High Performance Adaptive Physics Refinement to Enable Large-Scale Tracking of Cancer Cell Trajectory.

The ability to track simulated cancer cells through the circulatory system, important for developing a mechanistic understanding of metastatic spread, pushes the limits of today's supercomputers by requiring the simulation of large fluid volumes at cellular-scale resolution. To overcome this challenge, we introduce a new adaptive physics refinement (APR) method that captures cellular-scale interaction across large domains and leverages a hybrid CPU-GPU approach to maximize performance. Through algorithmic advances that integrate multi-physics and multi-resolution models, we establish a finely resolved window with explicitly modeled cells coupled to a coarsely resolved bulk fluid domain. In this work we present multiple validations of the APR framework by comparing against fully resolved fluid-structure interaction methods and employ techniques, such as latency hiding and maximizing memory bandwidth, to effectively utilize heterogeneous node architectures. Collectively, these computational developments and performance optimizations provide a robust and scalable framework to enable system-level simulations of cancer cell transport.

Influence of chloride ions on the reduction of mercury species in the presence of dissolved organic matter.

Mercuric species, Hg(II), interacts strongly with dissolved organic matter (DOM) through the oxidation, reduction, and complexation that affect the fate, bioavailability, and cycling of mercury, Hg, in aquatic environments. Despite its importance, the reactions between Hg(II) and DOM have rarely been studied in the presence of different concentrations of chloride ions (Cl-) under anoxic conditions. Here, we report that the extent of Hg(II) reduction in the presence of the reduced DOM decreases with increasing Cl- concentrations. The rate constants of Hg(II) reduction ranged from 0.14 to 1.73 h-1 in the presence of Cl- and were lower than the rate constant (2.41 h-1) in the absence of Cl-. Using a thermodynamic model, we showed that stable Hg(II)-chloride complexes were formed in the presence of Cl-. We further examined that H(0) was oxidized to Hg(II) in the presence of the reduced DOM and Cl- under anoxic conditions, indicating that Hg(II) reduction is inhibited by the Hg(0) oxidation. Therefore, the Hg(II) reduction by the reduced DOM can be offset due to the Hg(II)-chloride complexation and Hg(0) oxidation in chloride-rich environments. These processes can significantly influence the speciation of Hg and have an important implication for the behavior of Hg under environmentally relevant concentrations.

Colloid mobilization and heavy metal transport in the sampling of soil solution from Duckum soil in South Korea.

Colloid mobilization is a significant process governing colloid-associated transport of heavy metals in subsurface environments. It has been studied for the last three decades to understand this process. However, colloid mobilization and heavy metal transport in soil solutions have rarely been studied using soils in South Korea. We investigated the colloid mobilization in a variety of flow rates during sampling soil solutions in sand columns. The colloid concentrations were increased at low flow rates and in saturated regimes. Colloid concentrations increased 1000-fold higher at pH 9.2 than at pH 7.3 in the absence of 10 mM NaCl solution. In addition, those were fourfold higher in the absence than in the presence of the NaCl solution at pH 9.2. It was suggested that the mobility of colloids should be enhanced in porous media under the basic conditions and the low ionic strength. In real field soils, the concentrations of As, Cr, and Pb in soil solutions increased with the increase in colloid concentrations at initial momentarily changed soil water pressure, whereas the concentrations of Cd, Cu, Fe, Ni, Al, and Co lagged behind the colloid release. Therefore, physicochemical changes and heavy metal characteristics have important implications for colloid-facilitated transport during sampling soil solutions.

Oxidation and reduction of redox-sensitive elements in the presence of humic substances in subsurface environments: A review.

The oxidation and reduction (redox) processes of redox-sensitive elements (RSE) in the presence of humic substances (HS) have become a significantly important issue in the terms of biogeochemical cycles. Redox processes are crucial for determining the speciation, mobility, toxicity, and bioavailability of RSE in natural environments. It is known that HS act as an effective redox mediator for accepting and donating electrons, and thereby transfers them to RSE. We review the recent progress in the field of the redox processes of RSE including As, Cr, Cu, Fe, Hg, and Se in the presence of HS. The extent and rate of the redox processes of these RSE are significantly affected by the concentration of functional groups and the chemical composition of HS. In subsurface environments, pH, ionic strength, and the presence of competitive components, microorganisms, and oxygen need to be considered to elucidate the redox processes of RSE in the presence of HS. In addition, improved analytical techniques for the characterization of HS has the potential to advance the study on the redox processes of RSE in the presence of HS. It may contribute to understanding the mechanism for the redox processes between RSE and HS in the biogeochemical cycles.

The enhancement and inhibition of mercury reduction by natural organic matter in the presence of Shewanella oneidensis MR-1.

Reduction-oxidation (Redox) processes of mercury (Hg) are of significant importance in influencing Hg speciation, bioavailability, and fate in anoxic environments where natural organic matter (NOM) and dissimilatory metal reducing bacteria (DMRB) are widely observed. However, the redox reaction between Hg and NOM, has not yet been studied in the presence of S. oneidensis MR-1 in anoxic environments. We have found that the reduction rate of mercuric mercury [Hg(II)] in the presence of Elliott soil humic acid (ESHA) was 0.02 h-1. It was faster than the rate (0.01 h-1) in the direct microbial Hg(II) reduction, suggesting that ESHA acts as an electron transfer mediator between cells and Hg, which enhances Hg(II) reduction under anoxic conditions. The overall rate of Hg(II) reduction in the presence of ESHA is determined by the rate of electron transfer from S. oneidensis MR-1 to ESHA (rate-limiting step) since the rate of electron transfer from reduced ESHA to Hg(II) was so rapid. In the reaction between S. oneidensis MR-1 and a variety of NOM analogs, the production rate of elemental mercury [Hg (0)] was linearly correlated with the free radical concentrations and aromaticities in reduced NOM analogs. However, at the high ESHA concentrations or cell contents, Hg(II) reduction might be inhibited by thiol functional groups in reduced ESHA and on cells. We suggest that the presence of NOM, cell concentration and NOM source can significantly affect the redox processes of Hg and therefore, have important implications for elucidating Hg redox processes under environmentally relevant complex conditions.

Mutation spectrum in the Wnt/ß-catenin signaling pathway in gastric fundic gland-associated neoplasms/polyps.

Frequent activation of the Wnt/ß-catenin signaling pathway has recently been demonstrated in gastric adenocarcinoma/neoplasia of chief cell predominant type (GA-CCP/GN-CCP) with submucosal involvement. In this study, we examined the activation status of the Wnt/ß-catenin signaling pathway in GN-CCP without submucosal involvement, which is referred to as gastric dysplasia-CCP (GD-CCP). We also examined ß-catenin expression and the mutation spectrum of PPP2R1A and Wnt pathway genes in 11 cases of GD-CCP, 25 cases of gastric polyps of fundic gland type (GPs-FG), and 21 cases of GPs-FG with dysplasia (GP-FGD). ß-catenin nuclear staining was observed in 3 cases of GD-CCP, none of GPs-FG, and 6 cases of GPs-FGD. Mutations in Wnt pathway genes, including PPP2R1A, were observed in 4 cases of GDs-CCP, 10 cases of GPs-FG, and 7 cases of GPs-FGD. Two of these seven GPs-FGD cases showed ß-catenin nuclear staining. However, none of the 4 GD-CCP cases with mutations or the 10 GPs-FG cases with mutations showed ß-catenin nuclear staining. PPP2R1A mutations were observed in 1 GD-CCP case and 1 GPs-FGD case. Although the mutation spectra of the Wnt pathway genes in GD-CCP and GP-FG differed, based on the absence of ß-catenin nuclear staining despite the genetic alterations, GD-CCP is more similar to GP-FG than to GN-CCP, which shows ß-catenin nuclear staining and submucosal involvement. Activation of the Wnt/ß-catenin signaling by the ß-catenin nuclear transition may be required during progression from GD-CCP to GN-CCP. Furthermore, this is the first report describing PPP2R1A mutations in gastric fundic gland-associated neoplasms.

Mercury accumulation in hydrothermal vent mollusks from the southern Tonga Arc, southwestern Pacific Ocean.

We provide the mercury (Hg) and monomethylmercury (MMHg) levels of the plume water, sulfide ore, sediment, and mollusks located at the hydrothermal vent fields of the southern Tonga Arc, where active volcanism and intense seismic activity occur frequently. Our objectives were: (1) to address the potential release of Hg from hydrothermal fluids and (2) to examine the distribution of Hg and MMHg levels in hydrothermal mollusks (mussels and snails) harboring chemotrophic bacteria. While high concentrations of Hg in the sediment and Hg, As, and Sb in the sulfide ore indicates that their source is likely hydrothermal fluids, the MMHg concentration in the sediment was orders of magnitude lower than the Hg (<0.001%). It suggests that Hg methylation may have not been favorable in the vent field sediment. In addition, Hg concentrations in the mollusks were much higher (10-100 times) than in other hydrothermal vent environments, indicating that organisms located at the Tonga Arc are exposed to exceedingly high Hg levels. While Hg concentration was higher in the gills and digestive glands than in the mantles and residues of snails and mussels, the MMHg concentrations in the gills and digestive glands were orders of magnitude lower (0.004-0.04%) than Hg concentrations. In summary, our results suggest that the release of Hg from the hydrothermal vent fields of the Tonga Arc and subsequent bioaccumulation are substantial, but not for MMHg.

GNAS mutation as an alternative mechanism of activation of the Wnt/ß-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type.

Gastric adenocarcinoma of the fundic gland type (GAFG) is a rare variant of gastric tumor. We have recently reported the frequent accumulation of ß-catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in CTNNB1/AXINs/APC, leading to the constitutive activation of the Wnt/ß-catenin pathway. However, the mechanisms of Wnt signaling activation in the remaining cases are unknown. Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt/ß-catenin pathway or the ERK1/2 MAPK pathway. Therefore, we analyzed the mutations in GNAS (exons 8 and 9) and in KRAS (exon 2) in 26 GAFGs. Immunohistochemistry revealed nuclear ß-catenin expression in 22 of 26 GAFGs, and 10 (38.5%) of 26 cases harbored at least 1 mutation in CTNNB1/AXINs/APC. Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations. Activating mutations in KRAS were found in 2 (7.7%) of 26 GAFGs, and both of these also contained GNAS activating mutations. Four of 5 cases with GNAS mutation showed nuclear ß-catenin expression, and presence of GNAS mutation was associated with ß-catenin nuclear expression (P = .01). Furthermore, 3 of these 4 cases did not harbor mutations in CTNNB1, APC, or AXINs, suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively. These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt/ß-catenin signaling pathway.

Alteration in the Wnt/ß-catenin signaling pathway in gastric neoplasias of fundic gland (chief cell predominant) type.

Gastric neoplasia of chief cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar cells mimicking chief cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear ß-catenin immunolabeling and direct sequencing of members of the Wnt/ß-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear ß-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear ß-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/ß-catenin pathway.

Multiple carcinoid tumors of the small intestine preoperatively diagnosed by double-balloon endoscopy.

BACKGROUND: Multiple carcinoid tumors of the small intestine are rare and are very difficult to detect preoperatively. CASE REPORT: A 75-year-old woman in whom the bleeding focus could not be found by upper and lower endoscopy and abdominal CT was admitted for evaluation of anemia. We examined the patient with total double-balloon endoscopy (DBE) and located multiple submucosal tumors. The multiple carcinoid tumors were resected successfully under laparoscopy. CONCLUSIONS: We report a case of a successful laparoscopic operation for multiple carcinoid tumors in the small intestine without intraoperative endoscopy. Total digestive tract observation using DBE is very useful for laparoscopic operation for multiple tumors in the small intestine.

Estuarine mixing behavior of colloidal organic carbon and colloidal mercury in Galveston Bay, Texas.

Mercury (Hg) in estuarine water is distributed among different physical phases (i.e. particulate, colloidal, and truly dissolved). This phase speciation influences the fate and cycling of Hg in estuarine systems. However, limited information exists on the estuarine distribution of colloidal phase Hg, mainly due to the technical difficulties involved in measuring it. In the present study, we determined Hg and organic carbon levels from unfiltered, filtered (<0.45 µm), colloidal (10 kDa-0.45 µm), and truly dissolved (<10 kDa) fractions of Galveston Bay surface water in order to understand the estuarine mixing behavior of Hg species as well as interactions of Hg with colloidal organic matter. For the riverine end-member, the colloidal fraction comprised 43 ± 11% of the total dissolved Hg pool and decreased to 17 ± 8% in brackish water. In the estuarine mixing zone, dissolved Hg and colloidal organic carbon showed non-conservative removal behavior, particularly in the low salinity (<15 ppt) region. This removal may be caused by salt-induced coagulation of colloidal matter and consequent removal of dissolved Hg. The particle-water interaction, K(d) ([particulate Hg (mol kg(-1))]/[dissolved Hg (mol L(-1))]) of Hg decreased as particle concentration increased, while the particle-water partition coefficient based on colloidal Hg and the truly dissolved Hg fraction, K(c) ([colloidal Hg (mol kg(-1))]/[truly dissolved Hg (mol L(-1))]) of Hg remained constant as particle concentration increased. This suggests that the particle concentration effect is associated with the amount of colloidal Hg, increasing in proportion to the amount of suspended particulate matter. This work demonstrates that, colloidal organic matter plays an important role in the transport, particle-water partitioning, and removal of dissolved Hg in estuarine waters.