Numerical simulation of skin transport using Parareal

In silico investigation of skin permeation is an important but also computationally demanding problem. To resolve all scales involved in full detail will not only require exascale computing capacities but also suitable parallel algorithms. This article investigates the applicability of the time-parallel Parareal algorithm to a brick and mortar setup, a precursory problem to skin permeation. The C++ library Lib4PrM implementing Parareal is combined with the UG4 simulation framework, which provides the spatial discretization and parallelization. The combination’s performance is studied with respect to convergence and speedup. It is confirmed that anisotropies in the domain and jumps in diffusion coefficients only have a minor impact on Parareal’s convergence. The influence of load imbalances in time due to differences in number of iterations required by the spatial solver as well as spatio-temporal weak scaling is discussed

Metabolic Factors Limiting Performance in Marathon Runners

Each year in the past three decades has seen hundreds of thousands of runners register to run a major marathon. Of those who attempt to race over the marathon distance of 26 miles and 385 yards (42.195 kilometers), more than two-fifths experience severe and performance-limiting depletion of physiologic carbohydrate reserves (a phenomenon known as ‘hitting the wall’), and thousands drop out before reaching the finish lines (approximately 1–2% of those who start). Analyses of endurance physiology have often either used coarse approximations to suggest that human glycogen reserves are insufficient to fuel a marathon (making ‘hitting the wall’ seem inevitable), or implied that maximal glycogen loading is required in order to complete a marathon without ‘hitting the wall.’ The present computational study demonstrates that the energetic constraints on endurance runners are more subtle, and depend on several physiologic variables including the muscle mass distribution, liver and muscle glycogen densities, and running speed (exercise intensity as a fraction of aerobic capacity) of individual runners, in personalized but nevertheless quantifiable and predictable ways. The analytic approach presented here is used to estimate the distance at which runners will exhaust their glycogen stores as a function of running intensity. In so doing it also provides a basis for guidelines ensuring the safety and optimizing the performance of endurance runners, both by setting personally appropriate paces and by prescribing midrace fueling requirements for avoiding ‘the wall.’ The present analysis also sheds physiologically principled light on important standards in marathon running that until now have remained empirically defined: The qualifying times for the Boston Marathon

Respiratory Syncytial Virus Matrix Protein Induces Lung Epithelial Cell Cycle Arrest through a p53 Dependent Pathway

Respiratory syncytial virus (RSV) is the major cause of viral respiratory infections in children. Our previous study showed that the RSV infection induced lung epithelial cell cycle arrest, which enhanced virus replication. To address the mechanism of RSV-induced cell cycle arrest, we examined the contribution of RSV-matrix (RSV-M) protein. In this report, we show that in both the A549 cell line and primary human bronchial epithelial (PHBE) cells, transfection with RSV-M protein caused the cells to proliferate at a slower rate than in control cells. The cell cycle analysis showed that RSV-M protein induced G1 phase arrest in A549 cells, and G1 and G2/M phase arrest in PHBE cells. Interestingly, RSV-M expression induced p53 and p21 accumulation and decreased phosphorylation of retinoblastoma protein (Rb). Further, induction of cell cycle arrest by RSV-M was not observed in a p53-deficient epithelial cell line (H1299). However, cell cycle arrest was restored after transfection of p53 cDNA into H1299 cells. Taken together, these results indicate that RSV-M protein regulates lung epithelial cell cycle through a p53-dependent pathway, which enhances RSV replication

Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes

A nationwide analysis of incidence and outcome of breast cancer in the country of Surinam, during 1994-2003

In this study, we describe the incidence, treatment, and outcome of breast cancer (BC) during the period 1994-2003 in the South-American country of Surinam and compare these with those of BC in the Netherlands. Pathology reports and hospital charts from all BC cases diagnosed between 1994 and 2004 were retrieved from Surinam's single pathology laboratory and its five hospitals. Data on demographics, tumor characteristics, treatment, and follow-up were gathered. We compared our data to BC statistics of first generation immigrants from Surinam to the Netherlands. 421 patients were diagnosed with BC during the study period. The age-adjusted incidence rate was 26 per 100,000 compared to 65/100,000 in first generation Surinamese women in the Netherlands. The majority had a fairly advanced stage at presentation, with 60% of tumors larger than 2 cm, and 41.6% with lymph node involvement. Because of the absence of radiotherapy facilities, local treatment in most patients was radical mastectomy. Adjuvant hormonal therapy (51.6%) was administered more frequently than adjuvant chemotherapy (20.3%). A significant number of patients were lost to follow-up, resulting in a median follow-up duration of only 23 months. The 5-year overall survival was 79%. BC incidence in Surinam is low compared to that in the western world, but the advanced stage at diagnosis, the low utilization of systemic adjuvant therapy, and the inadequate follow-up may lead to poor outcomes. A number of steps are underway to improve the level of cancer care in Surina

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present — ‘D’, either elevated blood glucose levels or a family history of diabetes mellitus; ‘K’, the presence of high urinary or blood ketoacids; and ‘A’, a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children