The genomic basis of high-elevation adaptation in wild house mice (Mus musculus domesticus) from South America

Understanding the genetic basis of environmental adaptation in natural populations is a central goal in evolutionary biology. The conditions at high elevation, particularly the low oxygen available in the ambient air, impose a significant and chronic environmental challenge to metabolically active animals with lowland ancestry. To understand the process of adaptation to these novel conditions and to assess the repeatability of evolution over short timescales, we examined the signature of selection from complete exome sequences of house mice (Mus musculus domesticus) sampled across two elevational transects in the Andes of South America. Using phylogenetic analysis, we show that house mice colonized high elevations independently in Ecuador and Bolivia. Overall, we found distinct responses to selection in each transect and largely nonoverlapping sets of candidate genes, consistent with the complex nature of traits that underlie adaptation to low oxygen availability (hypoxia) in other species. Nonetheless, we also identified a small subset of the genome that appears to be under parallel selection at the gene and SNP levels. In particular, three genes (Col22a1, Fgf14, and srGAP1) bore strong signatures of selection in both transects. Finally, we observed several patterns that were common to both transects, including an excess of derived alleles at high elevation, and a number of hypoxia-associated genes exhibiting a threshold effect, with a large allele frequency change only at the highest elevations. This threshold effect suggests that selection pressures may increase disproportionately at high elevations in mammals, consistent with observations of some high-elevation diseases in humans.     

Yeast Cell Wall Extract Induces Disease Resistance against Bacterial and Fungal Pathogens in Arabidopsis thaliana and Brassica Crop

Housaku Monogatari (HM) is a plant activator prepared from a yeast cell wall extract. We examined the efficacy of HM application and observed that HM treatment increased the resistance of Arabidopsis thaliana and Brassica rapa leaves to bacterial and fungal infections. HM reduced the severity of bacterial leaf spot and anthracnose on A. thaliana and Brassica crop leaves with protective effects. In addition, gene expression analysis of A. thaliana plants after treatment with HM indicated increased expression of several plant defense-related genes. HM treatment appears to induce early activation of jasmonate/ethylene and late activation of salicylic acid (SA) pathways. Analysis using signaling mutants revealed that HM required SA accumulation and SA signaling to facilitate resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola and the fungal pathogen Colletotrichum higginsianum. In addition, HM-induced resistance conferred chitin-independent disease resistance to bacterial pathogens in A. thaliana. These results suggest that HM contains multiple microbe-associated molecular patterns that activate defense responses in plants. These findings suggest that the application of HM is a useful tool that may facilitate new disease control methods.     

Javanicinosides D-H, quassinoid glucosides from Picrasma javanica

From Picrasma javanica, five new quassinoid glucosides, javanicinosides D-H, together with known quassinoids, neoquassin and picrasin A and triterpenoids, hispidol A and lanosta-7,24-dien-3-one were isolated. The structures have been determined by spectral analysis and chemical evidence.     

Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study

Introduction

TNFAIP3 interacting protein 1, TNIP1 (ABIN-1) is involved in inhibition of nuclear factor-κB (NF-κB) activation by interacting with TNF alpha-induced protein 3, A20 (TNFAIP3), an established susceptibility gene to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recent genome-wide association studies revealed association of TNIP1 with SLE in the Caucasian and Chinese populations. In this study, we investigated whether the association of TNIP1 with SLE was replicated in a Japanese population. In addition, association of TNIP1 with RA was also examined.

Methods

A case-control association study was conducted on the TNIP1 single nucleotide polymorphism (SNP) rs7708392 in 364 Japanese SLE patients, 553 RA patients and 513 healthy controls.

Results

Association of TNIP1 rs7708392C was replicated in Japanese SLE (allele frequency in SLE: 76.5%, control: 69.9%, P = 0.0022, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.13-1.74). Notably, the risk allele frequency in the healthy controls was considerably greater in Japanese (69.9%) than in Caucasians (24.3%). A tendency of stronger association was observed in the SLE patients with renal disorder (P = 0.00065, OR 1.60 [95%CI 1.22-2.10]) than in all SLE patients (P = 0.0022, OR 1.40 [95%CI 1.13-1.74]). Significant association with RA was not observed, regardless of the carriage of human leukocyte antigen DR β1 (HLA-DRB1) shared epitope. Significant gene-gene interaction between TNIP1 and TNFAIP3 was detected neither in SLE nor RA.

Conclusions

Association of TNIP1 with SLE was confirmed in a Japanese population. TNIP1 is a shared SLE susceptibility gene in the Caucasian and Asian populations, but the genetic contribution appeared to be greater in the Japanese and Chinese populations because of the higher risk allele frequency. Taken together with the association of TNFAIP3, these observations underscore the crucial role of NF-κB regulation in the pathogenesis of SLE.     

Early activation does not translate into effector differentiation of peripheral CD8T cells during the acute phase of Kawasaki disease

Early diagnosis of acute Kawasaki disease (KD), lying in the spectrum between infectious and autoimmune diseases, can be difficult. To clarify the role of peripheral CD8T cells in KD, we examined their activation, proliferation, maturation, and effector function by four-color flow cytometry. Compared to healthy/febrile controls, acute KD patients showed striking increase in early activation marker CD69⁺CD8T cells and maturation subsets, but HLA-DR⁺CD8T cells representing late activation did not increase. Although Ki67⁺CD8T cells reflecting ongoing cell division increased in acute KD and febrile controls, absolute numbers of CD8T cells and maturation subsets decreased in acute KD versus healthy controls. Effector cells were lower in acute than in convalescent KD. Perforin⁺CD8T cells, denoting cytolytic activity, were lower in KD patients versus febrile controls. CD69⁺CD8T cells increase in acute KD but effector differentiation is absent. CD69⁺CD8T cells could be a marker to determine disease progression, treatment response, and convalescence in acute KD.     

Protonation and quaternization of 1, N6-ethenoadenosine: What are the species responsible for the fluorescence of 1, N6-ethenoadenosine?

Methylation of 1,N⁶-ethenoadenosine (εAdo) gives a mixture of N1- and N9-quaternized methyl-3-β-D -ribofuranosylimidazo[2,1-i] purinium salts (m¹εAdo⁺ and m⁹εAdo⁺, respectively). The ratio of the two forms of the protonated εAdo [H¹εAdo⁺]/[H⁹εAdo⁺] has been estimated to be approximately 0.10 by comparing the uv absorption spectra of the protonated species of εAdo and the two nontautomerizable model compounds. In relation to a study on the protonation effect on the fluorescence of εAdo, we have now determined the effect of quaternization on the fluorescence spectra at 293 and 77 K. We have found that m¹εAdo⁺ and m⁹εAdo⁺ are both fluorescent, and the high degree of coincidence between the fluorescence spectra of εAdo and m¹εAdo⁺ at pH 7 is noted. The m¹εAdo⁺ singlet form is a more efficient fluorescer than the m⁹εAdo⁺ ion at room temperature (quantum yields of 0.43 and 0.11, respectively). All the results which are presented in this paper are consistent with the picture that there exist more than one species responsible for the fluorescence of εAdo, depending on the environment of the molecule in aqueous solution (temperature and pH of solvent).     

A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor

PCSK9 (proprotein convertase subtilisin-like/kexin type 9) is an emerging target for pharmaceutical intervention. This multidomain protein interacts with the LDL receptor (LDLR), promoting receptor degradation. Insofar as PCSK9 inhibition induces a decrease in plasma cholesterol levels, understanding the nature of the binding interaction between PCSK9 and the LDLR is of critical importance. In this study, the ability of PCSK9 to compete with apoE3 N-terminal domain-containing reconstituted HDL for receptor binding was examined. Whereas full-length PCSK9 was an effective competitor, the N-terminal domain (composed of the prodomain and catalytic domain) was not. Surprisingly, the C-terminal domain (CT domain) of PCSK9 was able to compete. Using a direct binding interaction assay, we show that the PCSK9 CT domain bound to the LDLR in a calcium-dependent manner and that co-incubation with the prodomain and catalytic domain had no effect on this binding. To further characterize this interaction, two LDLR fragments, the classical ligand-binding domain (LBD) and the EGF precursor homology domain, were expressed in stably transfected HEK 293 cells and isolated. Binding assays showed that the PCSK9 CT domain bound to the LBD at pH 5.4. Thus, CT domain interaction with the LBD of the LDLR at endosomal pH constitutes a second step in the PCSK9-mediated LDLR binding that leads to receptor degradation.     

On the epidermal structure ofboleophthalmus andscartelaos mudskippers with reference to their adaptation to terrestrial life

The skin structures of 4 species of oxudercine gobies (3 species ofBoleophthalmus and 1 species ofScartelaos) were investigated in relation to the terrestrial exposure of these fishes. These species have similarities in both lifestyle and skin structure. The specializations for terrestrial life mainly include the presence of dermal bulges, a thick middle cell layer, and a vascularized epidermis. Moreover, mucous cells are distributed only on the epidermis where the capillaries are undeveloped. In all species, the dermal bulges are large on the head and dorsal body, which are most often exposed to the air, and push up a thin epidermis, forming so-called papillae. Capillaries are densely distributed on the apical area of each papilla. InBoleophthalmus, the middle cell layer is thicker, the bulges are larger and distributed over a greater part of the body, and the area of the skin surface having the papillae is larger than it is inScartelaos. These differences suggest that the contribution of the skin to respiration is comparatively large inBoleophthalmus species, reflecting their more frequent activities on mudflats relative to the activities of theScartelaos species, which prefer to stay in the water. Mucous cells are abundantly distributed on the epidermis surface between the papillae in all species. The separation of the capillaries and the mucous cells may be due to an impeding of gas exchange by the mucus.     

Identification of the Tslc1 gene,a mouse orthologue of the human tumor suppressor TSLC1 gene

We have recently identified the TSLC1 gene as a novel tumor suppressor in human non-small lung cancer on chromosome 11q23.2. TSLC1 encodes a membrane glycoprotein showing significant homology with immunoglobulin superfamily molecules. Here, we report the isolation of a mouse orthologous gene, Tslc1. The Tslc1 cDNA contains a single open reading frame of 1335 bp encoding a putative protein of 445 amino acids, and its expression was detected in all tissues examined. The Tslc1 gene is mapped on mouse chromosome 9, a synteny of human chromosome 11q, and is composed of ten exons, the exon-intron junctions being highly conserved between human and mouse. The predicted amino acids of mouse Tslc1 display 98% identity with that of human TSLC1. Furthermore, data base analysis indicates that the amino acid sequences corresponding to the cytoplasmic domain of Tslc1 are identical in five mammals and highly conserved in vertebrates, suggesting an important role of Tslc1 in normal cell-cell interaction.