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This paper summarizes the newly developed immersed finite element method (IFEM) and its applications to the modeling of biological systems. This work was inspired by the pioneering work of Professor T.J.R. Hughes in solving fluid-structure interaction problems. In IFEM, a Lagrangian solid mesh moves on top of a background Eulerian fluid mesh which spans the entire computational domain. Hence, mesh generation is greatly simplified. Moreover, both fluid and solid domains are modeled with the finite element method and the continuity between the fluid and solid subdomains is enforced via the interpolation of the velocities and the distribution of the forces with the reproducing Kernel particle method (RKPM) delta function. The proposed method is used to study the fluid-structure interaction problems encountered in human cardiovascular systems. Currently, the heart modeling is being constructed and the deployment process of an angioplasty stent has been simulated. Some preliminary results on monocyte and platelet deposition are presented. Blood rheology, in particular, the shear-rate dependent de-aggregation of red blood cell (RBC) clusters and the transport of deformable cells, are modeled. Furthermore, IFEM is combined with electrokinetics to study the mechanisms of nano/bio filament assembly for the understanding of cell motility.

SUMMARYThe red blood cell (RBC) aggregation plays an important role in many physiological phenomena, in particular the atherosclerosis and thrombotic processes. In this research, we introduce a new modelling technique that couples Navier-Stokes equations with protein molecular dynamics to investigate the behaviours of RBC aggregates and their e ects on the blood rheology. In essence, the Lagrangian solid mesh, which represents the immersed deformable cells, is set to move on top of a background Eulerian mesh. The e ects of cell-cell interaction (adhesive=repulsive) and hydrodynamic forces on RBC aggregates are studied by introducing equivalent protein molecular potentials into the immersed ÿnite element method. The aggregation of red blood cells in quiescent uids is simulated. The de-aggregation of a RBC cluster at di erent shear rates is also investigated to provide an explanation of the shear-rate-dependence of the blood viscoelastic properties. Finally, the inuences of cell-cell interaction, RBC rigidity, and vessel geometry are addressed in a series of test cases with deformable cells (normal and sickle RBCs) passing through micro-and capillary vessels.

BackgroundUsing antibody/aptamer-drug conjugates can be a promising method for decreasing toxicity, while increasing the efficiency of chemotherapy.Methodology/Principal FindingsIn this study, the antitumor agent Doxorubicin (Dox) was incorporated into the modified DNA aptamer TLS11a-GC, which specifically targets LH86, a human hepatocellular carcinoma cell line. Cell viability tests demonstrated that the TLS11a-GC-Dox conjugates exhibited both potency and target specificity. Importantly, intercalating Dox into the modified aptamer inhibited nonspecific uptake of membrane-permeable Dox to the non-target cell line. Since the conjugates are selective for cells that express higher amounts of target proteins, both criteria noted above are met, making TLS11a-GC-Dox conjugates potential candidates for targeted delivery to liver cancer cells.Conclusions/SignificanceConsidering the large number of available aptamers that have specific targets for a wide variety of cancer cells, this novel aptamer-drug intercalation method will have promising implications for chemotherapeutics in general.

We live in an increasingly interconnected world, with many organizations operating across countries or even continents. To serve their global user base, organizations are replacing their legacy DBMSs with cloud-based systems capable of scaling OLTP workloads to millions of users.CockroachDB is a scalable SQL DBMS that was built from the ground up to support these global OLTP workloads while maintaining high availability and strong consistency. Just like its namesake, CockroachDB is resilient to disasters through replication and automatic recovery mechanisms.This paper presents the design of CockroachDB and its novel transaction model that supports consistent geo-distributed transactions on commodity hardware. We describe how CockroachDB replicates and distributes data to achieve fault tolerance and high performance, as well as how its distributed SQL layer automatically scales with the size of the database cluster while providing the standard SQL interface that users expect. Finally, we present a comprehensive performance evaluation and share a couple of case studies of CockroachDB users. We conclude by describing lessons learned while building CockroachDB over the last five years.

Background Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. Methods A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males (M)/14 females (F)) admitted to an alcohol detoxification program, was stratified into two groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/L, 7M/8F) and Group 2 (ALT ≥ 40 U/L, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia and inflammation were examined at baseline, day 8 and day 15 of the admission. The drinking history was also evaluated. Results Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide (LPS) levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. Conclusions The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with two weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program.

Background and Aim Cancer invasion and metastasis are characterized by epithelial-mesenchymal transition (EMT). Hepatocellular carcinoma (HCC) causes metastasis and significant mortality. Elucidating factors promoting EMT in HCC is necessary to develop effective therapeutic strategies. Methods The LH86 cell line was developed in our laboratory from well-differentiated HCC without associated hepatitis or cirrhosis and used as a model to study EMT in HCC. Effects of transforming growth factor (TGF) β-1, epidermal growth factor (EGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) were examined using morphology, molecular markers, effects on migration and tumorigenicity. The involvement of cyclooxygenase-2 (COX-2) and Akt were examined. Results LH86 cells display epithelial morphology. TGFβ-1, EGF, HGF and bFGF induced mesenchymal changes in them associated with loss of E-cadherin, albumin, α-1 anti-trypsin expression and increased expression of vimentin, collagen I and fibronectin. There was associated increased migration, tumorigenicity and increased expression of COX-2, PGE2, Akt and phosphorylated Akt. Inhibition of COX-2 and Akt pathways led to inhibition of characteristics of EMT. Conclusions Multiple growth factors induce EMT in HCC. COX-2 and Akt may mediate EMT associated development and progression of HCC and molecular targeting of COX-2 and Akt may be an effective therapeutic or chemopreventative strategy in advanced and metastatic HCC.

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