Improving the cascade of cervical cancer prevention for women living with HIV: a protocol development

Cervical cancer is considered a threat to global public health and disproportionally affects people living with HIV. The World Health Organization has aimed to reduce the burden of cervical cancer worldwide. Because of this goal, the National Cancer Institute has created the CASCADE Network, a network with four main pillars to aid in reducing the burden cervical cancer has on women living with HIV, by targeting HPV screening as persistent HPV infections increase the risk of cervical cancer. Weill Cornell Medical College is a research base that has joined the CASCADE Network to develop studies to assist the network in achieving its goals. Our research base conducted and analyzed clinical site interviews, site surveys, and a review of current literature to develop a research protocol. From this, we found that the clinical sites must enhance their HPV screening methods and clinic capabilities to significantly lower the burden cervical cancer plays. A proposed protocol was developed for a mixed-methods study to examine the implementation and potential impact of HPV DNA testing for cervical cancer screening in resource-constrained settings. This proposed protocol will act as a framework for future studies to address the limitations of cervical cancer screening in low-resource areas. This paper describes the protocol development for a CASCADE research base housed within Weill Cornell Medical College

An in vivo control map for the eukaryotic mRNA translation machinery

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis

Dupuytren's: a systems biology disease

Dupuytren's disease (DD) is an ill-defined fibroproliferative disorder of the palm of the hands leading to digital contracture. DD commonly occurs in individuals of northern European extraction. Cellular components and processes associated with DD pathogenesis include altered gene and protein expression of cytokines, growth factors, adhesion molecules, and extracellular matrix components. Histology has shown increased but varying levels of particular types of collagen, myofibroblasts and myoglobin proteins in DD tissue. Free radicals and localised ischaemia have been suggested to trigger the proliferation of DD tissue. Although the existing available biological information on DD may contain potentially valuable (though largely uninterpreted) information, the precise aetiology of DD remains unknown. Systems biology combines mechanistic modelling with quantitative experimentation in studies of networks and better understanding of the interaction of multiple components in disease processes. Adopting systems biology may be the ideal approach for future research in order to improve understanding of complex diseases of multifactorial origin. In this review, we propose that DD is a disease of several networks rather than of a single gene, and show that this accounts for the experimental observations obtained to date from a variety of sources. We outline how DD may be investigated more effectively by employing a systems biology approach that considers the disease network as a whole rather than focusing on any specific single molecule

Generalized Smoluchowski equation with correlation between clusters

In this paper we compute new reaction rates of the Smoluchowski equation which takes into account correlations. The new rate K = KMF + KC is the sum of two terms. The first term is the known Smoluchowski rate with the mean-field approximation. The second takes into account a correlation between clusters. For this purpose we introduce the average path of a cluster. We relate the length of this path to the reaction rate of the Smoluchowski equation. We solve the implicit dependence between the average path and the density of clusters. We show that this correlation length is the same for all clusters. Our result depends strongly on the spatial dimension d. The mean-field term KMFi,j = (Di + Dj)(rj + ri)d-2, which vanishes for d = 1 and is valid up to logarithmic correction for d = 2, is the usual rate found with the Smoluchowski model without correlation (where ri is the radius and Di is the diffusion constant of the cluster). We compute a new rate: the correlation rate K_{i,j}^{C} (D_i+D_j)(r_j+r_i)^{d-1}M{\big(\frac{d-1}{d_f}}\big) is valid for d \leq 1(where M(\alpha) = \sum+\infty i=1i\alphaNi is the moment of the density of clusters and df is the fractal dimension of the cluster). The result is valid for a large class of diffusion processes and mass radius relations. This approach confirms some analytical solutions in d 1 found with other methods. We also show Monte Carlo simulations which illustrate some exact new solvable models

JNK Signalling Regulates Self-Renewal of Proliferative Urine-Derived Renal Progenitor Cells via Inhibition of Ferroptosis

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor—AEG3482 displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers—SIX2, SALL1 and VCAM1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis, an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study is the first to describe the importance of JNK signalling as a link between maintenance of self-renewal and protection against ferroptosis in SIX2-positive renal progenitor cells

Leverage-induced systemic risk under Basle II and other credit risk policies

We use a simple agent based model of value investors in financial markets to test three credit regulation policies. The first is the unregulated case, which only imposes limits on maximum leverage. The second is Basle II and the third is a hypothetical alternative in which banks perfectly hedge all of their leverage-induced risk with options. When compared to the unregulated case both Basle II and the perfect hedge policy reduce the risk of default when leverage is low but increase it when leverage is high. This is because both regulation policies increase the amount of synchronized buying and selling needed to achieve deleveraging, which can destabilize the market. None of these policies are optimal for everyone: Risk neutral investors prefer the unregulated case with low maximum leverage, banks prefer the perfect hedge policy, and fund managers prefer the unregulated case with high maximum leverage. No one prefers Basle II.Comment: 27 pages, 8 figure