Calculus and heat flow in metric measure spaces and applications to spaces with Ricci bounds from below

This paper is devoted to a deeper understanding of the heat flow and to the refinement of calculus tools on metric measure spaces (X,d,m). Our main results are: - A general study of the relations between the Hopf-Lax semigroup and Hamilton-Jacobi equation in metric spaces (X,d). - The equivalence of the heat flow in L^2(X,m) generated by a suitable Dirichlet energy and the Wasserstein gradient flow of the relative entropy functional in the space of probability measures P(X). - The proof of density in energy of Lipschitz functions in the Sobolev space W^{1,2}(X,d,m). - A fine and very general analysis of the differentiability properties of a large class of Kantorovich potentials, in connection with the optimal transport problem. Our results apply in particular to spaces satisfying Ricci curvature bounds in the sense of Lott & Villani [30] and Sturm [39,40], and require neither the doubling property nor the validity of the local Poincar\'e inequality.Comment: Minor typos corrected and many small improvements added. Lemma 2.4, Lemma 2.10, Prop. 5.7, Rem. 5.8, Thm. 6.3 added. Rem. 4.7, Prop. 4.8, Prop. 4.15 and Thm 4.16 augmented/reenforced. Proof of Thm. 4.16 and Lemma 9.6 simplified. Thm. 8.6 corrected. A simpler axiomatization of weak gradients, still equivalent to all other ones, has been propose

Reducing cell intrinsic immunity to mRNA vaccine alters adaptive immune responses in mice

The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment, but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ-modified mRNA (D1-modRNA), and D1-modRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an up-regulation of Stat1 and RnaseL, and increased systemic inflammation. This result correlated with significantly reduced antigen-specific antibody responses and reduced protection against influenza virus infection compared with D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material

Ricci curvature of finite Markov chains via convexity of the entropy

We study a new notion of Ricci curvature that applies to Markov chains on discrete spaces. This notion relies on geodesic convexity of the entropy and is analogous to the one introduced by Lott, Sturm, and Villani for geodesic measure spaces. In order to apply to the discrete setting, the role of the Wasserstein metric is taken over by a different metric, having the property that continuous time Markov chains are gradient flows of the entropy. Using this notion of Ricci curvature we prove discrete analogues of fundamental results by Bakry--Emery and Otto--Villani. Furthermore we show that Ricci curvature bounds are preserved under tensorisation. As a special case we obtain the sharp Ricci curvature lower bound for the discrete hypercube.Comment: 39 pages, to appear in Arch. Ration. Mech. Ana

Character evolution and missing (morphological) data across Asteridae

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/1/ajb21050-sup-0007-AppendixS7.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/2/ajb21050_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/3/ajb21050-sup-0019-AppendixS19.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/4/ajb21050-sup-0013-AppendixS13.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/5/ajb21050-sup-0014-AppendixS14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/6/ajb21050-sup-0012-AppendixS12.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/7/ajb21050-sup-0009-AppendixS9.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/8/ajb21050-sup-0018-AppendixS18.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/9/ajb21050.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/10/ajb21050-sup-0004-AppendixS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/11/ajb21050-sup-0008-AppendixS8.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/12/ajb21050-sup-0005-AppendixS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/13/ajb21050-sup-0017-AppendixS17.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/14/ajb21050-sup-0006-AppendixS6.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/15/ajb21050-sup-0011-AppendixS11.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/16/ajb21050-sup-0016-AppendixS16.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/17/ajb21050-sup-0015-AppendixS15.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/18/ajb21050-sup-0010-AppendixS10.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143691/19/ajb21050-sup-0003-AppendixS3.pd

Nipah Virus Infects Specific Subsets of Porcine Peripheral Blood Mononuclear Cells

Nipah virus (NiV), a zoonotic paramyxovirus, is highly contagious in swine, and can cause fatal infections in humans following transmission from the swine host. The main viral targets in both species are the respiratory and central nervous systems, with viremia implicated as a mode of dissemination of NiV throughout the host. The presented work focused on the role of peripheral blood mononuclear cells (PBMC) in the viremic spread of the virus in the swine host. B lymphocytes, CD4−CD8−, as well as CD4+CD8− T lymphocytes were not permissive to NiV, and expansion of the CD4+CD8− cells early post infection was consistent with functional humoral response to NiV infection observed in swine. In contrast, significant drop in the CD4+CD8− T cell frequency was observed in piglets which succumbed to the experimental infection, supporting the hypothesis that antibody development is the critical component of the protective immune response. Productive viral replication was detected in monocytes, CD6+CD8+ T lymphocytes and NK cells by recovery of infectious virus in the cell supernatants. Virus replication was supported by detection of the structural N and the non-structural C proteins or by detection of genomic RNA increase in the infected cells. Infection of T cells carrying CD6 marker, a strong ligand for the activated leukocyte cell adhesion molecule ALCAM (CD166) highly expressed on the microvascular endothelial cell of the blood-air and the blood-brain barrier may explain NiV preferential tropism for small blood vessels of the lung and brain

A Human Lung Xenograft Mouse Model of Nipah Virus Infection

Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecu

Efficient induction of T cells against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA

Focusing T cell responses on the most vulnerable parts of HIV-1, the functionally conserved regions of HIV-1 proteins, is likely a key prerequisite for vaccine success. For a T cell vaccine to efficiently control HIV-1 replication, the vaccine-elicited individual CD8+ T cells and as a population have to display a number of critical traits. If any one of these traits is suboptimal, the vaccine is likely to fail. Fine-tuning of individual protective characteristics of T cells will require iterative stepwise improvements in clinical trials. Although the second-generation tHIVconsvX immunogens direct CD8+ T cells to predominantly protective and conserved epitopes, in the present work, we have used formulated self-amplifying mRNA (saRNA) to deliver tHIVconsvX to the immune system. We demonstrated in BALB/c and outbred mice that regimens employing saRNA vaccines induced broadly specific, plurifunctional CD8+ and CD4+ T cells, which displayed structured memory subpopulations and were maintained at relatively high frequencies over at least 22 weeks post-administration. This is one of the first thorough analyses of mRNA vaccine-elicited T cell responses. The combination of tHIVconsvX immunogens and the highly versatile and easily manufacturable saRNA platform may provide a long-awaited opportunity to define and optimize induction of truly protective CD8+ T cell parameters in human volunteers