Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function.

BACKGROUND: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions. METHODS: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions. RESULTS: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis. CONCLUSION: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.

Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome.

BACKGROUND: Delay in type II alveolar epithelial cell (AECII) regeneration has been linked to higher mortality in patients with acute respiratory distress syndrome (ARDS). However, the interaction between Doublecortin-like kinase 1 (DCLK1) and the Hippo signaling pathway in ARDS-associated AECII differentiation remains unclear. Therefore, the objective of this study was to understand the role of the DCLK1/Hippo pathway in mediating AECII differentiation in ARDS. MATERIALS AND METHODS: AECII MLE-12 cells were exposed to 0, 0.1, or 1 µg/mL of lipopolysaccharide (LPS) for 6 and 12 h. In the mouse model, C57BL/6JNarl mice were intratracheally (i.t.) injected with 0 (control) or 5 mg/kg LPS and were euthanized for lung collection on days 3 and 7. RESULTS: We found that LPS induced AECII markers of differentiation by reducing surfactant protein C (SPC) and p53 while increasing T1α (podoplanin) and E-cadherin at 12 h. Concurrently, nuclear YAP dynamic regulation and increased TAZ levels were observed in LPS-exposed AECII within 12 h. Inhibition of YAP consistently decreased cell levels of SPC, claudin 4 (CLDN-4), galectin 3 (LGALS-3), and p53 while increasing transepithelial electrical resistance (TEER) at 6 h. Furthermore, DCLK1 expression was reduced in isolated human AECII of ARDS, consistent with the results in LPS-exposed AECII at 6 h and mouse SPC-positive (SPC+) cells after 3-day LPS exposure. We observed that downregulated DCLK1 increased p-YAP/YAP, while DCLK1 overexpression slightly reduced p-YAP/YAP, indicating an association between DCLK1 and Hippo-YAP pathway. CONCLUSIONS: We conclude that DCLK1-mediated Hippo signaling components of YAP/TAZ regulated markers of AECII-to-AECI differentiation in an LPS-induced ARDS model.

Feasibility of free-breathing 19 F MRI image acquisition to characterize ventilation defects in CF and healthy volunteers at wash-in.

PURPOSE: To explore the feasibility of measuring ventilation defect percentage (VDP) using 19 F MRI during free-breathing wash-in of fluorinated gas mixture with postacquisition denoising and to compare these results with those obtained through traditional Cartesian breath-hold acquisitions. METHODS: Eight adults with cystic fibrosis and 5 healthy volunteers completed a single MR session on a Siemens 3T Prisma. 1 H Ultrashort-TE MRI sequences were used for registration and masking, and ventilation images with 19 F MRI were obtained while the subjects breathed a normoxic mixture of 79% perfluoropropane and 21% oxygen (O2 ). 19 F MRI was performed during breath holds and while free breathing with one overlapping spiral scan at breath hold for VDP value comparison. The 19 F spiral data were denoised using a low-rank matrix recovery approach. RESULTS: VDP measured using 19 F VIBE and 19 F spiral images were highly correlated (r = 0.84) at 10 wash-in breaths. Second-breath VDPs were also highly correlated (r = 0.88). Denoising greatly increased SNR (pre-denoising spiral SNR, 2.46 ± 0.21; post-denoising spiral SNR, 33.91 ± 6.12; and breath-hold SNR, 17.52 ± 2.08). CONCLUSION: Free-breathing 19 F lung MRI VDP analysis was feasible and highly correlated with breath-hold measurements. Free-breathing methods are expected to increase patient comfort and extend ventilation MRI use to patients who are unable to perform breath holds, including younger subjects and those with more severe lung disease.

Photon color conversion enhancement of colloidal quantum dots inserted into a subsurface laterally-extended GaN nano-porous structure in an InGaN/GaN quantum-well template.

To improve the color conversion performance, we study the nanoscale-cavity effects on the emission efficiency of a colloidal quantum dot (QD) and the Förster resonance energy transfer (FRET) from quantum well (QW) into QD in a GaN porous structure (PS). For this study, we insert green-emitting QD (GQD) and red-emitting QD (RQD) into the fabricated PSs in a GaN template and a blue-emitting QW template, and investigate the behaviors of the photoluminescence (PL) decay times and the intensity ratios of blue, green, and red lights. In the PS samples fabricated on the GaN template, we observe the efficiency enhancements of QD emission and the FRET from GQD into RQD, when compared with the samples of surface QDs, which is attributed to the nanoscale-cavity effect. In the PS samples fabricated on the QW template, the FRET from QW into QD is also enhanced. The enhanced FRET and QD emission efficiencies in a PS result in an improved color conversion performance. Because of the anisotropic PS in the sample surface plane, the polarization dependencies of QD emission and FRET are observed.

Surface plasmon coupling effects on the photon color conversion behaviors of colloidal quantum dots in a GaN nanoscale hole with a nearby quantum-well structure.

To improve color conversion performance for color display application, we study the near-field-induced nanoscale-cavity effects on the emission efficiency and Förster resonance energy transfer (FRET) under the condition of surface plasmon (SP) coupling by inserting colloidal quantum dots (QDs) and synthesized Ag nanoparticles (NPs) into surface nano-holes fabricated on a GaN template and an InGaN/GaN quantum-well (QW) template. In the QW template, the inserted Ag NPs are close to either QWs or QDs for producing three-body SP coupling to enhance color conversion. Time-resolved and continuous-wave photoluminescence (PL) behaviors of the QW- and QD-emitting lights are investigated. The comparison between the nano-hole samples and the reference samples of surface QD/Ag NP shows that the nanoscale-cavity effect of the nano-hole leads to the enhancements of QD emission, FRET between QDs, and FRET from QW into QD. The SP coupling induced by the inserted Ag NPs can enhance the QD emission and FRET from QW into QD. Its result is further enhanced through the nanoscale-cavity effect. The relative continuous-wave PL intensities among different color components also show the similar behaviors. By introducing SP coupling to a color conversion device with the FRET process in a nanoscale cavity structure, we can significantly improve the color conversion efficiency. Simulation results confirm the basic observations in experiment.

Activin A downregulates the CD69-MT2A axis via p38MAPK to induce erythroid differentiation that sensitizes BCR-ABL-positive cells to imatinib.

Induction of differentiation sensitizes chronic myeloid leukemia (CML) cells to the BCR-ABL inhibitor imatinib by mechanisms that remain unknown. We previously identified the BCR-ABL downstream effector CD69 which inhibits imatinib-induced CML cell differentiation. Herein, we found that the erythroid differentiation inducers activin A and aclacinomycin A induced expression of erythroid markers (α-globin, ζ-globin, GATA-1, and glycophorin A) and simultaneously reduced CD69 levels in K562 CML cells. Blockade of p38MAPK by SB203580 and shRNA eliminated the inhibitory effect of activin A on the promoter, mRNA, and protein levels and positive cell population of CD69. CD69 overexpression inhibited activin A-induced erythroid marker expression. Pretreatment of K562 cells with activin A to induce differentiation followed by a subtoxic concentration of imatinib caused growth inhibition and apoptosis that was reduced by CD69 overexpression. Activin A also reduced the expression of CD69's potential downstream molecule metallothionein 2A (MT2A) via p38MAPK. MT2A-knockdown reduced CD69 inhibition of activin A-induced erythroid marker expression. Furthermore, MT2A-knockdown reduced CD69 inhibition of activin A-imatinib sequential treatment-mediated growth inhibition and apoptosis in K562 and BCR-ABL-expressing CD34+ cells. These results suggest that CD69 inhibits activin A induction of erythroid differentiation-mediated CML cell sensitivity to imatinib via MT2A. Therefore, activin A induction of erythroid differentiation sensitizes BCR-ABL-positive cells to imatinib by downregulating the erythroid differentiation suppressors CD69 and MT2A.

Determinants of residential greenness and its association with prostate cancer risk: A case-control study in Singapore.

BACKGROUND: Exposure to greenness has been shown to be beneficial to health, but few studies have examined the association between residential greenness and prostate cancer (PCa) risk. Our main objectives were to identify the determinants of residential greenness, and to investigate if residential greenness was associated with PCa risk in Singapore. METHODS: The hospital-based case-control study was conducted between April 2007 and May 2009. The Singapore Prostate Cancer Study (SPCS) comprised 240 prostate cancer cases and 268 controls, whose demographics and residential address were collected using questionnaires. Residential greenness was measured by normalized difference vegetation index (NDVI) around the participants' homes using a buffer size of 1 km. Determinants of NDVI were identified using a multivariable linear regression model. Logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of associations between NDVI and PCa risk, adjusting for potential confounders. RESULTS: Having a BMI within the second quartile, as compared to the lowest quartile, was associated with higher levels of NDVI (ß-coefficient = 0.263; 95% CI = 0.040-0.485) after adjusting for covariates. Additionally, being widowed or separated, as compared to being married, was associated with lower levels of NDVI (ß-coefficient = -0.393; 95% CI = -0.723, -0.063). An interquartile range (IQR) increase in NDVI was positively associated with prostate cancer risk OR = 1.45; 95% CI = 1.02-2.07). Stratified analysis by tumour grade and stage showed that higher NDVI was associated with higher risk of low grade PCa. CONCLUSION: Our findings suggested that residential greenness was associated with higher risk of PCa in Singapore. Future studies on the quality and type of green spaces, as well as other factors of residential greenness, in association with PCa risk should be conducted to better understand this relationship.

Machine learning for automated and real-time two-dimensional to three-dimensional registration of the spine using a single radiograph.

OBJECTIVE: The goal of this work was to methodically evaluate, optimize, and validate a self-supervised machine learning algorithm capable of real-time automatic registration and fluoroscopic localization of the spine using a single radiograph or fluoroscopic frame. METHODS: The authors propose a two-dimensional to three-dimensional (2D-3D) registration algorithm that maximizes an image similarity metric between radiographic images to identify the position of a C-arm relative to a 3D volume. This work utilizes digitally reconstructed radiographs (DRRs), which are synthetic radiographic images generated by simulating the x-ray projections as they would pass through a CT volume. To evaluate the algorithm, the authors used cone-beam CT data for 127 patients obtained from an open-source de-identified registry of cervical, thoracic, and lumbar scans. They systematically evaluated and tuned the algorithm, then quantified the convergence rate of the model by simulating C-arm registrations with 80 randomly simulated DRRs for each CT volume. The endpoints of this study were time to convergence, accuracy of convergence for each of the C-arm's degrees of freedom, and overall registration accuracy based on a voxel-by-voxel measurement. RESULTS: A total of 10,160 unique radiographic images were simulated from 127 CT scans. The algorithm successfully converged to the correct solution 82% of the time with an average of 1.96 seconds of computation. The radiographic images for which the algorithm converged to the solution demonstrated 99.9% registration accuracy despite utilizing only single-precision computation for speed. The algorithm was found to be optimized for convergence when the search space was limited to a ± 45° offset in the right anterior oblique/left anterior oblique, cranial/caudal, and receiver rotation angles with the radiographic isocenter contained within 8000 cm3 of the volumetric center of the CT volume. CONCLUSIONS: The investigated machine learning algorithm has the potential to aid surgeons in level localization, surgical planning, and intraoperative navigation through a completely automated 2D-3D registration process. Future work will focus on algorithmic optimizations to improve the convergence rate and speed profile.

Diagnosis and Treatment of Central Serous Chorioretinopathy in Patients with Scleritis.

Central serous chorioretinopathy (CSCR) is characterized by central neurosensory retinal detachment from the retinal pigment epithelium. While the association between CSCR and steroid use is widely recognized, it is difficult to distinguish whether the subretinal fluid (SRF) in ocular inflammatory disease results from steroid use or an inflammation-related uveal effusion. We report the case of a 40-year-old man who presented to our department with intermittent redness and dull pain in both eyes that had persisted for three months. He was diagnosed with scleritis with SRF in both eyes and steroid therapy was started. Inflammation improved with steroid use, but SRF increased. This indicated that the fluid was not caused by the posterior scleritis-related uveal effusion but by steroid use. SRF and clinical symptoms subsided after steroids were discontinued completely and immunomodulatory therapy was initiated. Our study highlights that steroid-associated CSCR must be considered in the differential diagnosis of patients with scleritis, and prompt diagnosis with an immediate shift from steroids to immunomodulatory therapy can resolve SRF and clinical symptoms.

CircVIS: a platform for circRNA visual presentation.

BACKGROUND: The collection of circRNAs mostly focused on their sequence composition such as protein/miRNA binding motif, and/or regulatory elements such as internal ribosome entry site. However, less attention was paid to subcellular localization. CircVIS aimed to provide a collection of circRNAs with information of subcellular compartments and also integrated the circRNA entries from previous circRNA databases. RESULTS: A collection of circRNAs from public circRNA databases and de novo identification were annotated according to subcellular localizations including nucleoplasm, chromatin-associated parts, cytoplasm and polyribosome. All circRNAs were aligned to a selected major transcript, and if presence, the circRNA-derived open reading frame with annotation of functional domain were compared to its parental protein. The results showed that distinct circRNAs may exert their molecular and cellular functions in different subcellular compartments. The web service is made freely available at http://lab-x-omics.nchu.edu.tw/circVIS . CONCLUSIONS: CircVIS allows users to visualize the alignment between a given circRNA and its most relevant reference transcript along with information of subcellular localization.