Pore-Scale Behavior of Darcy Flow in Static and Dynamic Porous Media

Lattice-Boltzmann numerical simulations are conducted to explore the pore-scale flow behavior inside modeled porous media over the Darcy regime. We use static (fixed) and dynamic (rotating) particles to form the porous media. The pore flow behavior (tortuosity) is found to be constant in the static medium within the Darcy range. However, the study reveals distinctively different flow structures in the dynamic case depending on the macroscopic Darcy flow rate and the level of internal energy imposed to the system (via the angular velocity of particles). With small Darcy flow rates, tortuous flow develops with vortices occupying a large portion of the pore space but contributing little to the net flow. The formation of the vortices is linked to spatial fluctuations of local pore fluid pressure. As the Darcy flow rate (and, hence, the global fluid pressure gradient across the medium) increases, the effect of local pressure fluctuations diminishes, and the flow becomes more channelized. Despite the large variations of the pore-scale flow characteristics in the dynamic porous media, the macroscopic flow satisfies Darcy's law with an invariant permeability. The applicability of Darcy's law is proven for an internally disturbed flow through porous media. The results raise questions concerning the generality of the models describing the Darcy flow as being channelized with constant (structure-dependent) tortuosity and how the internal sources of energy imposed to the porous media flow are considered

Preclinical models of arthritis for studying immunotherapy and immune tolerance

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms. Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period. This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Searching for stochastic gravitational waves using data from the two colocated LIGO Hanford detectors

Searches for a stochastic gravitational-wave background (SGWB) using terrestrial detectors typically involve cross-correlating data from pairs of detectors. The sensitivity of such cross-correlation analyses depends, among other things, on the separation between the two detectors: the smaller the separation, the better the sensitivity. Hence, a colocated detector pair is more sensitive to a gravitational-wave background than a noncolocated detector pair. However, colocated detectors are also expected to suffer from correlated noise from instrumental and environmental effects that could contaminate the measurement of the background. Hence, methods to identify and mitigate the effects of correlated noise are necessary to achieve the potential increase in sensitivity of colocated detectors. Here we report on the first SGWB analysis using the two LIGO Hanford detectors and address the complications arising from correlated environmental noise. We apply correlated noise identification and mitigation techniques to data taken by the two LIGO Hanford detectors, H1 and H2, during LIGO’s fifth science run. At low frequencies, 40–460 Hz, we are unable to sufficiently mitigate the correlated noise to a level where we may confidently measure or bound the stochastic gravitational-wave signal. However, at high frequencies, 460–1000 Hz, these techniques are sufficient to set a 95% confidence level upper limit on the gravitational-wave energy density of Ω(f) < 7.7 × 10[superscript -4](f/900  Hz)[superscript 3], which improves on the previous upper limit by a factor of ~180. In doing so, we demonstrate techniques that will be useful for future searches using advanced detectors, where correlated noise (e.g., from global magnetic fields) may affect even widely separated detectors.National Science Foundation (U.S.)United States. National Aeronautics and Space AdministrationCarnegie TrustDavid & Lucile Packard FoundationAlfred P. Sloan Foundatio

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Strain-Specific Properties and T Cells Regulate the Susceptibility to Papilloma Induction by <i>Mus musculus</i> Papillomavirus 1

<div><p>The immunocytes that regulate papillomavirus infection and lesion development in humans and animals remain largely undefined. We found that immunocompetent mice with varying H-2 haplotypes displayed asymptomatic skin infection that produced L1 when challenged with 6×10¹⁰ MusPV1 virions, the recently identified domestic mouse papillomavirus (also designated “MmuPV1”), but were uniformly resistant to MusPV1-induced papillomatosis. Broad immunosuppression with cyclosporin A resulted in variable induction of papillomas after experimental infection with a similar dose, from robust in Cr:ORL SENCAR to none in C57BL/6 mice, with lesional outgrowth correlating with early viral gene expression and partly with reported strain-specific susceptibility to chemical carcinogens, but not with H-2 haplotype. Challenge with 1×10¹² virions in the absence of immunosuppression induced small transient papillomas in Cr:ORL SENCAR but not in C57BL/6 mice. Antibody-induced depletion of CD3⁺ T cells permitted efficient virus replication and papilloma formation in both strains, providing experimental proof for the crucial role of T cells in controlling papillomavirus infection and associated disease. In Cr:ORL SENCAR mice, immunodepletion of either CD4⁺ or CD8⁺ T cells was sufficient for efficient infection and papillomatosis, although deletion of one subset did not inhibit the recruitment of the other subset to the infected epithelium. Thus, the functional cooperation of CD4⁺ and CD8⁺ T cells is required to protect this strain. In contrast, C57BL/6 mice required depletion of both CD4⁺ and CD8⁺ T cells for infection and papillomatosis, and separate CD4 knock-out and CD8 knock-out C57BL/6 were also resistant. Thus, in C57BL/6 mice, either CD4⁺ or CD8⁺ T cell-independent mechanisms exist that can protect this particular strain from MusPV1-associated disease. These findings may help to explain the diversity of pathological outcomes in immunocompetent humans after infection with a specific human papillomavirus genotype.</p></div

Papilloma formation can be observed in CD4- or CD8-depleted Cr:ORL SENCAR mice.

<p>Antibody-mediated depletion of (A) CD4⁺ T cells allows papilloma formation in Cr:ORL SENCAR mice after 7 weeks of immunodepletion (6 weeks post-infection). (B) Similarly, papilloma formation was observed in CD8-depleted littermates at the same time point. (C) Isotype-depleted and (D) MusPV1-infected controls did not develop papillomas. All mice were infected with 5.1×10⁹ MusPV1 virions. (E) Comparison of tail lesions of CD4- and CD8-depleted animals at this time point showed comparable mean lesion lengths, in mm, in these animals. Data represent the mean ± SEM of nine mice/group from a representative experiment. Immunofluorescent staining of skin tissues from (F,G) CD4-depleted or (H, I) CD8-depleted mice demonstrated abundant expression of MusPV1 L1 proteins (red, detected with an Alexa Fluor 594-labeled secondary antibody) in these tissues. Co-stainings using an Alexa Fluor 488-labeled anti-CD4 (F, H) or an Alexa Fluor 488-labeled anti-CD8 (G, I) antibody (green) confirmed the absence of the targeted T cell subpopulation in the tissues. There was no loss in the infiltration by the non-depleted subset. Quantification of CD4⁺ (left side) and CD8⁺ (right side) T lymphocytes in (J) skin, (K) blood, (L) spleen and (M) draining lymph nodes of CD4-, CD8- and isotype-depleted MusPV1-infected Cr:ORL SENCAR mice by flow cytometry analyses was performed after 5 weeks of immunodepletion (corresponding to 4 weeks post-infection) and demonstrated the efficient and specific depletion of the targeted subpopulation in each compartment.</p

CD3⁺ T cell depletion allows papilloma formation in Cr:ORL SENCAR mice.

<p>Infection of Cr:ORL SENCAR mice was performed on day 0 using 7.3×10¹⁰ MusPV1 virions and depletion of CD3⁺ T cells achieved by administration of anti-murine CD3 monoclonal antibodies for a total of 7 weeks. Efficient papilloma formation was observed when CD3⁺ immunodepletion was started (A) 7 days prior to, (B) on the day of, and (C) 7 days after infection. Efficiency was markedly reduced when depletion was started (D) 28 days post-infection, and no papilloma outgrowth was observed when depletion was started (E) 49 days after infection. (F) Isotype-depleted MusPV1-infected control animals and (G) MusPV1-infected control mice did not develop papillomas. (H) Comparison of tail lesions in these animals after 7 weeks of T cell depletion showed the differences in mean lesion lengths, given in mm, between the different experimental groups. Data represent the mean ± SEM of five mice/group from a representative experiment. (I) MusPV1 virions that had been extracted from lesions of CD3⁺ T cell depleted/MusPV1-infected Cr:ORL SENCAR mice gave rise to papillomas on the tail of an athymic NCr nude mouse after experimental transmission. (J–K) Immunofluorescent staining revealed exceptionally large amounts of MusPV1 L1 protein (red, detected with an Alexa Fluor 594-labeled secondary antibody) in the papillomatous lesions taken from MusPV1-infected Cr:ORL SENCAR mice after 7 weeks of CD3⁺ T cell depletion (day −7 group shown as representative). (L–M) In contrast, L1 expression was absent in skin tissues taken from isotype-depleted controls. Co-stainings of (J, L) CD4⁺ T cells or (K, M) CD8⁺ T cells in the tissues were performed using Alexa Fluor 488-labeled anti-CD4 or anti-CD8 antibodies (green), respectively, and confirmed the absence of T cells in the depleted animals. Infection of all animals was performed on day 0 using 7.3×10¹⁰ MusPV1 virions.</p