Comparison of symmetrical hemodialysis catheters using computational fluid dynamics

Purpose: Symmetric-tip dialysis catheters have become alternative devices because of low access recirculation and ease of tip positioning. Flow characteristics of three symmetric catheters were compared based on computational fluid dynamics (CFD) as they relate to catheter function. Materials And Methods: In Palindrome, GlidePath, and VectorFloW catheters, a computational fluid dynamics based approach was used to assess W regions of flow separation, which are prone to thrombus development; (ii) shear-induced platelet activation potency; (iii) recirculation; and (iv) venous outflow deflection. A steady-state, laminar flow model simulated: catheter tip position within the superior vena cava. Catheter performance was investigated at high hemodialysis flow rate (400 mL/min). Blood was assumed as a Newtonian fluid. Results: Wide regions of flow separation downstream of the Palindrome side slot and close to the distal tip were observed in forward and reversed line configurations. Geometric asymmetry of the distal guide wire aperture of the GlidePath catheter produced the highest levels of inverted velocity flow when run in reversed configuration. The lowest mean shear-induced platelet activation was exhibited by GlidePath and VectorFloW catheters; the Palindrome catheter exhibited 152% higher overall platelet activation potency. All catheters were associated with a recirculation close to zero; the helically contoured lumens of the VectorFlow catheter produced the greatest amount of deflection of venous flow away from the arterial lumen. Conclusions: The VectorFlow catheter produced less shear-induced platelet activation than the Palindrome catheter and less flow separation than the Palindrome and GlidePath catheters irrespective of line configuration These findings have,potential implications for differences in thrombogenic risk during clinical performance of these catheters

Heating of galactic gas by dark matter annihilation in ultracompact minihalos

The existence of substructure in halos of annihilating dark matter would be expected to substantially boost the rate at which annihilation occurs. Ultracompact minihalos of dark matter (UCMHs) are one of the more extreme examples of this. The boosted annihilation can inject significant amounts of energy into the gas of a galaxy over its lifetime. Here we determine the impact of the boost factor from UCMH substructure on the heating of galactic gas in a Milky Way-type galaxy, by means of N-body simulation. If $1\%$ of the dark matter exists as UCMHs, the corresponding boost factor can be of order $10^5$. For reasonable values of the relevant parameters (annihilation cross section $3\times10^{-26} ~\textrm{cm}^3~ \textrm{s}^{-1}$, dark matter mass 100 GeV, 10% heating efficiency), we show that the presence of UCMHs at the 0.1% level would inject enough energy to eject significant amounts of gas from the halo, potentially preventing star formation within $\sim$1 kpc of the halo centre.Comment: 14 pages, 3 figure

TCP throughput guarantee in the DiffServ Assured Forwarding service: what about the results?

Since the proposition of Quality of Service architectures by the IETF, the interaction between TCP and the QoS services has been intensively studied. This paper proposes to look forward to the results obtained in terms of TCP throughput guarantee in the DiffServ Assured Forwarding (DiffServ/AF) service and to present an overview of the different proposals to solve the problem. It has been demonstrated that the standardized IETF DiffServ conditioners such as the token bucket color marker and the time sliding window color maker were not good TCP traffic descriptors. Starting with this point, several propositions have been made and most of them presents new marking schemes in order to replace or improve the traditional token bucket color marker. The main problem is that TCP congestion control is not designed to work with the AF service. Indeed, both mechanisms are antagonists. TCP has the property to share in a fair manner the bottleneck bandwidth between flows while DiffServ network provides a level of service controllable and predictable. In this paper, we build a classification of all the propositions made during these last years and compare them. As a result, we will see that these conditioning schemes can be separated in three sets of action level and that the conditioning at the network edge level is the most accepted one. We conclude that the problem is still unsolved and that TCP, conditioned or not conditioned, remains inappropriate to the DiffServ/AF service

A Pathway to Solving the Structure of cl-Par-4 Tumor Suppressor Protein: Challenges & Findings

Prostate apoptosis response-4 (Par-4) is a pro-apoptotic tumor suppressor protein. Down-regulation of this protein has been reported in a myriad of cancers. Conversely, up-regulation of Par-4 is found to be associated with several neurodegenerative disorders. Par-4 is unique in the sense it can selectively induce apoptosis in cancer cells. For this, caspase-dependent intracellular cleavage of Par-4 is essential to produce the functionally active fragment, cl-Par-4 (caspase-cleaved Par-4). The cl-Par-4 protein inhibits the NF-κB-mediated cell survival pathway and causes selective apoptosis in various tumor cells. Our laboratory is interested in determining the structure of cl-Par-4 and understanding it’s interaction with various proteins. Currently, we are using biophysical techniques such as circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and SDS-PAGE to characterize the structure of cl-Par-4 in the presence of various concentrations of monovalent and divalent ions, in order to shed light on the possible ion-specific role of cl-Par-4 in inducing structure and self-association of this protein. Results show that effects on cl-Par-4 conformation are ion-specific, and effects of divalent cations are considerably more pronounced than effects from monovalent cations. We have also found that the cl-Par-4 shows a better stability in presence of Cl- ions than in presence of SO42- ions. Further, with the help of D313K mutant of cl-Par-4, we investigated that charge-charge repulsion between similar charged amino acid residues in leucine zipper is responsible for high salt at neutral pH or low salt at low pH requirement of cl-Par-4. All these findings will be helpful in getting the structured conformation of cl-Par-4 and, therefore, determining the structure of this protein via X-ray crystallography or via nuclear magnetic resonance (NMR).https://digitalcommons.odu.edu/gradposters2022_sciences/1013/thumbnail.jp

pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain

Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl-2 and NF-ƙB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non-aggregated conformation at acidic p

Characterization of Cl-Par-4: WT vs. Mutant

Intrinsically disordered proteins (IDPs) play important roles in regulation of cell signaling pathways as well as cellular processes. Dysregulation of these proteins is associated with several human diseases. Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is categorized as an intrinsically disordered protein and downregulation of this protein has been reported in myriad of cancers including glioma, breast cancers, and prostate cancers. The caspase-cleaved fragment of Par-4 (cl-Par-4) plays an active role in tumor suppression by inhibiting several cell survival pathways. Here, we employed site-directed mutagenesis to introduce a point mutation in the cl-Par-4 wildtype (WT) to generate the D313K cl-Par-4 mutant. We have characterized both the mutant and the WT using various biophysical techniques such as CD, DLS, and NMR to determine the effect of the D313K mutation. The results show that D313K cl-Par-4 attains a compact and well-folded helical conformation, possibly a tetramer, similar to that of the WT in presence of high salt at physiological pH. However, D313K does so with half the amount of salt required for the WT. This establishes that the substitution of a basic residue for an acidic residue at position 313 alleviates inter-helical charge repulsion between dimer partners and helps to stabilize the structural conformation.https://digitalcommons.odu.edu/gradposters2023_gradschool/1004/thumbnail.jp

Nietzsche and Amor Fati

This paper identifies two central paradoxes threatening the notion of amor fati [love of fate]: it requires us to love a potentially repellent object (as fate entails significant negativity for us) and this, in the knowledge that our love will not modify our fate. Thus such love may seem impossible or pointless. I analyse the distinction between two different sorts of love (eros and agape) and the type of valuation they involve (in the first case, the object is loved because we value it; in the second, we value the object because we love it). I use this as a lens to interpret Nietzsche?s cryptic pronouncements on amor fati and show that while an erotic reading is, up to a point, plausible, an agapic interpretation is preferable both for its own sake and because it allows for a resolution of the paradoxes initially identified. In doing so, I clarify the relation of amor fati to the eternal return on the one hand, and to Nietzsche?s autobiographical remarks about suffering on the other. Finally, I examine a set of objections pertaining both to the sustainability and limits of amor fati, and to its status as an ideal