Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation

PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell–cell junctions, was impaired in Tie2Cre;Piezo1cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin+ cell–cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation

Nature of protein family signatures: Insights from singular value analysis of position-specific scoring matrices

Position-specific scoring matrices (PSSMs) are useful for detecting weak homology in protein sequence analysis, and they are thought to contain some essential signatures of the protein families. In order to elucidate what kind of ingredients constitute such family-specific signatures, we apply singular value decomposition to a set of PSSMs and examine the properties of dominant right and left singular vectors. The first right singular vectors were correlated with various amino acid indices including relative mutability, amino acid composition in protein interior, hydropathy, or turn propensity, depending on proteins. A significant correlation between the first left singular vector and a measure of site conservation was observed. It is shown that the contribution of the first singular component to the PSSMs act to disfavor potentially but falsely functionally important residues at conserved sites. The second right singular vectors were highly correlated with hydrophobicity scales, and the corresponding left singular vectors with contact numbers of protein structures. It is suggested that sequence alignment with a PSSM is essentially equivalent to threading supplemented with functional information. The presented method may be used to separate functionally important sites from structurally important ones, and thus it may be a useful tool for predicting protein functions.Comment: 22 pages, 7 figures, 4 table

Comparative Membranome Expression Analysis in Primary Tumors and Derived Cell Lines

Despite the wide use of cell lines in cancer research, the extent to which their surface properties correspond to those of primary tumors is poorly characterized. The present study addresses this problem from a transcriptional standpoint, analyzing the expression of membrane protein genes - the Membranome – in primary tumors and immortalized in-vitro cultured tumor cells. 409 human samples, deriving from ten independent studies, were analyzed. These comprise normal tissues, primary tumors and tumor derived cell lines deriving from eight different tissues: brain, breast, colon, kidney, leukemia, lung, melanoma, and ovary. We demonstrated that the Membranome has greater power than the remainder of the transcriptome when used as input for the automatic classification of tumor samples. This feature is maintained in tumor derived cell lines. In most cases primary tumors show maximal similarity in Membranome expression with cell lines of same tissue origin. Differences in Membranome expression between tumors and cell lines were analyzed also at the pathway level and biological themes were identified that were differentially regulated in the two settings. Moreover, by including normal samples in the analysis, we quantified the degree to which cell lines retain the Membranome up- and down- regulations observed in primary tumors with respect to their normal counterparts. We showed that most of the Membranome up-regulations observed in primary tumors are lost in the in-vitro cultured cells. Conversely, the majority of Membranome genes down-regulated upon tumor transformation maintain lower expression levels also in the cell lines. This study points towards a central role of Membranome genes in the definition of the tumor phenotype. The comparative analysis of primary tumors and cell lines identifies the limits of cell lines as a model for the study of cancer-related processes mediated by the cell surface. Results presented allow for a more rational use of the cell lines as a model of cancer

Transplantation of mesenchymal stem cells from young donors delays aging in mice

Increasing evidence suggests that the loss of functional stem cells may be important in the aging process. Our experiments were originally aimed at testing the idea that, in the specific case of age-related osteoporosis, declining function of osteogenic precursor cells might be at least partially responsible. To test this, aging female mice were transplanted with mesenchymal stem cells from aged or young male donors. We find that transplantation of young mesenchymal stem cells significantly slows the loss of bone density and, surprisingly, prolongs the life span of old mice. These observations lend further support to the idea that age-related diminution of stem cell number or function may play a critical role in age-related loss of bone density in aging animals and may be one determinant of overall longevity

Health and economic impact of rotavirus vaccination in GAVI-eligible countries

<p>Abstract</p> <p>Background</p> <p>Rotavirus infection is responsible for about 500,000 deaths annually, and the disease burden is disproportionately borne by children in low-income countries. Recently the World Health Organization (WHO) has released a global recommendation that all countries include infant rotavirus vaccination in their national immunization programs. Our objective was to provide information on the expected health, economic and financial consequences of rotavirus vaccines in the 72 GAVI support-eligible countries.</p> <p>Methods</p> <p>We synthesized population-level data from various sources (primarily from global-level databases) for the 72 countries eligible for the support by the GAVI Alliance (GAVI-eligible countries) in order to estimate the health and economic impact associated with rotavirus vaccination programs. The primary outcome measure was incremental cost (in 2005 international dollars [I$]) per disability-adjusted life year (DALY) averted. We also projected the expected reduction in rotavirus disease burden and financial resources required associated with a variety of scale-up scenarios.</p> <p>Results</p> <p>Under the base-case assumptions (70$25 per vaccinated child (~$5 per dose), the number of countries with the incremental cost per DALY averted less than I$200 was 47. Using the WHO's cost-effectiveness threshold based on per capita GDP, the vaccines were considered cost-effective in 68 of the 72 countries (~94%). A 10-year routine rotavirus vaccination would prevent 0.9-2.8 million rotavirus associated deaths among children under age 5 in the poorest parts of the world, depending on vaccine scale-up scenarios. Over the same intervention period, rotavirus vaccination programs would also prevent 4.5-13.3 million estimated cases of hospitalization and 41-107 million cases of outpatient clinic visits in the same population.</p> <p>Conclusions</p> <p>Our findings suggest that rotavirus vaccination would be considered a worthwhile investment for improving general development as well as childhood health level in most low-income countries, with a favorable cost-effectiveness profile even under a vaccine price ($1.5-$5.0 per dose) higher than those of traditional childhood vaccines.</p

Paracrine IL-33 Stimulation Enhances Lipopolysaccharide-Mediated Macrophage Activation

BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation

Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis

BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. OBJECTIVES: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-–mediated mode of action was specifically explored. RESULTS: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. CONCLUSIONS: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion