Fluid–structure interaction for highly complex, statistically defined, biological media: Homogenisation and a 3D multi-compartmental poroelastic model for brain biomechanics

Numerous problems of relevance in physiology and biomechanics, have at their core, the presence of a deformable solid matrix which experiences flow-induced strain. Often, this fluid-structure interaction (FSI) is directed the opposite way, i.e. it is solid deformation that creates flow, with the heart being the most prominent example. In many cases, this interaction of fluid and solid is genuinely bidirectional and strongly coupled, with solid deformation inducing flow and fluid pressure deforming the solid. Although an FSI problem, numerous cases in biomechanics are not tractable via the traditional FSI methodologies: in the internal flows that are of interest to use, the number and range of fluid passages is so vast that the direct approach of a deterministically defined boundary between fluid and solid is impossible to apply. In these cases, homogenisation and statistical treatment of the material-fluid system is possibly the only way forward. Such homogenisation, quite common to flow-only systems through porous media considerations, is also possible for FSI systems, where the loading is effectively internal to the material. A prominent technique of this type is that of poroelasticity. In this paper, we discuss a class of poroelastic theory techniques that allow for the co-existence of a multitude of – always statistically treated –channels and passages of widely different properties: termed multiple-network poroelasticity (or multicompartmental poroelasticity). This paradigm is particularly suitable for the study of living tissue, that is invariably permeated – perfused – by fluids, often different in nature and across a wide range of scales. Multicompartmental poroelasticity is capable of accounting for a full bidirectional coupling between the fluids and the solid matrix and allows us to track transport of a multitude of substances together with the deformation of the solid material that this transport gives rise to or is caused by, or both. For the purposes of demonstration, we utilise a complex and physiologically very important system, the human brain (specifically, we target the hippocampus), to exemplify the qualities and efficacy of this methodology during the course of Alzheimer’s Disease. The methodology we present has been implemented through the Finite Element Method, in a general manner, allowing for the co-existence of an arbitrary number of compartments. For the applications used in this paper to exemplify the method, a four-compartment implementation is used. A unified pipeline is used on a cohort of 35 subjects to provide statistically meaningful insight into the underlying mechanisms of the neurovascular unit (NVU) in the hippocampus, and to ascertain whether physical activity would have an influence in both swelling and drainage by taking into account both the scaled strain field and the proportion of perfused blood injected into the brain tissue. A key result garnered from his study is the statistically significant differences in right hemisphere hippocampal NVU swelling between males in the control group and females with mild cognitive impairment during high and low activity states

Search for time-dependent B0s - B0s-bar oscillations using a vertex charge dipole technique

We report a search for B0s - B0s-bar oscillations using a sample of 400,000 hadronic Z0 decays collected by the SLD experiment. The analysis takes advantage of the electron beam polarization as well as information from the hemisphere opposite that of the reconstructed B decay to tag the B production flavor. The excellent resolution provided by the pixel CCD vertex detector is exploited to cleanly reconstruct both B and cascade D decay vertices, and tag the B decay flavor from the charge difference between them. We exclude the following values of the B0s - B0s-bar oscillation frequency: Delta m_s < 4.9 ps-1 and 7.9 < Delta m_s < 10.3 ps-1 at the 95% confidence level.Comment: 18 pages, 3 figures, replaced by version accepted for publication in Phys.Rev.D; results differ slightly from first versio

A Policy-into-Practice Intervention to Increase the Uptake of Evidence-Based Management of Low Back Pain in Primary Care: A Prospective Cohort Study

BACKGROUND: Persistent non-specific low back pain (nsLBP) is poorly understood by the general community, by educators, researchers and health professionals, making effective care problematic. This study evaluated the effectiveness of a policy-into-practice intervention developed for primary care physicians (PCPs). METHODS: To encourage PCPs to adopt practical evidence-based approaches and facilitate time-efficient, integrated management of patients with nsLBP, we developed an interdisciplinary evidence-based, practical pain education program (gPEP) based on a contemporary biopsychosocial framework. One hundred and twenty six PCPs from primary care settings in Western Australia were recruited. PCPs participated in a 6.5-hour gPEP. Self-report measures recorded at baseline and at 2 months post-intervention included PCPs' attitudes, beliefs (modified Health Care Providers Pain and Impairment Relationship Scale (HC-PAIRS), evidence-based clinical practices (knowledge and skills regarding nsLBP management: 5-point Likert scale with 1  =  nil and 5  =  excellent) and practice behaviours (recommendations based on a patient vignette; 5-point Likert scale). RESULTS: Ninety one PCPs participated (attendance rate of 72%; post-intervention response rate 88%). PCP-responders adopted more positive, guideline-consistent beliefs, evidenced by clinically significant HC-PAIRS score differences (mean change  =  -5.6±8.2, p<0.0001; 95% confidence interval: -7.6 to -3.6) and significant positive shifts on all measures of clinical knowledge and skills (p<0.0001 for all questions). Self management strategies were recommended more frequently post-intervention. The majority of responders who were guideline-inconsistent for work and bed rest recommendations (82% and 62% respectively) at pre-intervention, gave guideline-consistent responses at post-intervention. CONCLUSION: An interprofessional pain education program set within a framework that aligns health policy and practice, encourages PCPs to adopt more self-reported evidence-based attitudes, beliefs and clinical behaviours in their management of patients with nsLBP. However, further research is required to determine cost effectiveness of this approach when compared with other modes of educational delivery and to examine PCP behaviours in actual clinical practice

Analysis of Expressed Sequence Tags of the Cyclically Parthenogenetic Rotifer Brachionus plicatilis

Background. Rotifers are among the most common non-arthropod animals and are the most experimentally tractable members of the basal assemblage of metazoan phyla known as Gnathifera. The monogonont rotifer Brachionus plicatilis is a developing model system for ecotoxicology, aquatic ecology, cryptic speciation, and the evolution of sex, and is an important food source for finfish aquaculture. However, basic knowledge of the genome and transcriptome of any rotifer species has been lacking. Methodology/Principal Findings. We generated and partially sequenced a cDNA library from B. plicatilis and constructed a database of over 2300 expressed sequence tags corresponding to more than 450 transcripts. About 20% of the transcripts had no significant similarity to database sequences by BLAST; most of these contained open reading frames of significant length but few had recognized Pfam motifs. Sixteen transcripts accounted for 25% of the ESTs; four of these had no significant similarity to BLAST or Pfam databases. Putative up- and downstream untranslated regions are relatively short and AT rich. In contrast to bdelloid rotifers, there was no evidence of a conserved trans-spliced leader sequence among the transcripts and most genes were single-copy. Conclusions/Significance. Despite the small size of this EST project it revealed several important features of the rotifer transcriptome and of individual monogonont genes. Because there is little genomic data for Gnathifera, the transcripts we found with no known function may represent genes that are species-, class-, phylum- or even superphylum-specific; the fact that some are among the most highly expressed indicates their importance. The absence of trans-spliced leader exons in this monogonont species contrasts with their abundance in bdelloid rotifers and indicates that the presence of this phenomenon can vary at the subphylum level. Our EST database provides a relatively large quantity of transcript-level data for B. plicatilis, and more generally of rotifers and other gnathiferan phyla, and can be browsed and searched at gmod.mbl.edu

Structure and Novel Functional Mechanism of Drosophila SNF in Sex-Lethal Splicing

Sans-fille (SNF) is the Drosophila homologue of mammalian general splicing factors U1A and U2B″, and it is essential in Drosophila sex determination. We found that, besides its ability to bind U1 snRNA, SNF can also bind polyuridine RNA tracts flanking the male-specific exon of the master switch gene Sex-lethal (Sxl) pre-mRNA specifically, similar to Sex-lethal protein (SXL). The polyuridine RNA binding enables SNF directly inhibit Sxl exon 3 splicing, as the dominant negative mutant SNF1621 binds U1 snRNA but not polyuridine RNA. Unlike U1A, both RNA recognition motifs (RRMs) of SNF can recognize polyuridine RNA tracts independently, even though SNF and U1A share very high sequence identity and overall structure similarity. As SNF RRM1 tends to self-associate on the opposite side of the RNA binding surface, it is possible for SNF to bridge the formation of super-complexes between two introns flanking Sxl exon 3 or between a intron and U1 snRNP, which serves the molecular basis for SNF to directly regulate Sxl splicing. Taken together, a new functional model for SNF in Drosophila sex determination is proposed. The key of the new model is that SXL and SNF function similarly in promoting Sxl male-specific exon skipping with SNF being an auxiliary or backup to SXL, and it is the combined dose of SXL and SNF governs Drosophila sex determination

Dynamically-Driven Inactivation of the Catalytic Machinery of the SARS 3C-Like Protease by the N214A Mutation on the Extra Domain

Despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3C-like proteases (3CLpro) noticeably differ from picornavirus 3C proteases in acquiring an extra helical domain in evolution. Previously, the extra domain was demonstrated to regulate the catalysis of the SARS-CoV 3CLpro by controlling its dimerization. Here, we studied N214A, another mutant with only a doubled dissociation constant but significantly abolished activity. Unexpectedly, N214A still adopts the dimeric structure almost identical to that of the wild-type (WT) enzyme. Thus, we conducted 30-ns molecular dynamics (MD) simulations for N214A, WT, and R298A which we previously characterized to be a monomer with the collapsed catalytic machinery. Remarkably, three proteases display distinctive dynamical behaviors. While in WT, the catalytic machinery stably retains in the activated state; in R298A it remains largely collapsed in the inactivated state, thus implying that two states are not only structurally very distinguishable but also dynamically well separated. Surprisingly, in N214A the catalytic dyad becomes dynamically unstable and many residues constituting the catalytic machinery jump to sample the conformations highly resembling those of R298A. Therefore, the N214A mutation appears to trigger the dramatic change of the enzyme dynamics in the context of the dimeric form which ultimately inactivates the catalytic machinery. The present MD simulations represent the longest reported so far for the SARS-CoV 3CLpro, unveiling that its catalysis is critically dependent on the dynamics, which can be amazingly modulated by the extra domain. Consequently, mediating the dynamics may offer a potential avenue to inhibit the SARS-CoV 3CLpro

Genetic Interactions between the Drosophila Tumor Suppressor Gene ept and the stat92E Transcription Factor

Tumor Susceptibility Gene-101 (TSG101) promotes the endocytic degradation of transmembrane proteins and is implicated as a mutational target in cancer, yet the effect of TSG101 loss on cell proliferation in vertebrates is uncertain. By contrast, Drosophila epithelial tissues lacking the TSG101 ortholog erupted (ept) develop as enlarged undifferentiated tumors, indicating that the gene can have anti-growth properties in a simple metazoan. A full understanding of pathways deregulated by loss of Drosophila ept will aid in understanding potential links between mammalian TSG101 and growth control.We have taken a genetic approach to the identification of pathways required for excess growth of Drosophila eye-antennal imaginal discs lacking ept. We find that this phenotype is very sensitive to the genetic dose of stat92E, the transcriptional effector of the Jak-Stat signaling pathway, and that this pathway undergoes strong activation in ept mutant cells. Genetic evidence indicates that stat92E contributes to cell cycle deregulation and excess cell size phenotypes that are observed among ept mutant cells. In addition, autonomous Stat92E hyper-activation is associated with altered tissue architecture in ept tumors and an effect on expression of the apical polarity determinant crumbs.These findings identify ept as a cell-autonomous inhibitor of the Jak-Stat pathway and suggest that excess Jak-Stat signaling makes a significant contribution to proliferative and tissue architectural phenotypes that occur in ept mutant tissues

Economic gains and health benefits from a new cigarette tax scheme in Taiwan: a simulation using the CGE model

BACKGROUND: This study evaluates the impact of an increase in cigarette tax in Taiwan in terms of the effects it has on the overall economy and the health benefits that it brings. METHODS: The multisector computable general equilibrium (CGE) model was used to simulate the impact of reduced cigarette consumption resulting from a new tax scheme on the entire economy gains and on health benefits. RESULTS: The results predict that because of the new tax scheme, there should be a marked reduction in cigarette consumption but a notable increase in health benefits that include saving between 28,125 and 56,250 lives. This could save NT$1.222~2.445 billion (where US$1 = NT$34.6) annually in life-threatening, cigarette-related health insurance expenses which exceeds the projected decrease of NT$1.275 billion in Gross Domestic Product (GDP) because of reduced consumption and therefore tax revenue. CONCLUSION: Overall, the increased cigarette excise tax will be beneficial in terms of both the health of the general public and the economy as a whole

On the Strength of First Order Phase Transitions

Electroweak baryogenesis may solve one of the most fundamental questions we can ask about the universe, that of the origin of matter. It has become clear in the past few years that it also poses a multi-faceted challenge. In order to compute the tiny primordial baryonic excess, we probably must invoke physics beyond the standard model (an exciting prospect for most people), we must push perturbation theory to its ``limits'' (or beyond), and we must deal with nonequilibrium aspects of the phase transition. In this talk, I focus mainly on the latter issue, that of nonequilibrium aspects of first order transitions. In particular, I discuss the elusive question of ``weakness''. What does it mean to have a weak first order transition, and how can we distinguish between weak and strong? I argue that weak and strong transitions have very different dynamics; while strong transitions proceed by the usual bubble nucleation mechanism, weak transitions are characterized by a mixing of phases as the system reaches the critical temperature from above. I show that it is possible to clearly distinguish between the two, and discuss consequences for studies of first order transitions in general. (Invited talk given at the ``Electroweak Physics and the Early Universe'' workshop, Sintra, March 23-25, 1994.)Comment: 16 pages, 4 figures not included (can be obtained from hep-ph/9403310, or by request) RevTeX, DART-HEP-94/0