Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.Peer reviewe

Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.Peer reviewe

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

MFAP4 (microfibrillar-associated protein 4) is an extracellular glycoprotein found in elastic fibers without a clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues Phe(241) and Ser(203) in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization

AMACO is a component of the basement membrane-associated fraser complex

Fraser syndrome (FS) is a phenotypically variable, autosomal recessive disorder characterized by cryptophthalmus, cutaneous syndactyly, and other malformations resulting from mutations in FRAS1, FREM2, and GRIP1. Transient embryonic epidermal blistering causes the characteristic defects of the disorder. Fras1, Frem1, and Frem2 form the extracellular Fraser complex, which is believed to stabilize the basement membrane. However, several cases of FS could not be attributed to mutations in FRAS1, FREM2, or GRIP1, and FS displays high clinical variability, suggesting that there is an additional genetic, possibly modifying contribution to this disorder. An extracellular matrix protein containing VWA-like domains related to those in matrilins and collagens (AMACO), encoded by the VWA2 gene, has a very similar tissue distribution to the Fraser complex proteins in both mouse and zebrafish. Here, we show that AMACO deposition is lost in Fras1-deficient zebrafish and mice and that Fras1 and AMACO interact directly via their chondroitin sulfate proteoglycan (CSPG) and P2 domains. Knockdown of vwa2, which alone causes no phenotype, enhances the phenotype of hypomorphic Fras1 mutant zebrafish. Together, our data suggest that AMACO represents a member of the Fraser complex

Tactical urbanism as a means of testing relational processes in space: A complex systems perspective

Too often, master planning strategies have failed to produce spaces responding to the social, cultural, and economic needs of their inhabitants. Accordingly, many planners have turned to relational strategies to redefine their practices. These tend toward methodologies that explore relational forces preceding design interventions rather than unfolding by means of design interventions. This article considers an alternative mode of understanding relational processes: one that considers tactical urban strategies theorized through the lens of complexity theory. This article argues that tactical approaches harness relational junctures in situ, effectively exploring relational configurations of cohesive urban environments. A design competition entry provides an illustrative example of this approach: one that channels and choreographs relational urban processes

Exotic ρ±ρ0\rho^\pm\rho^0 state photoproduction

It is shown that the list of unusual mesons planned for a careful study in photoproduction can be extended by the exotic states $X^\pm(1600)$ with $I^G(J ^{PC})=2^+(2^{++})$ which should be looked for in the $\rho^\pm\rho^0$ decay channels in the reactions $\gamma N\to\rho^\pm\rho^0N$ and $\gamma N\to\rho^\pm \rho^0\Delta$. The full classification of the $\rho^\pm\rho^0$ states by their quantum numbers is presented. A simple model for the spin structure of the $\gamma p\to f_2(1270)p$, $\gamma p\to a^0_2(1320)p$, and $\gamma N\to X^\pm (N, \Delta)$ reaction amplitudes is formulated and the tentative estimates of the corresponding cross sections at the incident photon energy $E_\gamma\approx 6$ GeV are obtained: $\sigma(\gamma p\to f_2(1270)p)\approx0.12$ $\mu$b, $\sigma(\gamma p\to a^0_2(1320)p)\approx0.25$ $\mu$b, $\sigma(\gamma N\to X^\pm N\to\rho^\pm\rho^0N)\approx0.018$ $\mu$b, and $\sigma(\gamma p\to X^-\Delta^{++ }\to\rho^-\rho^0\Delta^{++})\approx0.031$ $\mu$b. The problem of the $X^\pm$ signal extraction from the natural background due to the other $\pi^\pm\pi^0 \pi^+\pi^-$ production channels is discussed. In particular the estimates are presented for the $\gamma p\to h_1(1170)\pi^+n$, $\gamma p\to\rho'^{+}n\to \pi^+\pi^0\pi^+\pi^-n$, and $\gamma p\to\omega\rho^0p$ reaction cross sections. Our main conclusion is that the search for the exotic $X^\pm(2^+(2^{++}))$ states is quite feasible at JEFLAB facility. The expected yield of the $\gamma N\to X^\pm N\to\rho^\pm\rho^0N$ events in a 30-day run at the 100% detection efficiency approximates $2.8\times10^6$ events.Comment: 19 pages, revtex, 1 figure in postscipt, some comments and references added, a few minor typos corrected, to be published in Phys. Rev.

Variant-Specific Viral Kinetics in Acute COVID-19

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410

National identity predicts public health support during a global pandemic (vol 13, 517, 2022) : National identity predicts public health support during a global pandemic (Nature Communications, (2022), 13, 1, (517), 10.1038/s41467-021-27668-9)

Publisher Copyright: © The Author(s) 2022.In this article the author name ‘Agustin Ibanez’ was incorrectly written as ‘Augustin Ibanez’. The original article has been corrected.Peer reviewe

National identity predicts public health support during a global pandemic.

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics