Nitric Oxide Derived from Cytoglobin-Deficient Hepatic Stellate Cells Causes Suppression of Cytochrome c Oxidase Activity in Hepatocytes.

Aims: Cell-cell interactions between hepatocytes (Hep) and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes Hep dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of nitric oxide (NO). Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression. Results: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into the neighboring Hep to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. Its inhibitory action toward CcO-specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through the formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo. Innovation and Conclusion: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring Hep dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO. Antioxid. Redox Signal. 38, 463-479.

Vertical distributions and risk assessment of phosphorus in core sediments from the Can Gio coastal district in southern Vietnam.

In this study, total phosphorus (P) and P released forms were measured in core sediments from the areas affected by human settlement and shrimp farming activities and the core zone of the Can Gio Biosphere Reserve, a coastal district in south Vietnam. Furthermore, ecological risk assessment and parameters controlling P release from sediments were investigated, including pH, major elements (Al-Ca-Mg-Fe), and fine fraction. The average total amount of P in the sediments varied from 287 to 669 mg/kg, with significantly lower values being observed in the mangrove biosphere reserve area. According to the results of the correlation analysis, organic matter was the primary source of P in the sediments, but the majority of the P released was inorganic. Positive correlations were found between Fe and non-apatite inorganic P (NAIP) and apatite P (AP), as well as intercorrelations between P fractions (r = 0.40-0.79, p < 0.05), suggesting that Fe might be the controlling factor of P release in the investigated sediments. The rank orders of concentrations of P forms were significantly different between the areas. The range of P forms was AP (35-248 mg/kg) > NAIP (63-201 mg/kg) > LP (labile P) (4-25 mg/kg) in the human settlement and aquaculture areas and NAIP (84-99 mg/kg) > AP (20-38 mg/kg) > LP (7-12 mg/kg) in the mangrove biosphere reserve area. Risk assessment based on the total concentration of P and the availability of P from a single extraction suggested a relatively low risk of P from sediment as an internal load in the studied areas.

Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms.

Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23-dependent tumor necrosis factor-α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.

An Ensemble of Deep Learning Frameworks for Predicting Respiratory Anomalies.

This paper evaluates a range of deep learning frameworks for detecting respiratory anomalies from input audio. Audio recordings of respiratory cycles collected from patients are transformed into time-frequency spectrograms to serve as front-end two-dimensional features. Cropped spectrogram segments are then used to train a range of back-end deep learning networks to classify respiratory cycles into predefined medically-relevant categories. A set of those trained high-performance deep learning frameworks are then fused to obtain the best score. Our experiments on the ICBHI benchmark dataset achieve the highest ICBHI score to date of 57.3%. This is derived from a late fusion of inception based and transfer learning based deep learning frameworks, easily outperforming other state-of-the-art systems. Clinical relevance--- Respiratory disease, wheeze, crackle, inception, convolutional neural network, transfer learning.

A Cough-based deep learning framework for detecting COVID-19.

This paper presents a deep learning framework for detecting COVID-19 positive subjects from their cough sounds. In particular, the proposed approach comprises two main steps. In the first step, we generate a feature representing the cough sound by combining an embedding extracted from a pre-trained model and handcrafted features extracted from draw audio recording, referred to as the front-end feature extraction. Then, the combined features are fed into different back-end classification models for detecting COVID-19 positive subjects in the second step. Our experiments on the Track-2 dataset of the Second 2021 DiCOVA Challenge achieved the second top ranking with an AUC score of 81.21 and the top F1 score of 53.21 on a Blind Test set, improving the challenge baseline by 8.43% and 23.4% respectively and showing deployability, robustness and competitiveness with the state-of-the-art systems.

Soluble Immune Checkpoint Protein CD27 Is a Novel Prognostic Biomarker of Hepatocellular Carcinoma Development in Hepatitis C Virus-Sustained Virological Response Patients.

Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.

Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.

Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion.

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB. APPROACH & RESULTS: We characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl4)-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by H2O2 or transforming growth factor ß1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix-encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl4-induced mouse liver fibrosis. CONCLUSIONS: These findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease.

Lean management for improving hospital waiting times-Case study of a Vietnamese public/general hospital emergency department.

INTRODUCTION: Emergency departments (EDs) at public hospitals in Vietnam typically face problems with overcrowding, as well as being populated by a wide variety of illnesses, resulting in increasing dissatisfaction from patients. To alleviate these problems, we used the increasingly popular value-stream mapping (VSM) and lean strategy approaches to (1) evaluate the current patient flow in EDs; (2) identify and eliminate the non-valued-added components; and (3) modify the existing process in order to improve waiting times. METHODS: Data from a total of 742 patients who presented at the ED of 108 Military Central Hospital in Hanoi, Vietnam, were collected. A VSM was developed where improvement possibilities were identified and attempts to eliminate non-value-added activities were made. A range of issues that were considered as a resource waste were highlighted, which led to a re-design process focusing on prioritizing blood tests and ultrasound procedures. On the administrative side, various measures were considered, including streamlining communication with medical departments, using QR codes for healthcare insurance payments, and efficient management of X-ray and CT scan online results. RESULTS: By implementing a lean approach, the following reductions in delay and waiting time were incurred: (1) pre-operative test results (for patients requiring medical procedures/operations) by 33.3% (from 134.4 to 89.4 min); (2) vascular interventions by 10.4% (from 54.6 to 48.9 min); and (3) admission to other hospital departments by 49.5% (from 118.3 to 59.8 min). Additionally, prior to the implementation of the lean strategy approach, only 22.9% of patients or their proxies (family members or friends), who responded to the survey, expressed satisfaction with the ED services. This percentage increased to 76.5% following the curtailment of non-value-added activities. Through statistical inferential test analyses, it can be confidently concluded that applying lean strategy and tools can improve patient flow in public/general hospital EDs and achieve better staff coordination within the various clinical and administrative hospital departments. To the authors' knowledge, such analysis in a Vietnamese hospital's ED context has not been previously undertaken.

Development and validation of a model for predicting 18-month mortality in type 2 myocardial infarction.

BACKGROUND: Despite the poor prognosis in patients with type 2 myocardial infarction (MI), no prospective data on risk stratification exists. The aim of this study was to develop and validate a model for prediction of 18-month mortality of among patients with type 2 MI (T2MI) and compare its performance with GRACE and TARRACO scores. METHODS: The prospective observational study included 712 consecutive patients diagnosed with MI undergoing coronary angiography <24 h between January 2017 and December 2018. Diagnosis of T2MI was adjusted according to Third universal definition. A prognostic model was developed by using Bayesian approach and logistic regression analysis with identifying predictors for mortality. The model was validated by bootstrap validation. Comparison performance between scores using Delong test. RESULTS: T2MI was identified in 174 (24.4%) patients. The median age of patients was 69 years, 52% were female. The mortality rate was 20.1% at 18 months. Prior MI, presence of ST elevation, hemoglobin level at admission, Charlson comorbidity index and were independently associated with 18-month mortality. The model to predict 18-month mortality showed excellent discrimination (optimism corrected c-statistic = 0.822) and calibration (corrected slope = 0.893). GRACE and TARRACO scores had moderate discrimination [c-statistic = 0.748 (95% CI 0.652-0.843) and 0.741, 95% CI 0.669-0.805), respectively] and inferior compared with model (p = 0.043 and 0.037, respectively). CONCLUSIONS: The risk of mortality among T2MI patients could be accurately predicted by using common clinical characteristics and laboratory tests. Further studies are required with external validation of nomogram prior to clinical implementation.

Concordance and Prognostic Relevance of Angiographic and Clinical Definitions of Myocardial Infarction Type.

BACKGROUND: Atherothrombosis is the principal mechanism of type 1 (T1) myocardial infarction (MI), while type 2 (T2) MI is typically diagnosed in the presence of triggers (anemia, arrhythmia, etc.). We aimed to evaluate the proportions of T1 vs. T2 MI based on angiographic and clinical definitions, their concordance and prognosis. METHODS: Consecutive MI patients [n = 712, 61% male; age 64.6 ± 12.3 years] undergoing coronary angiography were classified according to the presence of atherothrombosis and identifiable triggers. Association of angiographic and clinical MI type criteria with adverse outcomes (Time follow-up was 1.5 years) was evaluated. Predictive ability of GRACE risk score for all-cause mortality was then assessed. RESULTS: Atherothrombosis and clinical triggers were identified in 397 (55.6%) and 324 (45.5%) subjects, respectively. Only 247 (34.7%) patients had "true" T1MI (atherothrombosis+ / triggers-); 174 (24.4%) were diagnosed with "true" T2MI (atherothrombosis- / triggers+), while 291 (40.9%) had discordant clinical and angiographic characteristics. All-cause mortality in T2MI (20.1%) patients was higher than in T1MI (9.3%), P = 0.002. Presence of triggers [odds ratio (OR) 2.4, 95% CI 1.5-3.6, P < 0.0001] but not atherothrombosis [OR 0.8, 95% confidence interval (CI) 0.5-1.3, P = 0.26] was associated with worse prognosis. GRACE score is a better predictor of death in T1MI vs. T2MI: area under curve 0.893 (95% CI 0.830-0.956) vs 0.748 (95% CI 0.652-0.843), P = 0.013. CONCLUSION: Angiographic and clinical definitions of MI type are discordant in a substantial proportion of patients. Clinical triggers are associated with all-cause mortality. Predictive performance of GRACE score is worse in T2MI patients.

Hexa Histidine-Tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species.

BACKGROUND AND AIMS: Antifibrotic therapy remains an unmet medical need in human chronic liver disease. We report the antifibrotic properties of cytoglobin (CYGB), a respiratory protein expressed in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis. APPROACH AND RESULTS: Cygb-deficient mice that had bile duct ligation-induced liver cholestasis or choline-deficient amino acid-defined diet-induced steatohepatitis significantly exacerbated liver damage, fibrosis, and reactive oxygen species (ROS) formation. All of these manifestations were attenuated in Cygb-overexpressing mice. We produced hexa histidine-tagged recombinant human CYGB (His-CYGB), traced its biodistribution, and assessed its function in HSCs or in mice with advanced liver cirrhosis using thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). In cultured HSCs, extracellular His-CYGB was endocytosed and accumulated in endosomes through a clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type 1 alpha 1 production and α-smooth muscle actin expression. Replacement the iron center of the heme group with cobalt nullified the effect of His-CYGB. In addition, His-CYGB induced interferon-ß secretion by HSCs that partly contributed to its antifibrotic function. Momelotinib incompletely reversed the effect of His-CYGB. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis, and oxidative cell damage in mice administered TAA or DDC mice without adverse effects. RNA-sequencing analysis revealed the down-regulation of inflammation- and fibrosis-related genes and the up-regulation of antioxidant genes in both cell culture and liver tissues. The injected His-CYGB predominantly localized to HSCs but not to macrophages, suggesting specific targeting effects. His-CYGB exhibited no toxicity in chimeric mice with humanized livers. CONCLUSIONS: His-CYGB could have antifibrotic clinical applications for human chronic liver diseases.

An electrochemical sensor based on copper-based metal-organic framework-reduced graphene oxide composites for determination of 2,4-dichlorophenol in water.

In the present work, we reported the fabrication of a novel electrochemical sensing platform to detect 2,4-dichlorophenol (2,4-DCP) by using a copper benzene-1,3,5-tricarboxylate-graphene oxide (Cu-BTC/GO) composite. The sensor was prepared by drop-casting Cu-BTC/GO suspension onto the electrode surface followed by electrochemical reduction, leading to the generation of an electrochemically reduced graphene oxide network (ErGO). By combining the large specific area of the Cu-BTC matrix with the electrical percolation from the graphene network, the number of accessible reaction sites was strongly increased, which consequently improved the detection performance. The electrochemical characteristics of the composite were revealed by cyclic voltammetry and electrochemical impedance spectroscopy. For the detection of 2,4-DCP, differential pulse voltammetry was used to emphasize the faradaic reaction related to the oxidation of the analyte. The results displayed a low detection limit (83 × 10-9 M) and a linear range from 1.5 × 10-6 M to 24 × 10-6 M alongside high reproducibility (RSD = 2.5% for eight independent sensors) and good stability. Importantly, the prepared sensors were sufficiently selective against interference from other pollutants in the same electrochemical window. Notably, the presented sensors have already proven their ability in detecting 2,4-DCP in real field samples with high accuracy (recovery range = 97.17-104.15%).

Discordance between the Clinical Presentation and Morphology of Myocardial Infarction in a Patient with Acute Post-Hemorrhagic Anemia.

While atherosclerotic plaque disruption remains the hallmark of type 1 myocardial infarction (T1MI), multiple other mechanisms provoking myocardial supply/demand mismatch (eg, anemia and tachyarrhythmias) are recognized as the potential causes of type 2 myocardial infarction (T2MI). In clinical practice, angiography is underutilized in patients with MI that have typical T2MI triggers, although the presence of these triggers and various forms of atherosclerotic coronary artery disease is not mutually exclusive. We describe a 70-year-old man that developed MI during hospitalization for gastrointestinal bleeding. He was treated conservatively without angiography due to posthemorrhagic anemia, which is a recognized T2MI trigger, and subsequently developed refractory cardiogenic shock. Autopsy revealed atherothrombosis, which is characteristic of T1MI.

Contamination status and potential release of trace metals in a mangrove forest sediment in Ho Chi Minh City, Vietnam.

Can Gio district is located in the coastal area of Ho Chi Minh City, southern Vietnam. Discharge of wastewater from Ho Chi Minh City and neighboring provinces to the rivers of Can Gio has led to concerns about the accumulation of trace metals (As, Cu, Cr, Ni, Pb, and Zn) in the coastal sediments. The main objective of this study was to assess the distribution of As, Cu, Cr, Ni, Pb, and Zn in surface and core sediments and to evaluate the contamination status in relation to local background values, as well as the potential release of these selected trace metals from sediments to the water environment. Sediment characteristization, including determination of fine fraction, pH, organic matter, and major elements (Al, Fe, Ca, K, Mg, and S), was carried out to investigate which parameters affect the trace metal enrichment. Fine fraction and Al contents were found to be the controlling proxies affecting the distribution of trace metals while other sediment characteristics did not show any clear influence on trace metals' distribution. Although As concentrations in the sediments were much higher compared to its reference value in other areas, the enrichment factor based on local background values suggests minor contamination of this element as well as for Cr, Cu, and Pb. Risk assessment suggested a medium to very high risk of Mn, Zn, and Ni under acidification. Of importance is also that trace metals in sediments were not easily mobilized by organic complexation based on their low extractabilities by ammonium-EDTA extraction.

Integrating Metal-Catalyzed C-H and C-O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation.

One major goal of organometallic chemists is the direct functionalization of the bonds most recurrent in organic molecules: C-H, C-C, C-O, and C-N. An even grander challenge is C-C bond formation when both precursors are of this category. Parallel to this is the synthetic goal of achieving reaction selectivity that contrasts with conventional methods. Electrophilic aromatic substitution (EAS) via Friedel-Crafts acylation is the most renowned method for the synthesis of aryl ketones, a common structural motif of many pharmaceuticals, agrochemicals, fragrances, dyes, and other commodity chemicals. However, an EAS synthetic strategy is only effective if the desired site for acylation is in accordance with the electronic-controlled regioselectivity of the reaction. Herein we report steric-controlled regioselective arene acylation with salicylate esters via iridium catalysis to access distinctly substituted benzophenones. Experimental and computational data indicate a unique reaction mechanism that integrates C-O activation and C-H activation with a single iridium catalyst without an exogenous oxidant or base. We disclose an extensive exploration of the synthetic scope of both the arene and the ester components, culminating in the concise synthesis of the potent anticancer agent hydroxyphenstatin.

The influence of delta formation mechanism on geotechnical property sequence of the late Pleistocene-Holocene sediments in the Mekong River Delta.

The aim of the study was to characterize a variety of microstructure development-levels and geotechnical property sequences of the late Pleistocene-Holocene deposits in the Mekong River delta (MRD), and the paper furthermore discusses the influences of delta formation mechanisms on them. The survey associated the geotechnical engineering and the sedimentary geology of the late Pleistocene-Holocene deposits at five sites and also undifferentiated Pleistocene sediments. A cross-section which was rebuilt in the delta progradation-direction and between the Mekong and Bassac rivers represents the stratigraphy. Each sedimentary unit was formed under a different delta formation mechanism and revealed a typical geotechnical property sequence. The mechanical behaviors of the sediment succession in the tide-dominated delta with significant fluvial-activity and material source tend to be more cohesionless soils and strengths than those in the tide- and wave-dominated delta and even the coast. The particular tendency of the mechanical behavior of the deposit succession can be reasonably estimated from the delta formation mechanism. The characteristics of the clay minerals from the Mekong River produced the argillaceous soil which does not have extremely high plasticity. The microstructure development-levels are low to very high indicating how to choose hydraulic conductivity value, k, for estimating overconsolidation ratio, OCR, by the piezocone penetration tests (CPTU). The OCR of sediments in the delta types strangely change with depth but none less than 1. The post-depositional processes significantly influenced the microstructure development, particularly the dehydrating and oxidizing processes.

Inositol-Triphosphate 3-Kinase C Mediates Inflammasome Activation and Treatment Response in Kawasaki Disease.

Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1ß and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1ß and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.

Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency.

MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.

Corticosteroids for dengue - why don't they work?

BACKGROUND: Dysregulated immune responses may contribute to the clinical complications that occur in some patients with dengue. FINDINGS: In Vietnamese pediatric dengue cases randomized to early prednisolone therapy, 81 gene-transcripts (0.2% of the 47,231 evaluated) were differentially abundant in whole-blood between high-dose (2 mg/kg) prednisolone and placebo-treated patients two days after commencing therapy. Prominent among the 81 transcripts were those associated with T and NK cell cytolytic functions. Additionally, prednisolone therapy was not associated with changes in plasma cytokine levels. CONCLUSION: The inability of prednisolone treatment to markedly attenuate the host immune response is instructive for planning future therapeutic strategies for dengue.