spots for the detection of two categories of emerging contaminants: sulfonamide antibiotics and nanoplastics, using surface-enhanced Raman spectroscopy (SERS). Au seeds (∼10 nm) were generated on the COFs, leveraging the reducing properties of the vinyl and imino groups within the framework. This ensured the growth of dense and uniformly distributed Ag nanoparticles. The COFs exceptionally large surface area (2324 m2 g-1) and high adsorption capacity, significantly contributed to the enrichment and detection of trace pollutants. As a result, using a portable Raman spectrometer, limits of detection of 0.008 µmol L-1 for sulfamethoxazole and 0.029 mg L-1 for polystyrene nanoplastics were achieved.

Impdh2 deficiency suppresses osteoclastogenesis through mitochondrial oxidative phosphorylation and alleviates ovariectomy-induced osteoporosis.

Abnormalities in osteoclastic generation or activity disrupt bone homeostasis and are highly involved in many pathologic bone-related diseases, including rheumatoid arthritis, osteopetrosis, and osteoporosis. Control of osteoclast-mediated bone resorption is crucial for treating these bone diseases. However, the mechanisms of control of osteoclastogenesis are incompletely understood. In this study, we identified that inosine 5'-monophosphate dehydrogenase type II (Impdh2) positively regulates bone resorption. By histomorphometric analysis, Impdh2 deletion in mouse myeloid lineage cells (Impdh2LysM-/- mice) showed a high bone mass due to the reduced osteoclast number. qPCR and western blotting results demonstrated that the expression of osteoclast marker genes, including Nfatc1, Ctsk, Calcr, Acp5, Dcstamp, and Atp6v0d2, was significantly decreased in the Impdh2LysM-/- mice. Furthermore, the Impdh inhibitor MPA treatment inhibited osteoclast differentiation and induced Impdh2-cytoophidia formation. The ability of osteoclast differentiation was recovered after MPA deprivation. Interestingly, genome-wide analysis revealed that the osteoclastic mitochondrial biogenesis and functions, such as oxidative phosphorylation, were impaired in the Impdh2LysM-/- mice. Moreover, the deletion of Impdh2 alleviated ovariectomy-induced bone loss. In conclusion, our findings revealed a previously unrecognized function of Impdh2, suggesting that Impdh2-mediated mechanisms represent therapeutic targets for osteolytic diseases.

Enhanced reduction of Cd uptake by wheat plants using iron and manganese oxides combined with citrate in Cd-contaminated weakly alkaline arable soils.

Iron (Fe) and manganese (Mn) oxides can be used to remediate Cd-polluted soils due to their excellent performance in heavy metal adsorption. However, their remediation capability is rather limited, and a higher content of available Mn and Fe in soils can reduce Cd accumulation in wheat plants due to the competitive absorption effect. In this study, goethite and cryptomelane were first respectively used to immobilize Cd in Cd-polluted weakly alkaline soils, and sodium citrate was then added to increase the content of available Mn and Fe content for further reduction of wheat Cd absorption. In the first season, the content of soil-available Cd and Cd in wheat plants significantly decreased when cryptomelane, goethite and their mixture were used as the remediation agents. Cryptomelane showed a better remediation effect, which could be attributed to its higher adsorption performance. The grain Cd content could be decreased from 0.35 mg kg-1 to 0.25 mg kg-1 when the content of cryptomelane was controlled at 0.5%. In the second season, when sodium citrate at 20 mmol kg-1 was further added to the soils with 0.5% cryptomelane treatment in the first season, the content of soil available Cd was increased by 14.8%, and the available Mn content was increased by 19.5%, leading to a lower Cd content in wheat grains (0.16 mg kg-1) probably due to the competitive absorption. This work provides a new strategy for the remediation of slightly Cd-polluted arable soils with safe and high-quality production of wheat.

COVID-19 vaccination-related tinnitus is associated with pre-vaccination metabolic disorders.

Cases of tinnitus have been reported following administration of COVID-19 vaccines. The aim of this study was to characterize COVID-19 vaccination-related tinnitus to assess whether there is a causal relationship, and to examine potential risk factors for COVID-19 vaccination-related tinnitus. We analyzed a survey on 398 cases of COVID-19 vaccination-related tinnitus, and 699,839 COVID-19 vaccine-related reports in the Vaccine Adverse Effect Reporting System (VAERS) database that was retrieved on 4 December 2021. We found that following COVID-19 vaccination, 1) tinnitus report frequencies for Pfizer, Moderna and Janssen vaccines in VAERS are 47, 51 and 70 cases per million full vaccination; 2) the symptom onset was often rapid; 3) more women than men reported tinnitus and the sex difference increased with age; 4) for 2-dose vaccines, the frequency of tinnitus was higher following the first dose than the second dose; 5) for 2-dose vaccines, the chance of worsening tinnitus symptoms after second dose was approximately 50%; 6) tinnitus was correlated with other neurological and psychiatric symptoms; 7) pre-existing metabolic syndromes were correlated with the severity of the reported tinnitus. These findings suggest that COVID-19 vaccination increases the risk of tinnitus, and metabolic disorders is a risk factor for COVID-19 vaccination-related tinnitus.

[Progress in the application of artificial intelligence-assisted molecular modification of enzymes].

Natural enzymes are often difficult to meet the needs of application and research in terms of activity, enantiomer selectivity or thermal stability. Therefore, it is an important task of enzyme engineering to explore efficient molecular modification technologies to improve the properties of such enzymes. The molecular modification technologies of enzymes mainly include rational design, directed evolution, and artificial intelligence-assisted design. Directed evolution and rational design are experiment-driven molecular modification approaches of enzymes and have been successfully applied to enzyme engineering. However, due to the huge space sizes of protein sequences and the lack of experimental data, the current modification methods still face major challenges. With the development of next-generation sequencing, high-throughput screening, protein databases, and artificial intelligence (AI), data-driven enzyme engineering is emerging as a promising solution to these challenges. The AI-assisted statistical learning method has been used to establish a model for predicting the sequence/structure-properties of enzymes in a data-driven manner. Excellent mutant enzymes can be selected according to the prediction results, which greatly improve the efficiency of molecular modification. Considering the application requirements of molecular modification of enzymes, this paper reviews the data acquisition methods and application examples of AI-assisted molecular modification of enzymes, with focuses on the convolutional neural network method for predicting protein thermostability, aiming to provide reference for researchers in this field.

A p38 MAP kinase inhibitor suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss through the inhibition of bone turnover.

Inhibition of excessive osteoclastic activity is an efficient therapeutic strategy for many bone diseases induced by increased bone resorption, such as osteoporosis. BMS-582949, a clinical p38α inhibitor, is a promising drug in Phase II studies for treating rheumatoid arthritis. However, its function on bone resorption is largely unknown. In this study, we find that BMS-582949 represses RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, BMS-582949 inhibits osteoclastic F-actin ring formation and osteoclast-specific gene expression. Mechanically, BMS-582949 treatment attenuates RANKL-mediated osteoclastogenesis through mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) signaling pathways without disturbing nuclear factor-κB (NF-κB) signaling. Interestingly, BMS-582949 impairs osteoclastic mitochondrial biogenesis and functions, such as oxidative phosphorylation (OXPHOS). Furthermore, BMS-582949 administration prevents bone loss in ovariectomized mouse mode by inhibiting both bone resorption and bone formation in vivo. Taken together, these findings indicate that BMS-582949 may be a potential and effective drug for the therapy of osteolytic diseases.

Novel Alkaloids from Aspergillus fumigatus VDL36, an Endophytic Fungus Associated with Vaccinium dunalianum.

Eleven alkaloids (1-11) including seven new ones, 1-7, were isolated from the solid fermentation of Aspergillus fumigatus VDL36, an endophytic fungus isolated from the leaves of Vaccinium dunalianum Wight (Ericaceae), a perennial evergreen shrub distributed across the Southwest regions of China, Myanmar, and Vietnam. Their structures were elucidated on the basis of extensive spectroscopic methods. The isolates were evaluated for in vitro antifungal activities against five phytopathogenic fungi (Fusarium oxysporum, Coriolus versicolor, Fusarium solani, Botrytis cinerea, Fusarium graminearum). As a result, the new compounds fumigaclavine I (1), 13-ethoxycyclotryprostatin A (5), 13-dehydroxycyclotryprostatin A (6), and 12ß-hydroxy-13-oxofumitremorgin C (7) exhibited antifungal activities with MIC values of 7.8-62.5 µg/mL which were comparable to the two positive controls ketoconazole (MIC = 7.8-31.25 µg/mL) and carbendazim (MIC = 1.95-7.8 µg/mL). Furthermore, compounds 1 and 5 demonstrated potent protective and curative effects against the tomato gray mold in vivo. Preliminary structure-activity relationships of the tested indole diketopiperazine alkaloids indicate that the introduction of a substituent group at position C-13 enhances their biological activities.

Females adopt sexual catalepsy to facilitate mating.

Theory predicts that males and females of dioecious species typically engage in an evolutionary sexual conflict over the frequency and choice of mating partner. Female sexual cannibalism, a particularly dramatic illustration of this conflict, is widespread in certain animal taxa including spiders. Nevertheless, females of some funnel weaving spiders that are generally aggressive to conspecifics enter a cataleptic state after male courtship, ensuring the males can mate without risk of attack. In this study, we demonstrated that the physical posture and duration, metabolites, and central neurotransmitters of females of Aterigena aculeata in sexual catalepsy closely resemble females in thanatosis but are distinct from those in anesthesia, indicating that the courted females feign death to eliminate the risk of potentially aggressive responses and thereby allow preferred males to mate. Unlike the taxonomically widespread thanatosis, which generally represents a deceptive visual signal that acts against the interest of the receivers, sexual catalepsy of females in the funnel weaving spiders may deliver a sexual-receptive signal to the courting males and thereby benefit both the signal senders and receivers. Therefore, sexual catalepsy in A. aculeata may not reflect a conflict but rather a confluence of interest between the sexes.

Microstructural Evolution and Failure in Fibrous Network Materials: Failure Mode Transition from the Competition between Bond and Fiber.

For the complex structure of fibrous network materials, it is a challenge to analyze the network strength and deformation mechanism. Here, we identify a failure mode transition within the network material comprising brittle fibers and bonds, which is related to the strength ratio of the bond to the fiber. A failure criterion for this type of fibrous network is proposed to quantitatively characterize this transition between bond damage and fiber damage. Additionally, tensile experiments on carbon and ceramic fibrous network materials were conducted, and the experimental results show that the failure modes of these network materials satisfy the theoretical prediction. The relationship between the failure mode, the relative density of network and strength of the components is established based on finite element analysis of the 3D network model. The failure mode transforms from bond damage to fiber damage as increasing of bond strength. According to the transition of the failure modes in the brittle fibrous network, it is possible to tailor the mechanical properties of fibrous network material by balancing the competition between bond and fiber properties, which is significant for optimizing material design and engineering applications.

Cyp6g2 is the major P450 epoxidase responsible for juvenile hormone biosynthesis in Drosophila melanogaster.

BACKGROUND: Juvenile hormones (JH) play crucial role in regulating development and reproduction in insects. The most common form of JH is JH III, derived from MF through epoxidation by CYP15 enzymes. However, in the higher dipterans, such as the fruitfly, Drosophila melanogaster, a bis-epoxide form of JHB3, accounted most of the JH detected. Moreover, these higher dipterans have lost the CYP15 gene from their genomes. As a result, the identity of the P450 epoxidase in the JH biosynthesis pathway in higher dipterans remains unknown. RESULTS: In this study, we show that Cyp6g2 serves as the major JH epoxidase responsible for the biosynthesis of JHB3 and JH III in D. melanogaster. The Cyp6g2 is predominantly expressed in the corpus allatum (CA), concurring with the expression pattern of jhamt, another well-studied gene that is crucial in the last steps of JH biosynthesis. Mutation in Cyp6g2 leads to severe disruptions in larval-pupal metamorphosis and exhibits reproductive deficiencies, exceeding those seen in jhamt mutants. Notably, Cyp6g2-/-::jhamt2 double mutants all died at the pupal stage but could be rescued through the topical application of JH analogs. JH titer analyses revealed that both Cyp6g2-/- mutant and jhamt2 mutant lacking JHB3 and JH III, while overexpression of Cyp6g2 or jhamt caused a significant increase in JHB3 and JH III titer. CONCLUSIONS: These findings collectively established that Cyp6g2 as the major JH epoxidase in the higher dipterans and laid the groundwork for the further understanding of JH biosynthesis. Moreover, these findings pave the way for developing specific Cyp6g2 inhibitors as insect growth regulators or insecticides.

Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives.

Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.

Dual-phase nano-glass-hydrides overcome the strength-ductility trade-off and magnetocaloric bottlenecks of rare earth based amorphous alloys.

Metal-hydrogen systems have attracted intense interest for diverse energy-related applications. However, metals usually reduce their ductility after hydrogenation. Here, we show that hydrogen can take the form of nano-sized ordered hydrides (NOH) homogeneously dispersed in a stable glassy shell, leading to remarkable enhancement in both strength and ductility. The yield strength is enhanced by 44% and the plastic strain is substantially improved from almost zero to over 70%, which is attributed to the created NOH and their interplay with the glassy shell. Moreover, the hydride-glass composite GdCoAlH possesses a giant magnetic entropy change (-ΔSM) of 18.7 J kg-1K-1 under a field change of 5 T, which is 105.5% larger than the hydrogen-free sample and is the largest value among amorphous alloys and related composites. The prominent ΔSM-ductility combination overcomes the bottlenecks of amorphous alloys as magnetic refrigerants. These results provide a promising strategy for property breakthrough of structural-functional alloys.

Prediction of the pathological subtypes by intraoperative frozen section for patients with cT1N0M0 invasive lung adenocarcinoma (ECTOP-1015): a prospective multi-center study.

BACKGROUND: The aim of this study is to assess the diagnostic accuracy of intraoperative frozen section (FS) in determining the pathological subtypes among patients diagnosed with cT1N0M0 invasive lung adenocarcinoma. MATERIALS AND METHODS: This was a prospective, multi-center (7 centers in China) clinical trial of Eastern Cooperative Thoracic Oncology Projects (ECTOP-1015). Patients with cT1N0M0 invasive lung adenocarcinoma were enrolled in the study. Pathological images obtained from FS and final pathology (FP) were reviewed by at least two pathologists. The primary endpoint was the concordance between FS and FP diagnoses. The inter-observer agreement for identifying pathological subtypes on FS was evaluated among three pathologists. RESULTS: A total of 935 patients were enrolled. The best sensitivity of diagnosing the predominant subtype was 78.2% in the evaluation of acinar pattern. Presence of acinar pattern diagnosed by FS was an independent factor for the concordance between FS and FP (P=0.007, 95% CI: 2.332-4.736). Patients with tumor size ＞2 cm measured by pathology showed a better concordance rate for the predominant subtype (81.6% vs 74.6%, P=0.023). The presence of radiological ground glass opacity (GGO) component did not affect the diagnosis accuracy of FS for predominant subtype (concordance rate: 76.4% vs 75.2%, P=0.687). Patients with GGO component showed better accuracy of the identification in the presence of LPA (82.1% vs 71.0%, P= 0.026). Substantial agreement between the FS diagnosis from 3 pathologists for the predominant pathological pattern was revealed with κ = 0.846. CONCLUSIONS: This is the largest prospective trial evaluating FS diagnosing pathological subtype in cT1N0M0 invasive lung adenocarcinoma. A favorable concordance in the assessment of the pathological subtypes between FS and FP was observed, indicating the feasibility of utilizing accurate intraoperative pathological diagnoses from FS in guiding surgical strategies. And combination of radiology could improve the precision of FS.

The effectiveness of intervention in hepatitis C patients and improvement in their referral rate.

BACKGROUND: To investigate the effectiveness of the intervention with critical value management and push short messaging service (SMS), and to determine improvement in the referral rate of patients with positive hepatitis C antibody (anti-HCV). METHODS: No intervention was done for patients with positive anti-HCV screening results from 1 January 2015 to 31 October 2021. Patients with positive anti-HCV results at our hospital from 1 November 2021 to 31 July 2022 were informed vide critical value management and push SMS. For inpatients, a competent physician was requested to liaise with the infectious disease physician for consultation, and patients seen in the OPD (outpatient department) were asked to visit the liver disease clinic. The Chi-square correlation test, one-sided two-ratio test and linear regression were used to test the relationship between intervention and referral rate. RESULTS: A total of 638,308 cases were tested for anti-hepatitis C virus (HCV) in our hospital and 5983 of them were positive. 51.8% of the referred patients were aged 18-59 years and 10.8% were aged ≥75 years. The result of Chi-square correlation test between intervention and referral was p = .0000, p < .05. One-sided two-ratio test was performed for statistics of pre-intervention referral rate (p1) and post-intervention referral rate (p2). Normal approximation and Fisher's exact test for the results obtained were 0.000, p < .05, and the alternative hypothesis p1 - p2 < 0 was accepted. The linear regression equation was referral = 0.1396 × intervention + 0.3743, and the result model p = 8.79e - 09, p < .05. The model was significant, and the coefficient of intervention was 0.1396. CONCLUSIONS: The interventions of critical value management and push SMS were correlated with the referral rate of patients with positive anti-HCV.

Toonanoronoids A-E, five new limonoids from Toona ciliata var. yunnanensis.

Five new B-seco-limonoids, namely toonanoronoids A-E (1-5), in conjunction with three previously reported compounds, were isolated from the EtOAc extract of the twigs and leaves of Toona ciliata var. yunnanensis. Their structures were elucidated through comprehensive spectroscopic and X-ray crystallographic analysis. The cytotoxic activities of new compounds against five human tumor cell lines (HL-60, SMMC-7721, A549, MCF-7, and SW480) were screened, Compounds 4 and 5 exerted inhibition toward two tumor cell lines (HL-60, SW-480) with IC50 values between 1.7 and 5.9 µM.

Comparative study of nasal cavity drug delivery efficiency with different nozzles in a 3D printed model.

Background: Nasal sprays are widely used in treating nasal and sinus diseases; however, there are very few studies on the drug delivery efficiency of nasal sprays. In this study, the drug delivery efficiency of three different nasal spray devices was evaluated in vitro using a 3D printed cast model of nasal cavity. Methods: Three nasal spray devices with different nozzles and angles of administration were used in the 3D model of the nasal cavity and paranasal sinuses. The spraying area (SA), maximal spraying distance (MSD), and spraying distribution scores on the nasal septum and lateral nasal wall were recorded. Results: Different nasal spray devices have their own characteristics, including volume of each spray, SA, and plume angle. The SA of the three nozzles on the nasal septum increased with an increasing angle of administration. When the angle of administration was 50°, each nozzle reached the maximal SA. There was no statistically significant difference in MSD among the three nozzles at the three angles. The total scores for each nozzle using the three different spraying angles were as follows: nozzle A, 40° > 30° > 50°; nozzle B, 30° > 40° > 50°; and nozzle C, 30° > 40° > 50°. The total scores for different nozzles using the same angle were statistically significantly different and the scores for nozzle C were the highest. Nozzle C had the minimum plume angle. None of the three nozzles could effectively delivered drugs into the middle meatus at any angle in this model. Conclusions: The design of the nozzle affects drug delivery efficiency of nasal spray devices. The ideal angle of administration is 50°. The nozzle with smaller plume angle has higher drug delivery efficiency. Current nasal spray devices can easily deliver drugs to most areas of the nasal cavity, such as the turbinate, nasal septum, olfactory fissure, and nasopharynx, but not the middle meatus. These findings are meaningful for nozzle selection and device improvements.

Observation of the nonanalytic behavior of optical phonons in monolayer hexagonal boron nitride.

Phonon splitting of the longitudinal and transverse optical modes (LO-TO splitting), a ubiquitous phenomenon in three-dimensional polar materials, will break down in two-dimensional (2D) polar systems. Theoretical predictions propose that the LO phonon in 2D polar monolayers becomes degenerate with the TO phonon, displaying a distinctive "V-shaped" nonanalytic behavior near the center of the Brillouin zone. However, the full experimental verification of these nonanalytic behaviors has been lacking. Here, using monolayer hexagonal boron nitride (h-BN) as a prototypical example, we report the comprehensive and direct experimental verification of the nonanalytic behavior of LO phonons by inelastic electron scattering spectroscopy. Interestingly, the slope of the LO phonon in our measurements is lower than the theoretically predicted value for a freestanding monolayer due to the screening of the Cu foil substrate. This enables the phonon polaritons in monolayer h-BN/Cu foil to exhibit ultra-slow group velocity (~5 × 10-6 c, c is the speed of light) and ultra-high confinement (~ 4000 times smaller wavelength than that of light). These exotic behaviors of the optical phonons in h-BN presents promising prospects for future optoelectronic applications.