Helical van der Waals crystals with discretized Eshelby twist.

The ability to manipulate the twisting topology of van der Waals structures offers a new degree of freedom through which to tailor their electrical and optical properties. The twist angle strongly affects the electronic states, excitons and phonons of the twisted structures through interlayer coupling, giving rise to exotic optical, electric and spintronic behaviours1-5. In twisted bilayer graphene, at certain twist angles, long-range periodicity associated with moiré patterns introduces flat electronic bands and highly localized electronic states, resulting in Mott insulating behaviour and superconductivity3,4. Theoretical studies suggest that these twist-induced phenomena are common to layered materials such as transition-metal dichalcogenides and black phosphorus6,7. Twisted van der Waals structures are usually created using a transfer-stacking method, but this method cannot be used for materials with relatively strong interlayer binding. Facile bottom-up growth methods could provide an alternative means to create twisted van der Waals structures. Here we demonstrate that the Eshelby twist, which is associated with a screw dislocation (a chiral topological defect), can drive the formation of such structures on scales ranging from the nanoscale to the mesoscale. In the synthesis, axial screw dislocations are first introduced into nanowires growing along the stacking direction, yielding van der Waals nanostructures with continuous twisting in which the total twist rates are defined by the radii of the nanowires. Further radial growth of those twisted nanowires that are attached to the substrate leads to an increase in elastic energy, as the total twist rate is fixed by the substrate. The stored elastic energy can be reduced by accommodating the fixed twist rate in a series of discrete jumps. This yields mesoscale twisting structures consisting of a helical assembly of nanoplates demarcated by atomically sharp interfaces with a range of twist angles. We further show that the twisting topology can be tailored by controlling the radial size of the structure.

Characterisation of the pruritus responses and pruritic behaviours in an interleukin 31-induced canine model of pruritus.

BACKGROUND: Intravenous administration of interleukin (IL)-31 in healthy dogs has been used as a model to assess antipruritic drugs. However, there is no known in-depth characterisation of pruritic behaviours, and the repeatability of the IL-31-induced pruritus in the individual dogs is currently unknown. OBJECTIVES: To evaluate the immediate/delayed pruritus responses and the pruritic behaviours observed in the IL-31-induced pruritic model in healthy dogs after repeated IL-31 injections. ANIMALS: Fifteen healthy laboratory beagles. METHODS: All dogs were video-recorded for 270 min after two intravenous recombinant IL-31 injections (1.75 µg/kg) and vehicle (phosphate-buffered saline, control) injections, respectively; interventions were randomised and performed with a 2 week wash-out period. Two blinded investigators reviewed the pruritic behaviours of all video recordings. RESULTS: Both canine IL-31 (IL-31_01, IL-31_02) injections significantly increased pruritic seconds and categorical minutes ('YES'/'NO' behaviour per discrete 1 min interval) in healthy dogs compared with both vehicle groups (Vehicle_01, Vehicle_02). The second intravenous canine IL-31 (IL-31_02) administered 14 days after the first IL-31 injection induced a significant increase in pruritic seconds (p = 0.021) and not pruritic categorical minutes (p = 0.231). An increase in pruritic seconds was observed in both IL-31 groups in the first 30 min post-administration, while there was no significant difference between IL-31 and vehicle groups. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, intravenous IL-31 reproducibly induces itch responses in dogs. Future evaluations of the canine IL-31 pruritic model should assess total pruritic behaviours in seconds rather than using a biased 'YES/NO' behaviour per 1 min scoring system.

Genetic diversity assessment and genome-wide association study reveal candidate genes associated with component traits in sweet potato (Ipomoea batatas (L.) Lam).

The Korean sweet potatoes were bred by various cultivars introduced from Japanese, American, Porto Rico, China, and Burundi. This issue enriched their genetic diversity but also resulted in a mixture of cultivars. For genotyping, we collected and sequenced 66 sweet potato germplasms from different localities around Korea, including 36 modern cultivars, 5 local cultivars, and 25 foreign cultivars. This identified 447.6 million trimmed reads and 324.8 million mapping reads and provided 39,424 single nucleotide polymorphisms (SNPs) markers. Phylogenetic clustering and population structure analysis distinctly classified these germplasms into 5 genetic groups, group 1, group 2, group 3, group 4, and group 5, containing 20, 15, 10, 7, and 14 accessions, respectively. Sixty-three significant SNPs were selected by genome-wide association for sugar composition-related traits (fructose, glucose, and total sugars), total starch, amylose content, and total carotenoid of the storage root. A total of 37 candidate genes encompassing these significant SNPs were identified, among which, 7 genes were annotated to involve in sugar and starch metabolism, including galactose metabolism (itf04g30630), starch and sucrose metabolism (itf03g13270, itf15g09320), carbohydrate metabolism (itf14g10250), carbohydrate and amino acid metabolism (itf12g19270), and amino sugar and nucleotide sugar metabolism (itf03g21950, itf15g04880). This results indicated that sugar and starch are important characteristics to determine the genetic diversity of sweet potatoes. These findings not only illustrate the importance of component traits to genotyping sweet potatoes but also explain an important reason resulting in genetic diversity of sweet potato.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 directly binds and stabilizes Nrf2 in breast cancer.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) has been frequently overexpressed in many types of malignancy, suggesting its oncogenic function. It recognizes phosphorylated serine or threonine (pSer/Thr) of a target protein and isomerizes the adjacent proline (Pro) residue, thereby altering folding, subcellular localization, stability, and function of target proteins. The oncogenic transcription factor, Nrf2 harbors the pSer/Thr-Pro motif. This prompted us to investigate whether Pin1 could bind to Nrf2 and influence its stability and function in the context of implications for breast cancer development and progression. The correlation between Pin1 and Nrf2 in the triple-negative breast cancer cells was validated by RNASeq analysis as well as immunofluorescence staining. Interaction between Pin1 and Nrf2 was assessed by co-immunoprecipitation and an in situ proximity ligation assay. We found that mRNA and protein levels of Pin1 were highly increased in the tumor tissues of triple-negative breast cancer patients and the human breast cancer cell line. Genetic or pharmacologic inhibition of Pin1 enhanced the ubiquitination and degradation of Nrf2. In contrast, the overexpression of Pin1 resulted in the accumulation of Nrf2 in the nucleus, without affecting its transcription. Notably, the phosphorylation of Nrf2 at serine 215, 408, and 577 is essential for its interaction with Pin1. We also identified phosphorylated Ser104 and Thr277 residues in Keap1, a negative regulator of Nrf2, for Pin1 binding. Pin1 plays a role in breast cancer progression through stabilization and constitutive activation of Nrf2 by competing with Keap1 for Nrf2 binding.

Internal structural analysis of the nasomaxillary complex in patients with skeletal class III asymmetry: A study on asymmetry patterns.

OBJECTIVES: To investigate the internal structure of the nasomaxillary complex, including the maxillary sinus, nasal cavity and nasal septum according to the facial asymmetry pattern and to evaluate its correlation with external maxillomandibular asymmetry in Class III patients based on cone-beam computerized tomography (CBCT) images. MATERIALS AND METHODS: Facial asymmetry was analysed in a total of 100 Class III patients aged 16 years or older using CBCT scans. Patients were categorized into subgroups based on asymmetry pattern. Measurements of the nasomaxillary complex were obtained from the CBCT scans, including the volume and width of the maxillary sinuses and nasal cavities on deviated and non-deviated sides, as well as the displacement of the nasal septum. Statistical analysis was performed to compare the internal nasomaxillary variables within and between groups, and regression analysis was conducted to evaluate the correlation between facial asymmetry and the internal nasomaxillary variables. RESULTS: Group comparisons showed that there were no significant differences in the volume of the maxillary sinus and nasal cavity. However, the direction and extent of nasal septum deviation, as well as the width of the nasal cavity, varied depending on the maxillary asymmetry pattern. Regression analysis indicated a correlation between nasal septum deviation and the difference in maxillary height, while the difference in nasal cavity width was correlated with the difference in maxillary width. CONCLUSION: A comprehensive evaluation of the internal nasal anatomy is vital for understanding the intricate relationship between nasal structure and maxillary growth.

Firing of Replication Origins Is Disturbed by a CDK4/6 Inhibitor in a pRb-Independent Manner.

Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, underlining a need to characterize the effects of CDK4/6 inhibitors beyond pRb. Our study demonstrates how palbociclib impairs origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA while showing no cell cycle arrest. Furthermore, this CDK4/6 inhibitor treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of the Pre-initiation complex (Pre-IC) proteins on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and of its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib in combination with other drugs to target genomic instability in pRB-deficient cancers.

Correlation between craniofacial changes and respiratory improvement after nasomaxillary skeletal expansion in pediatric obstructive sleep apnea patients.

PURPOSE: The aim of this study was to investigate the correlation between the changes in respiratory function and dimensions of the nasomaxillary complex (NMC) and upper airway (UA) compartments after nasomaxillary skeletal expansion (NMSE) treatment for pediatric patients with obstructive sleep apnea (OSA). METHODS: Nonobese OSA patients (mean age, 13.6 ± 2.9 years; mean body mass index, 18.1 ± 3.0 kg/m2); mean apnea-hypopnea index (AHI, 7.0 ± 5.4 events/h) presenting with transverse nasomaxillary constriction were evaluated before and after NMSE using cone-beam computed tomography (CBCT), home sleep test, and modified pediatric sleep questionnaire (m-PSQ). Paired t tests were performed to examine the treatment-related changes in all the parameters, and a multiple regression analysis adjusted for age and sagittal and vertical skeletal patterns was conducted to determine the dimensional parameters to affect the functional improvement. RESULTS: Among 26 patients, NMSE treatment significantly increased NMC dimensions at all tested levels and all UA compartments in CBCT, except glossopharyngeal airway. Concurrently, AHI, oxygen desaturation index, the lowest oxygen saturation (LSaO2), flow limitation (FL), snoring, and m-PSQ were significantly improved. AHI reduction was correlated with UA enlargement with no correlation with NMC expansion, whereas FL reduction was affected by NMC expansion. The minimal cross-sectional area was the most predictive of functional improvement, presenting correlations with AHI, LSaO2, and m-PSQ. CONCLUSION: NMSE can be a good treatment for pediatric OSA patients when applied to enhance the nasal and pharyngeal airway patencies beyond the NMC, ultimately to improve pharyngeal collapsibility as well as nasal airflow.

Genetic effect of single nucleotide polymorphisms in growth hormone receptor gene on the risk of non-syndromic mandibular prognathism in the Korean population.

OBJECTIVES: To evaluate the association of three single-nucleotide polymorphisms (SNPs) of growth hormone receptor (GHR) gene with mandibular prognathism (MP) and relationships between mandibular morphology and GHR gene SNPs in the Korean population. MATERIALS AND METHODS: A total of 325 subjects were divided into two groups based on sagittal maxillomandibular relationship by the lateral cephalography: the MP and control groups. From the SNPs in the GHR gene, three SNPs (rs6180, rs6182 and rs6184) were selected. SNP genotyping was performed using direct sequencing. The craniofacial measurements of lateral cephalography were analysed. RESULTS: We found a lack of association between GHR and MP. However, in the analysis according to the values of cephalometric measurements, rs6180 was significantly associated with ANB, SNB, effective mandibular length and SNMP in females. Additionally, rs6182 and rs6184 were significantly associated with ramal height in males. CONCLUSION: Growth hormone receptor SNPs may affect not only the sagittal development of mandible but also the vertical development of ramal height, and GHR SNPs may gender-differently influence mandibular morphology. This finding supports that the GHR might be susceptible on mandibular morphogenesis in the Korean population.

Effect of locally delivered protein complex-loaded nanoparticles on bone remodelling of atrophic alveolar ridge in beagles.

OBJECTIVE: To investigate the effect of local injection of mineralized hybrid nanoparticles loading dentin matrix protein-1 (DMP-1) and matrix metalloproteinase-13 (MMP-13) complex (P-NPs) on the bone remodelling on atrophic alveolar ridges (AAR) ahead of orthodontic tooth movement (OTM). SETTINGS AND SAMPLE POPULATION: Four beagles were randomly allocated into Group C (OTM only) and Group NP (OTM with P-NPs injection). Experimental model of AAR was prepared in 8 mandibular quadrants after extraction of the third premolars (n = 4 per Group). MATERIALS AND METHODS: Reciprocal traction of the second and fourth premolars was performed towards AAR for 8 weeks. P-NPs were prepared by loading recombinant DMP-1 and MMP-13 complex into calcium carbonate (CaCO3 )-mineralized hybrid nanoparticles and injected at 0, 3 and 6 weeks. The rate of OTM and the bone remodelling characteristics were compared between Groups using fluorescent microscopic analysis and microstructural histomorphometric analysis. RESULTS: Group NP revealed higher bone volume fraction and higher trabecular ratio with lower bone mineral density than Group C on AAR area. Meanwhile, the root movement towards AAR was facilitated in Group NP representing more bodily movement than Group C. CONCLUSION: Non-invasive intervention of P-NPs injection suggested a clinical potential to facilitate translational movement into the AAR with sustaining woven bone-like microstructural environment.

Tumor Promoting Effects of Sulforaphane on Diethylnitrosamine-Induced Murine Hepatocarcinogenesis.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that aberrant activation of NRF2 accelerates the proliferation and progression of cancer cells. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. This prompted us to assess the effects of sulforaphane (SFN), a prototypic NRF2 activating chemopreventive phytochemical, on experimentally induced carcinogenesis. In the present study, SFN was daily injected intraperitoneally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The liver to body weight ratio, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than those in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1, and the cell proliferation marker, proliferating cell nuclear antigen was further elevated in DEN plus SFN-treated mice. These results suggest that once hepatocarcinogenesis is initiated, SFN may stimulate tumor progression.

Accuracy of convolutional neural networks-based automatic segmentation of pharyngeal airway sections according to craniofacial skeletal pattern.

INTRODUCTION: This study aimed to evaluate a 3-dimensional (3D) U-Net-based convolutional neural networks model for the fully automatic segmentation of regional pharyngeal volume of interests (VOIs) in cone-beam computed tomography scans to compare the accuracy of the model performance across different skeletal patterns presenting with various pharyngeal dimensions. METHODS: Two-hundred sixteen cone-beam computed tomography scans of adult patients were randomly divided into training (n = 100), validation (n = 16), and test (n = 100) datasets. We trained the 3D U-Net model for fully automatic segmentation of pharyngeal VOIs and their measurements: nasopharyngeal, velopharyngeal, glossopharyngeal, and hypopharyngeal sections as well as total pharyngeal airway space (PAS). The test datasets were subdivided according to the sagittal and vertical skeletal patterns. The segmentation performance was assessed by dice similarity coefficient, volumetric similarity, precision, and recall values, compared with the ground truth created by 1 expert's manual processing using semiautomatic software. RESULTS: The proposed model achieved highly accurate performance, showing a mean dice similarity coefficient of 0.928 ± 0.023, the volumetric similarity of 0.928 ± 0.023, precision of 0.925 ± 0.030, and recall of 0.921 ± 0.029 for total PAS segmentation. The performance showed region-specific differences, revealing lower accuracy in the glossopharyngeal and hypopharyngeal sections than in the upper sections (P <0.001). However, the accuracy of model performance at each pharyngeal VOI showed no significant difference according to sagittal or vertical skeletal patterns. CONCLUSIONS: The 3D-convolutional neural network performance for region-specific PAS analysis is promising to substitute for laborious and time-consuming manual analysis in every skeletal and pharyngeal pattern.

Craniofacial treatment protocol for a pediatric patient with obstructive sleep apnea and skeletal Class III malocclusion: A 13-year follow-up.

This report aimed to describe the long-term effects of craniofacial growth modification treatment on sleep and breathing functions in a 7-year-old girl diagnosed with skeletal Class III malocclusion and sleep-disordered breathing. Based on the flowchart of orthodontic intervention protocol that we proposed for phenotype-based patient selection and skeletal target-based treatment selection for pediatric patients with sleep-disordered breathing, a 2-phase treatment targeting the nasomaxillary complex was performed. Posttreatment 3-dimensional changes in the skeletal structure and upper airway were evaluated in association with functional assessment using a validated pediatric sleep questionnaire and home sleep test. Esthetic improvement and obstructive sleep apnea cure were achieved without skeletal surgery. The 2-year retention records showed stable occlusion and improved facial profile with normal breathing and sleep.

Accuracy of auto-identification of the posteroanterior cephalometric landmarks using cascade convolution neural network algorithm and cephalometric images of different quality from nationwide multiple centers.

INTRODUCTION: The purpose of this study was to evaluate the accuracy of auto-identification of the posteroanterior (PA) cephalometric landmarks using the cascade convolution neural network (CNN) algorithm and PA cephalogram images of a different quality from nationwide multiple centers nationwide. METHODS: Of the 2798 PA cephalograms from 9 university hospitals, 2418 images (2075 training set and 343 validation set) were used to train the CNN algorithm for auto-identification of 16 PA cephalometric landmarks. Subsequently, 99 pretreatment images from the remaining 380 test set images were used to evaluate the accuracy of auto-identification of the CNN algorithm by comparing with the identification by a human examiner (gold standard) using V-Ceph 8.0 (Ostem, Seoul, South Korea). Pretreatment images were used to eliminate the effects of orthodontic bracket, tube and wire, surgical plate, and surgical screws. Paired t test was performed to compare the x- and y-coordinates of each landmark. The point-to-point error and the successful detection rate (range, within 2.0 mm) were calculated. RESULTS: The number of landmarks without a significant difference between the location identified by the human examiner and by auto-identification by the CNN algorithm were 8 on the x-coordinate and 5 on the y-coordinate, respectively. The mean point-to-point error was 1.52 mm. The low point-to-point error (<1.0 mm) was observed at the left and right antegonion (0.96 mm and 0.99 mm, respectively) and the high point-to-point error (>2.0 mm) was observed at the maxillary right first molar root apex (2.18 mm). The mean successful detection rate of auto-identification was 83.3%. CONCLUSIONS: Cascade CNN algorithm for auto-identification of PA cephalometric landmarks showed a possibility of an effective alternative to manual identification.

Vertical bony step between proximal and distal segments after mandibular setback is related with relapse: A cone-beam computed tomographic study.

INTRODUCTION: Vertical bony step (VBS) occurs between proximal and distal segments of the mandible during mandibular setback surgery with bilateral sagittal split ramus osteotomy. The purpose of this study was to investigate whether VBS is correlated with the relapse of mandibular setback using 3-dimensional models constructed from cone-beam computed tomography. METHODS: The subjects consisted of 30 patients who underwent bilateral sagittal split ramus osteotomy for a mandibular setback. Double jaw surgery was performed in 18 patients, and isolated mandibular setback surgery was performed in 12 patients. Cone-beam computed tomography scans were taken at pretreatment (T0), postsurgery (T1), and posttreatment (T2). Treatment changes and the correlations between measurements were evaluated. RESULTS: The mean mandibular setback was -11.9 mm, and the mean VBS was -5.6 mm. Correlations with the relapse of mandibular setback were found in the amount of mandibular setback (T1 - T0), development of VBS (T1 - T0), posterior movement of the proximal segment (T1 - T0), counterclockwise rotation of symphysis (T2 - T1), and the resolution of VBS (T2 - T1). CONCLUSIONS: The development and resolution of VBS were correlated with the relapse of mandibular setback. Minimizing VBS is recommended to reduce the relapse of mandibular setback.

Fully automated identification of cephalometric landmarks for upper airway assessment using cascaded convolutional neural networks.

OBJECTIVES: The aim of the study was to evaluate the accuracy of a cascaded two-stage convolutional neural network (CNN) model in detecting upper airway (UA) soft tissue landmarks in comparison with the skeletal landmarks on the lateral cephalometric images. MATERIALS AND METHODS: The dataset contained 600 lateral cephalograms of adult orthodontic patients, and the ground-truth positions of 16 landmarks (7 skeletal and 9 UA landmarks) were obtained from 500 learning dataset. We trained a UNet with EfficientNetB0 model through the region of interest-centred circular segmentation labelling process. Mean distance errors (MDEs, mm) of the CNN algorithm was compared with those from human examiners. Successful detection rates (SDRs, per cent) assessed within 1-4 mm precision ranges were compared between skeletal and UA landmarks. RESULTS: The proposed model achieved MDEs of 0.80 ± 0.55 mm for skeletal landmarks and 1.78 ± 1.21 mm for UA landmarks. The mean SDRs for UA landmarks were 72.22 per cent for 2 mm range, and 92.78 per cent for 4 mm range, contrasted with those for skeletal landmarks amounting to 93.43 and 98.71 per cent, respectively. As compared with mean interexaminer difference, however, this model showed higher detection accuracies for geometrically constructed UA landmarks on the nasopharynx (AD2 and Ss), while lower accuracies for anatomically located UA landmarks on the tongue (Td) and soft palate (Sb and St). CONCLUSION: The proposed CNN model suggests the availability of an automated cephalometric UA assessment to be integrated with dentoskeletal and facial analysis.

Alternative regulation of HIF-1α stability through Phosphorylation on Ser451.

The hypoxia-inducible factor (HIF-1α) functions as a master regulator of oxygen homeostasis. Oxygen-dependent hydroxylation of HIF-1α is tightly regulated by prolyl hydroxylase domain containing proteins (PHD1, PHD2, and PHD3). The prolyl hydroxylation facilitates the recruitment of the von Hippel-Lindau (VHL) protein, leading to ubiquitination and degradation of HIF-1α by the proteasomes. Besides prolyl hydroxylation, phosphorylation of HIF-1α is another central post-translational modification, which regulates its stability under hypoxic conditions as well as normoxic conditions. By use of LC/MS/MS-based analysis, we were able to identify a specific serine residue (Ser451) of HIF-1α phosphorylated under hypoxic conditions. Using plasmids expressing wild type (WT), non-phosphorylatable mutant HIF-1α (S451A), and phosphomimetic mutant HIF-1α (S451E), we demonstrated that the phosphorylation at Ser451 is important in maintaining the HIF-1α protein stability. Notably, phosphorylation at S451 interrupts the interaction of HIF-1α with PHD and pVHL. A phosphomimetic construct of HIF-1α at Ser451 (S451E) is significantly more stable than WT HIF-1α under normoxic conditions. Cells transfected with unphosphorylatable HIF-1α exhibited significantly lower HIF-1 transcriptional activity than WT cells and markedly reduced tumor cell migration. Further, tumors derived from the phosphomimetic mutant cells grew faster, whereas the tumors derived from non-phosphorylatable mutant cells grew slower than the control tumors, suggesting that the phosphorylation of HIF-1α at the Ser451 site is critical to promote tumor growth in vivo. Taken together, our data suggest an alternative mechanism responsible for the regulation of HIF-1α stability.

Stabilization of C/EBPß through direct interaction with STAT3 in H-Ras transformed human mammary epithelial cells.

Signal transducer and activator of transcription 3 (STAT3) plays important roles in cancer-associated inflammation by controlling expression of proinflammatory cytokines and chemokines. Recent studies suggest that C/EBPß (CCAAT-enhancer binding protein beta) and STAT3 synergistically stimulate cancer cell proliferation and epithelial-mesenchymal transition. C/EBPß is a leucine-zipper transcription factor that regulates expression of a variety of inflammatory cytokines or chemokines, such as IL-8, G-CSF (granulocyte colony stimulating factor), and GM-CSF (granulocyte macrophage colony stimulating factor) which induce neutrophil infiltration and differentiation. However, molecular mechanisms by which STAT3 and C/EBPß cooperatively interact had not been fully elucidated. In this study, we found that the level of C/EBPß protein, but not that of its mRNA transcript, was decreased in the absence of STAT3 in H-Ras transformed human mammary epithelial (H-Ras MCF10A) cells. In addition, silencing STAT3 dramatically induced ubiquitination of C/EBPß for proteasomal degradation. Furthermore, direct interaction between STAT3 and C/EBPß was confirmed by immunoprecipitation and proximity ligation assays. Taken together, these results suggest that STAT3 stabilizes C/EBPß, thereby promoting cancer-associated inflammation.

IL-1ß induces expression of proinflammatory cytokines and migration of human colon cancer cells through upregulation of SIRT1.

SIRT1 is a mammalian NAD+-dependent deacetylase, which is known to be involved in various physiological events, such as adaptive response to environmental stresses including caloric restriction, as well as in aging and cellular senescence. However, recent studies have revealed overexpression of SIRT1 in many different types of human malignancies, particularly colon cancer. Interleukin-1ß (IL-1ß) is a proinflammatory cytokine that plays a major role in invasiveness, stemness and progression of colon cancer. However, the interaction between IL-1ß and SIRT1 in the tumor development and progression remains elusive. In this study, we found that IL-1ß induces SIRT1 protein expression in human colon cancer HCT-116 cells. IL-1ß-induced SIRT1 upregulation led to enhanced expression of mRNA transcripts of pro-inflammatory cytokines, IL-6 and IL-8 as well as that of IL-1ß. Knockdown of SIRT1 prevented IL-1ß-induced phosphorylation and nuclear accumulation of c-Jun. Furthermore, pharmacologic inhibition of SIRT1 abrogated clonogenicity and migrative capability of human colon cancer cells stimulated with IL-1ß. In summary, IL-1ß-induced SIRT1 upregulation stimulates production of proinflammatory cytokines via a nuclear accumulation of c-Jun, leadng to colon cancer growth and progression.

Multi-perspective clustering of obstructive sleep apnea towards precision therapeutic decision including craniofacial intervention.

PURPOSE: Previous studies focusing on phenotyping obstructive sleep apnea (OSA) have outlined its heterogeneity in clinical symptoms, comorbidities, and polysomnographic features. However, the role of anatomical or pathophysiological causality including craniofacial skeletal deformity has not been studied. We aimed to identify and characterize phenotypes of OSA based on multi-perspective clustering by incorporating craniofacial risks with obesity, apnea severity, arousability, symptom, and comorbidity. METHODS: A total of 421 Korean patients with OSA (apnea-hypopnea index, AHI ≥ 5; age ≥ 20 years old) were recruited. A K-means cluster analysis was performed following principal component analysis with sagittal and vertical skeletal variables (ANB and mandibular plane angle), AHI, body mass index, and Epworth sleepiness scale. Inter-cluster comparison was conducted using demographic, cephalometric, and polysomnographic variables in addition to presence of diabetes and hypertension. Risk factors contributing to OSA severity were evaluated in each cluster using multivariable regression analysis with adjustment for age and gender. RESULTS: Three phenotypic clusters were identified and characterized as follows: Cluster-1 (noncraniofacial phenotype, 39%), non-obese moderate-to-severe OSA with no skeletal discrepancy representing low arousal threshold (ArTh), little sleepiness, and low comorbidity; Cluster-2 (craniofacial skeletal phenotype, 33%), non-obese moderate OSA with definite skeletal discrepancy showing low ArTh, mild sleepiness, and low comorbidity; and Cluster-3 (complicated phenotype, 28%), obese severe OSA with skeletal discrepancy exhibiting high ArTh, excessive daytime sleepiness, and high incidence of hypertension. CONCLUSIONS: The three OSA phenotypes from multi-perspective clustering may provide a basis for precise therapeutic decision-making including craniofacial skeletal intervention beyond usual characterization of OSA subgroups.

Comprehensive transcriptome profiling of Caragana microphylla in response to salt condition using de novo assembly.

OBJECTIVE: To investigate the response of Caragana microphylla in salt condition, transcriptome analysis, differentially expressed genes (DEGs) comparison with Arabidopsis thaliana, and the chlorophyll content analysis were performed. RESULTS: Gene Ontology (GO) term, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs indicated that salt condition affected photosynthesis and chlorophyll in C. microphylla. The DEGs compared with salt responsive genes of A. thaliana indicated that C. microphylla's responses to salt differed greatly from those of the model plant and that the results also indicated up-regulated genes related to photosynthesis and chlorophyll in C. microphylla. Moreover, we confirmed that salt-treated C. microphylla increased chlorophyll content, and the genes of protoporphyrin IX downstream in chlorophyll biosynthesis were induced in the heatmap analysis. CONCLUSIONS: These results showed a similar pattern to some halophytes plants with increased chlorophyll at a certain salt concentration, and we assumed that C. microphylla also has a mechanism to adapt or tolerate moderate salt conditions.