PP2 protects from keratin mutation-associated liver injury and filament disruption via SRC kinase inhibition in male but not female mice.

BACKGROUND AND AIMS: Hepatocyte keratin polypeptides 8/18 (K8/K18) are unique among intermediate filaments proteins (IFs) in that their mutation predisposes to, rather than causes, human disease. Mice that overexpress human K18 R90C manifest disrupted hepatocyte keratin filaments with hyperphosphorylated keratins and predisposition to Fas-induced liver injury. We hypothesized that high-throughput screening will identify compounds that protect the liver from mutation-triggered predisposition to injury. APPROACH AND RESULTS: Using A549 cells transduced with a lentivirus K18 construct and high-throughput screening, we identified the SRC-family tyrosine kinases inhibitor, PP2, as a compound that reverses keratin filament disruption and protects from apoptotic cell death caused by K18 R90C mutation at this highly conserved arginine. PP2 also ameliorated Fas-induced apoptosis and liver injury in male but not female K18 R90C mice. The PP2 male selectivity is due to its lower turnover in male versus female livers. Knockdown of SRC but not another kinase target of PP2, protein tyrosine kinase 6, in A549 cells abrogated the hepatoprotective effect of PP2. Phosphoproteomic analysis and validation showed that the protective effect of PP2 associates with Ser/Thr but not Tyr keratin hypophosphorylation, and differs from the sex-independent effect of the Ser/Thr kinase inhibitor PKC412. Inhibition of RAF kinase, a downstream target of SRC, by vemurafenib had a similar protective effect to PP2 in A549 cells and male K18 R90C mice. CONCLUSIONS: PP2 protects, in a male-selective manner, keratin mutation-induced mouse liver injury by inhibiting SRC-triggered downstream Ser/Thr phosphorylation of K8/K18, which is phenocopied by RAF kinase inhibitor vemurafenib. The PP2/vemurafenib-associated findings, and their unique mechanisms of action, further support the potential role of select kinase inhibition as therapeutic opportunities for keratin and other IF-associated human diseases.

Hypoosmosis alters hepatocyte mitochondrial morphology and induces selective release of carbamoyl phosphate synthetase 1.

Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hypothesized that increased CPS1 release during hypoosmosis is selective and associates with altered mitochondrial morphology. Both ex vivo and in vivo models were assessed. Mouse hepatocytes and livers were challenged with isotonic or hypoosmotic (35 mosM) buffer. Mice were injected intraperitoneally with water (10% body weight) with or without an antidiuretic. Mitochondrial and cytosolic fractions were isolated using differential centrifugation, then analyzed by immunoblotting to assess subcellular redistribution of four mitochondrial proteins: CPS1, ornithine transcarbamylase (OTC), pyrroline-5-carboxylate reductase 1 (PYCR1), and cytochrome c. Mitochondrial morphology alterations were examined using electron microscopy. Hypoosmotic treatment of whole livers or hepatocytes led to preferential or increased mitochondrial release, respectively, of CPS1 as compared with two mitochondrial matrix proteins (OTC/PYCR1) and with the intermembrane space protein, cytochrome c. Mitochondrial apoptosis-induced channel opening using staurosporine in hepatocytes led to preferential CPS1 and cytochrome c release. The CPS1-selective changes were accompanied by dramatic alterations in ultrastructural mitochondrial morphology. In mice, hypoosmosis/hyponatremia led to increased liver vascular congestion and increased CPS1 in bile but not blood, coupled with mitochondrial structural alterations. In contrast, isotonic increase of intravascular volume led to a decrease in mitochondrial size with limited change in bile CPS1 compared with hypoosmotic conditions and absence of the hypoosmosis-associated histological alterations. Taken together, hepatocyte CPS1 is selectively released in response to hypoosmosis/hyponatremia and provides a unique biomarker of mitochondrial injury.NEW & NOTEWORTHY Exposure of isolated mouse livers, primary cultured hepatocytes, or mice to hypoosmosis/hyponatremia conditions induces significant mitochondrial shape alterations accompanied by preferential release of the mitochondrial matrix protein CPS1, a urea cycle enzyme. In contrast, the intermembrane space protein, cytochrome c, and two other matrix proteins, including the urea cycle enzyme ornithine transcarbamylase, remain preferentially retained in mitochondria. Therefore, hepatocyte CPS1 manifests unique mitochondrial stress response compartmentalization and is a sensitive sensor of mitochondrial hypoosmotic/hyponatremic injury.

Effects of morphine and P2Y inhibitor amongst patients with acute coronary syndrome: A meta-analysis of comparative studies.

BACKGROUND: P2Y inhibitor and morphine are widely used in caring for patients with the acute coronary syndrome (ACS), but there are some concerns about the combination use due to interaction in metabolism. Therefore, this study aimed to examine whether using morphine with antiplatelets in patients with ACS affects the clinical outcomes based on currently available evidence. METHODS: Three databases were searched for comparative studies on this topic by using relevant keywords of ACS and morphine. Two authors independently extracted study information, mortality, major adverse cardiac event (MACE), major bleeding, and length of hospital stay. Then, they evaluated the quality of evidence independently. Meta-analysis was planned to be conducted in random-effects model. Risk ratio (RR) was used for most outcomes except hospital stay, and Peto odds ratio (POR) was used if there were any zero cells. Pooled estimate was presented with 95% confidence interval (CI). RESULTS: Fourteen studies (n = 73,033) met eligibility criteria, and there was non-significant difference in mortality between antiplatelet with and without morphine (RR = 1.13, 95%CI: 0.78 to 1.64). Antiplatelet therapy without morphine significantly reduced the risk of MACE (RR = 0.78, 95%CI: 0.67 to 0.89; I-square = 0%), but increased the odds of major bleeding (POR = 1.87, 95%CI: 1.04 to 3.35; I-square = 0%) as compared with the combined use of antiplatelet therapy and morphine. CONCLUSION: In conclusion, there is no statistically significant difference in mortality in patients with ACS using morphine or not, but clinicians ought to make a trade-off between a lower risk of MACE and a higher risk of major bleeding before adding morphine to antiplatelet therapy.

Wiring Specificity and Synaptic Diversity in the Mouse Lateral Central Amygdala.

The central amygdala (CeA) nucleus, a subcortical structure composed of mostly GABA-releasing (GABAergic) neurons, controls fear expression via projections to downstream targets in the hypothalamus and brainstem. The CeA consists of the lateral (CeL) and medial (CeM) subdivisions. The CeL strongly gates information transfer to the CeM, the main output station of the amygdala, but little is known about the functional organization of local circuits in this region. Using cluster analysis, we identified two major electrophysiologically distinct CeL neuron classes in mouse amygdala slices, the early-spiking (ES) and late-spiking (LS) neurons. These two classes displayed distinct autaptic transmission. Compared with LS neurons, ES neurons had strong and depressing autapses, which enhanced spike-timing precision. With multiple patch-clamp recordings, we found that CeL neurons made chemical, but not electrical, synapses. Analysis of individual connections revealed cannabinoid type 1 receptor-mediated suppression of the ES, but not of the LS cell output synapse. More interestingly, the efficacy of the ES→LS or LS→ES synapse was ~2-fold greater than that of the LS→LS or ES→ES synapse. When tested at 20 Hz, synapses between different neurons, but not within the same class, were markedly depressing and were more powerful to sculpt activity of postsynaptic neurons. Moreover, neurons of different classes also form synapses with higher degree of connectivity. We demonstrate that ES and LS neurons represent two functionally distinct cell classes in the CeL and interactions between presynaptic and postsynaptic neurons dictate synaptic properties between neurons. SIGNIFICANCE STATEMENT: The central lateral amygdala (CeL) is a key node in fear circuits, but the functional organization of local circuits in this region is largely unknown. The CeL consists of mostly GABAergic inhibitory neurons with different functional and molecular features. Here, we report that the presynaptic cell class determines functional properties of autapses and cannabinoid-mediated modulation of synaptic transmission between neurons, whereas presynaptic versus postsynaptic cell classes dictate the connectivity, efficacy, and dynamics of GABAergic synapses between any two neurons. The wiring specificity and synaptic diversity have a great impact on neuronal output in amygdala inhibitory networks. Such synaptic organizing principles advance our understanding of the significance of physiologically defined neuronal phenotypes in amygdala inhibitory networks.

Damping ratio analysis of tooth stability under various simulated degrees of vertical alveolar bone loss and different root types.

BACKGROUND: The purpose of this study was to evaluate the feasibility of using damping ratio (DR) analysis combined with resonance frequency (RF) and periotest (PTV) analyses to provide additional information about natural tooth stability under various simulated degrees of alveolar vertical bone loss and various root types. METHODS: Three experimental tooth models, including upper central incisor, upper first premolar, and upper first molar were fabricated using Ti6Al4V alloy. In the tooth models, the periodontal ligament and alveolar bone were simulated using a soft lining material and gypsum, respectively. Various degrees of vertical bone loss were simulated by decreasing the surrounding bone level apically from the cementoenamel junction in 2-mm steps incrementally downward for 10 mm. A commercially available RF analyzer was used to measure the RF and DR of impulse-forced vibrations on the tooth models. RESULTS: The results showed that DRs increased as alveolar vertical bone height decreased and had high coefficients of determination in the linear regression analysis. The damping ratio of the central incisor model without a simulated periodontal ligament were 11.95 ± 1.92 and 27.50 ± 0.67% respectively when their bone levels were set at 2 and 10 mm apically from the cementoenamel junction. These values significantly changed to 28.85 ± 2.54% (p = 0.000) and 51.25 ± 4.78% (p = 0.003) when the tooth model was covered with simulated periodontal ligament. Moreover, teeth with different root types showed different DR and RF patterns. Teeth with multiple roots had lower DRs than teeth with single roots. CONCLUSION: Damping ratio analysis combined with PTV and RF analysis provides more useful information on the assessment of changes in vertical alveolar bone loss than PTV or RF analysis alone.

Myeloid cells in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is highly associated with inflammation. Myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells, are abundant in the HCC microenvironment and are often associated with poor prognosis. Myeloid cells in HCC play a vital role in supporting tumor initiation, progression, angiogenesis, metastasis, and therapeutic resistance. Here, we summarize our current knowledge about myeloid cells in HCC and focus on their immune-suppressive activities and tumor-promoting functions, as well as the relevance to potential new therapies in HCC.

Intestinal Failure: Adaptation, Rehabilitation, and Transplantation.

Intestinal failure (IF) is a state in which the nutritional demands are not met by the gastrointestinal absorptive surface. A majority of IF cases are associated with short-bowel syndrome, which is a result of malabsorption after significant intestinal resection for numerous reasons, some of which include Crohn's disease, vascular thrombosis, and radiation enteritis. IF can also be caused by obstruction, dysmotility, and congenital defects. Recognition and management of IF can be challenging, given the complex nature of this condition. This review discusses the management of IF with a focus on intestinal rehabilitation, parenteral nutrition, and transplantation.

Chemotherapeutic agents enhance cell migration and epithelial-to-mesenchymal transition through transient up-regulation of tNOX (ENOX2) protein.

BACKGROUND: Tumor-associated NADH oxidase (tNOX; ENOX2) is a growth-related protein expressed in transformed cells. High concentrations of numerous chemotherapeutic agents have shown to inhibit tNOX activity and protein levels leading to a reduction in cell growth while little is known for the effects of low concentrations of chemotherapeutic agents on tNOX expression. METHODS: Effects of chemotherapeutic agents on cell function were evaluated with traditional in vitro assays and the xCELLigence System. Western blot analyses were used to study protein expression profiles of the epithelial-to-mesenchymal transition. RESULTS: We showed that doxorubicin treatment transiently up-regulates tNOX expression in human lung carcinoma A549 cells in association with enhanced cell migration. Similar results were observed in tamoxifen-exposed A549 cells. Furthermore, protein marker analyses revealed that the enhanced migration induced by tamoxifen was correlated with epithelial-to-mesenchymal transition, as evidenced by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Importantly, tNOX overexpression enhanced cell migration, confirming the essential role of tNOX in cell migration. CONCLUSIONS: Based on these findings, we conclude that doxorubicin and tamoxifen induce a transient up-regulation of tNOX expression, leading to enhanced cell migration and EMT. GENERAL SIGNIFICANCE: These findings establish an essential role for tNOX in cell migration and survival and may provide a rational framework for the further development of tNOX inhibitors as a novel class of antitumor agents.

Coefficient Extraction of SAC305 Solder Constitutive Equations Using Equation-Informed Neural Networks.

Equation-Informed Neural Networks (EINNs) are developed as an efficient method for extracting the coefficients of constitutive equations. Subsequently, numerical Bayesian Inference (BI) iterations were applied to estimate the distribution of these coefficients, thereby further refining them. We could generate coefficients optimally aligned with the targeted application scenario by carefully adjusting pre-processing mapping parameters and identifying dataset preferences. Leveraging graphical representation techniques, the EINNs formulation is implemented in temperature- and strain-rate-dependent hyperbolic Garofalo, Anand, and Chaboche constitutive models to extract the corresponding coefficients for lead-free SAC305 solder material. The performance of the EINNs-based extracted coefficients, obtained from experimental results of SAC305 solder material, is comparable to existing studies. The methodology offers the dual advantage of providing the coefficients' value and distribution against the training dataset.

Surface modification of zirconia ceramics through cold plasma treatment and the graft polymerization of biomolecules.

Background/purpose: Although zirconia ceramics were highly versatile as dental implants, their long-term presence in the human body may slow down healing and impede cell growth in the past. To enhance the cytocompatibility of zirconia ceramics, surface activation modification was used to immobilize biopolymers such that a biomimetic environment was created. Materials and methods: Hexamethyldisilazane thin films were deposited onto the surface of inorganic zirconia through cold plasma treatment under various power and deposition time settings to form an organosilane interface layer. Next, oxygen plasma treatment was performed to activate the free radicals on the surface. Subsequently, ultraviolet light was employed to graft and polymerize acrylic acid for generating carboxyl groups on the surface. This was followed by a condensation reaction with biopolymers (chitosan, chitosan/poly-γ-glutamic acid, and gelatin). Results: Under a 20-min deposition time at 40 W and 150 mTorr, the thin films had a maximum graft density of 2.1 mg/cm2. MG-63 cells (human osteosarcoma cells) were employed to evaluate cell compatibility. Chitosan and chitosan/poly-γ-glutamic acid promoted the compatibility of MG-63 cells (a human osteosarcoma cell line) with zirconia ceramics, whereas gelatin reduced this compatibility. Conclusion: The findings confirm that cold plasma treatment and graft polymerization can promote the immobilization of biomolecules and improve the biocompatibility of zirconia ceramics. This approach can be applied to the modification of zirconia ceramic implants.

Effects of acetaminophen and ibuprofen monotherapy in febrile children: a meta-analysis of randomized controlled trials.

Introduction: When a child presents with fever in the clinical encounter, parents are usually concerned about alleviating the fever. However, the indications for selecting an appropriate drug from the most commonly used antipyretic drugs, acetaminophen and ibuprofen, remain unclear. The purpose of this study was to assess the efficacy and safety of acetaminophen and ibuprofen in febrile children through a systematic review with meta-analysis of randomized controlled trials (RCTs). Material and methods: Cochrane, Embase, and PubMed databases were searched for the relevant RCTs. Two authors individually extracted information on trial design, demography, rate of fever resolution, body temperature, and overall adverse events. Data were pooled mainly using a random-effects model; however, because of some sparse data, Peto odds ratios (PORs) were used for outcomes of fever resolution and adverse event. 95% confidence intervals (CIs) were also presented. Results: In total, 26 RCTs (n = 4137) fulfilled eligibility criteria. Pooled estimates demonstrated that acetaminophen led to significantly lower fever resolution rates than ibuprofen did (POR = 0.91, 95% CI: 0.84-0.98; I 2 = 0%) in the subgroup of trials with a mean age of < 2 years. However, the treatment-time interaction model for body temperature demonstrated that the fever resolution effect was mainly from the time factor based on the available data (effect size = -0.20; 95% CI: -0.30 to -0.11; I 2 = 6.9%). Acetaminophen demonstrated lower overall adverse event rates than ibuprofen (POR = 0.71; 95% CI: 0.58-0.87; I 2 = 0%). Conclusions: The effects of ibuprofen are similar to acetaminophen even in children with mean age of approximately 5 years. Nevertheless, acetaminophen is safer than ibuprofen, particularly in children approximately 5 years old.

Predicting Wafer-Level Package Reliability Life Using Mixed Supervised and Unsupervised Machine Learning Algorithms.

With the increasing demand for electronic products, the electronic package gradually developed toward miniaturization and high density. The most significant advantage of the Wafer-Level Package (WLP) is that it can effectively reduce the volume and footprint area of the package. An important issue in the design of WLP is how to quickly and accurately predict the reliability life under the accelerated thermal cycling test (ATCT). If the simulation approach is not adopted, it usually takes several ACTCs to design a WLP, and each ACTC will take several months to get the reliability life results, which increases development time considerably. However, simulation results may differ depending on the designer's domain knowledge, ability, and experience. This shortcoming can be overcome with artificial intelligence (AI). In this study, finite element analysis (FEA) is combined with machine learning algorithms, e.g., Kernel Ridge Regression (KRR), to create an AI model for predicting the reliability life of electronic packaging. Kernel Ridge Regression (KRR) combined with the K-means cluster algorithm provides a highly accurate and efficient way to obtain AI models for large-scale data sets.

Fever, Tachypnea, and Monocyte Distribution Width Predicts Length of Stay for Patients with COVID-19: A Pioneer Study.

(1) Background: Our study investigated whether monocyte distribution width (MDW) could be used in emergency department (ED) settings as a predictor of prolonged length of stay (LOS) for patients with COVID-19. (2) Methods: A retrospective cohort study was conducted; patients presenting to the ED of an academic hospital with confirmed COVID-19 were enrolled. Multivariable logistic regression models were used to obtain the odds ratios (ORs) for predictors of an LOS of >14 days. A validation study for the association between MDW and cycle of threshold (Ct) value was performed. (3) Results: Fever > 38 °C (OR: 2.82, 95% CI, 1.13−7.02, p = 0.0259), tachypnea (OR: 4.76, 95% CI, 1.67−13.55, p = 0.0034), and MDW ≥ 21 (OR: 5.67, 95% CI, 1.19−27.10, p = 0.0269) were robust significant predictors of an LOS of >14 days. We developed a new scoring system in which patients were assigned 1 point for fever > 38 °C, 2 points for tachypnea > 20 breath/min, and 3 points for MDW ≥ 21. The optimal cutoff was a score of ≥2. MDW was negatively associated with Ct value (ß: −0.32 per day, standard error = 0.12, p = 0.0099). (4) Conclusions: Elevated MDW was associated with a prolonged LOS.

Melatonin enhances osteogenic differentiation of dental pulp mesenchymal stem cells by regulating MAPK pathways and promotes the efficiency of bone regeneration in calvarial bone defects.

BACKGROUND: Mesenchymal stem cell (MSC)-based tissue engineering plays a major role in regenerative medicine. However, the efficiency of MSC transplantation and survival of engrafted stem cells remain challenging. Melatonin can regulate MSC biology. However, its function in the osteogenic differentiation of dental pulp-derived MSCs (DPSCs) remains unclear. We investigated the effects and mechanisms of melatonin on the osteogenic differentiation and bone regeneration capacities of DPSCs. METHODS: The biological effects and signaling mechanisms of melatonin with different concentrations on DPSCs were evaluated using a proliferation assay, the quantitative alkaline phosphatase (ALP) activity, Alizarin red staining, a real-time polymerase chain reaction, and a western blot in vitro cell culture model. The in vivo bone regeneration capacities were assessed among empty control, MBCP, MBCP + DPSCs, and MBCP + DPSCs + melatonin preconditioning in four-created calvarial bone defects by using micro-computed tomographic, histological, histomorphometric, and immunohistochemical analyses after 4 and 8 weeks of healing. RESULTS: In vitro experiments revealed that melatonin (1, 10, and 100 µM) significantly and concentration-dependently promoted proliferation, surface marker expression (CD 146), ALP activity and extracellular calcium deposition, and osteogenic gene expression of DPSCs (p < 0.05). Melatonin activated the protein expression of ALP, OCN, and RUNX-2 and inhibited COX-2/NF-κB expression. Furthermore, the phosphorylation of mitogen-activated protein kinase (MAPK) p38/ERK signaling was significantly increased in DPSCs treated with 100 µM melatonin, and their inhibitors significantly decreased osteogenic differentiation. In vivo experiments demonstrated that bone defects implanted with MBCP bone-grafting materials and melatonin-preconditioned DPSCs exhibited significantly greater bone volume fraction, trabecular bone structural modeling, new bone formation, and osteogenesis-related protein expression than the other three groups at 4 and 8 weeks postoperatively (p < 0.05). CONCLUSIONS: These results suggest that melatonin promotes the proliferation and osteogenic differentiation of DPSCs by regulating COX-2/NF-κB and p38/ERK MAPK signaling pathways. Preconditioning DPSCs with melatonin before transplantation can efficiently enhance MSCs function and regenerative capacities.

Reliability Evaluation of Fan-Out Type 3D Packaging-On-Packaging.

The development of fan-out packaging technology for fine-pitch and high-pin-count applications is a hot topic in semiconductor research. To reduce the package footprint and improve system performance, many applications have adopted packaging-on-packaging (PoP) architecture. Given its inherent characteristics, glass is a good material for high-speed transmission applications. Therefore, this study proposes a fan-out wafer-level packaging (FO-WLP) with glass substrate-type PoP. The reliability life of the proposed FO-WLP was evaluated under thermal cycling conditions through finite element simulations and empirical calculations. Considering the simulation processing time and consistency with the experimentally obtained mean time to failure (MTTF) of the packaging, both two- and three-dimensional finite element models were developed with appropriate mechanical theories, and were verified to have similar MTTFs. Next, the FO-WLP structure was optimized by simulating various design parameters. The coefficient of thermal expansion of the glass substrate exerted the strongest effect on the reliability life under thermal cycling loading. In addition, the upper and lower pad thicknesses and the buffer layer thickness significantly affected the reliability life of both the FO-WLP and the FO-WLP-type PoP.

An Overview of AI-Assisted Design-on-Simulation Technology for Reliability Life Prediction of Advanced Packaging.

Several design parameters affect the reliability of wafer-level type advanced packaging, such as upper and lower pad sizes, solder volume, buffer layer thickness, and chip thickness, etc. Conventionally, the accelerated thermal cycling test (ATCT) is used to evaluate the reliability life of electronic packaging; however, optimizing the design parameters through ATCT is time-consuming and expensive, reducing the number of experiments becomes a critical issue. In recent years, many researchers have adopted the finite-element-based design-on-simulation (DoS) technology for the reliability assessment of electronic packaging. DoS technology can effectively shorten the design cycle, reduce costs, and effectively optimize the packaging structure. However, the simulation analysis results are highly dependent on the individual researcher and are usually inconsistent between them. Artificial intelligence (AI) can help researchers avoid the shortcomings of the human factor. This study demonstrates AI-assisted DoS technology by combining artificial intelligence and simulation technologies to predict wafer level package (WLP) reliability. In order to ensure reliability prediction accuracy, the simulation procedure was validated by several experiments prior to creating a large AI training database. This research studies several machine learning models, including artificial neural network (ANN), recurrent neural network (RNN), support vector regression (SVR), kernel ridge regression (KRR), K-nearest neighbor (KNN), and random forest (RF). These models are evaluated in this study based on prediction accuracy and CPU time consumption.

Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models.

Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.

Temporal variation and potential origins of atmospheric speciated mercury at a remote island in South China Sea based on two-year field measurement data.

This study explored the temporal variation, gas-particle partition, and potential origins of atmospheric speciated mercury at a remote island in the South China Sea. Two-year data of three mercury species was measured at the Taiping Island. Air masses were clustered into five transport routes (A-E) to resolve the potential origins of atmospheric mercury. Field measurement showed that the concentration of gaseous elemental mercury (GEM) (1.33 ± 0.52 ng/m3) was close to the GEM background level of Northern Hemisphere, while those of GOM and PHg were 13.39 ± 3.58 and 94.33 ± 30.25 pg/m3, respectively. Both regular and intensive samplings concluded a consistent trend of higher mercury level in winter and spring than that in summer and fall. GEM dominated atmospheric mercury in all seasons (86.2-98.5%), while the highest partition of particle-bound mercury (PHg) was observed in winter (13.8%). The highest GEM concentrations were observed for Route A originating from central China and western Taiwan Island, and followed by Routes D and E from the Philippines, Malaysia, and Indonesia, while the lowest concentrations of GEM were observed for Routes B and C originating from North China, Korea, and Japan. Most importantly, high correlation of GEM versus levoglucosan and K+ in PM2.5 (r = 0.764 and 0.758, p < 0.01) confirmed that GEM was mainly emitted from biomass burning sources at the surrounding countries.

New Labyrinth Microfluidic Device Detects Circulating Tumor Cells Expressing Cancer Stem Cell Marker and Circulating Tumor Microemboli in Hepatocellular Carcinoma.

Hepatocellular Carcinoma (HCC) is one of the most lethal cancers with a high mortality and recurrence rate. Circulating tumor cell (CTC) detection offers various opportunities to advance early detection and monitoring of HCC tumors which is crucial for improving patient outcome. We developed and optimized a novel Labyrinth microfluidic device to efficiently isolate CTCs from peripheral blood of HCC patients. CTCs were identified in 88.1% of the HCC patients over different tumor stages. The CTC positivity rate was significantly higher in patients with more advanced HCC stages. In addition, 71.4% of the HCC patients demonstrated CTCs positive for cancer stem cell marker, CD44, suggesting that the major population of CTCs could possess stemness properties to facilitate tumor cell survival and dissemination. Furthermore, 55% of the patients had the presence of circulating tumor microemboli (CTM) which also correlated with advanced HCC stage, indicating the association of CTM with tumor progression. Our results show effective CTC capture from HCC patients, presenting a new method for future noninvasive screening and surveillance strategies. Importantly, the detection of CTCs with stemness markers and CTM provides unique insights into the biology of CTCs and their mechanisms influencing metastasis, recurrence and therapeutic resistance.

RNA interference targeting tNOX attenuates cell migration via a mechanism that involves membrane association of Rac.

tNOX, a tumor-associated NADH oxidase, is a growth-related protein present in transformed cells. In this study, we employed RNA interference (RNAi)-mediated down-regulation of tNOX protein expression to explore the role of tNOX in regulating cell growth in human cervical adenocarcinoma (HeLa) cells. In this first reported use of RNAi to decrease tNOX expression, we found that HeLa cell growth was significantly inhibited by shRNA-knockdown of tNOX. Furthermore, cell migration and membrane association of Rac were decreased concomitantly with the reduction in tNOX protein expression. These results indicate that shRNA targeting of tNOX inhibits the growth of cervical cancer cells, and reduces cell migration via a decrease in the membrane association of Rac. We propose that tNOX is a potential upstream mediator of Rho activation that plays a role in regulating cell proliferation, migration, and invasion.