Mammal disparity decreases during the Cretaceous angiosperm radiation

Fossil discoveries over the past 30 years have radically transformed traditional views of Mesozoic mammal evolution. In addition, recent research provides a more detailed account of the Cretaceous diversification of flowering plants. Here, we examine patterns of morphological disparity and functional morphology associated with diet in early mammals. Two analyses were performed: (i) an examination of diversity based on functional dental type rather than higher-level taxonomy, and (ii) a morphometric analysis of jaws, which made use of modern analogues, to assess changes in mammalian morphological and dietary disparity. Results demonstrate a decline in diversity of molar types during the mid-Cretaceous as abundances of triconodonts, symmetrodonts, docodonts and eupantotherians diminished. Multituberculates experience a turnover in functional molar types during the mid-Cretaceous and a shift towards plant-dominated diets during the late Late Cretaceous. Although therians undergo a taxonomic expansion coinciding with the angiosperm radiation, they display small body sizes and a low level of morphological disparity, suggesting an evolutionary shift favouring small insectivores. It is concluded that during the mid-Cretaceous, the period of rapid angiosperm radiation, mammals experienced both a decrease in morphological disparity and a functional shift in dietary morphology that were probably related to changing ecosystems.     

Senescence‐associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence‐associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence‐associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.     

Vocal divergence is concordant with genomic evidence for strong reproductive isolation in grasshopper mice (Onychomys)

Behavioral barriers to gene flow often evolve faster than intrinsic incompatibilities and can eliminate the opportunity for hybridization between interfertile species. While acoustic signal divergence is a common driver of premating isolation in birds and insects, its contribution to speciation in mammals is less studied. Here we characterize the incidence of, and potential barriers to, hybridization among three closely related species of grasshopper mice (genus Onychomys). All three species use long‐distance acoustic signals to attract and localize mates; Onychomys arenicola and Onychomys torridus are acoustically similar and morphologically cryptic whereas Onychomys leucogaster is larger and acoustically distinct. We used genotyping‐by‐sequencing (GBS) to test for evidence of introgression in 227 mice from allopatric and sympatric localities in the western United States and northern Mexico. We conducted laboratory mating trials for all species pairs to assess reproductive compatibility, and recorded vocalizations from O. arenicola and O. torridus in sympatry and allopatry to test for evidence of acoustic character displacement. Hybridization was rare in nature and, contrary to prior evidence for O. torridus/O. arenicola hybrids, only involved O. leucogaster and O. arenicola. In contrast, laboratory crosses between O. torridus and O. arenicola produced litters whereas O. leucogaster and O. arenicola crosses did not. Call fundamental frequency in O. torridus and O. arenicola was indistinguishable in allopatry but significantly differentiated in sympatry, a pattern consistent with reproductive character displacement. These results suggest that assortative mating based on a long‐distance signal is an important isolating mechanism between O. torridus and O. arenicola and highlight the importance of behavioral barriers in determining the permeability of species boundaries.     

Endothermy in African platypleurine cicadas: the influence of body size and habitat (Hemiptera: Cicadidae)

The platypleurine cicadas have a wide distribution across Africa and southern Asia. We investigate endothermy as a thermoregulatory strategy in 11 South African species from five genera, with comparisons to the lone ectothermic platypleurine we found, in an attempt to ascertain any influence that habitat and/or body size have on the expression of endothermy in the platypleurine cicadas. Field measurements of body temperature (T(b)) show that these animals regulate T(b) through endogenous heat production. Heat production in the laboratory elevated T(b) to the same range as in animals active in the field. Maximum T(b) measured during calling activity when there was no access to solar radiation ranged from 13.2 degrees to 22.3 degrees C above ambient temperature in the five species measured. The mean T(b) during activity without access to solar radiation did not differ from the mean T(b) during diurnal activity. All platypleurines exhibit a unique behavior for cicadas while warming endogenously, a temperature-dependent telescoping pulsation of the abdomen that probably functions in ventilation. Platypleurines generally call from trunks and branches within the canopy and appear to rely on endothermy even when the sun is available to elevate T(b), in contrast to the facultative endothermy exhibited by New World endothermic species. The two exceptions to this generalization we found within the platypleurines are Platypleura wahlbergi and Albanycada albigera, which were the smallest species studied. The small size of P. wahlbergi appears to have altered their thermoregulatory strategy to one of facultative endothermy, whereby they use the sun when it is available to facilitate increases in T(b). Albanycada albigera is the only ectothermic platypleurine we found. The habitat and host plant association of A. albigera appear to have influenced the choice of ectothermy as a thermoregulatory strategy, as the species possesses the metabolic machinery to elevate to the T(b) range observed in the endothermic species. Therefore, size and habitat appear to influence the expression of thermoregulatory strategies in African platypleurine cicadas.     

Defining the structure-function relationships of bluetongue virus helicase protein VP6

The VP6 protein of bluetongue virus possesses a number of activities, including nucleoside triphosphatase, RNA binding, and helicase activity (N. Stauber, J. Martinez-Costas, G. Sutton, K. Monastyrskaya, and P. Roy, J. Virol. 71:7220-7226, 1997). Although the enzymatic functions of the protein have been documented, a detailed structure and function study has not been completed and the oligomeric form of the protein in solution has not been described. In this study, we have characterized VP6 activity by creating site-directed mutations in the putative functional helicase domains. Mutant proteins were expressed at high levels in an insect cell by using recombinant baculoviruses purified and analyzed for ATP binding, ATP hydrolysis, and RNA unwinding activities. UV cross-linking experiments indicated that the lysine residue in the conserved motif AXXGXGK(110)V is directly involved in ATP binding, whereas mutant R(205)Q in the arginine-rich motif ER(205)XGRXXR bound ATP at a level comparable to that of the wild-type protein. The RNA binding activity was drastically altered in the R(205)Q mutant and was also affected in the K(110)N mutant. Helicase activity was altered in both mutants. The mutation E(157)N in the DEXX sequence, presumed to act as a Walker B motif, showed an intermediate activity, implying that this motif does not play a crucial role in VP6 function. Purified protein demonstrated stable oligomers with a ring-like morphology in the presence of nucleic acids similar to those shown by other helicases. Gel filtration chromatography, native gel electrophoresis, and glycerol gradient analysis clearly indicated multiple oligomeric forms of VP6.     

Two distinctly HLA-associated contiguous linear epitopes uniquely expressed within the islet antigen 2 molecule are major autoantibody epitopes of the diabetes-specific tyrosine phosphatase-like protein autoantigens

The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2beta are autoantigens of type 1 diabetes in humans. Autoantibodies are predominantly against IA-2, and IA-2-specific epitopes are major autoantibody targets. We used the close homology of IA-2 and IA-2beta to design chimeras and mutants to identify humoral IA-2-specific epitopes. Two major IA-2 epitopes that are absent from the related autoantigens IA-2beta and IA-2Delta 13 splice variant ICA512.bdc were found contiguous to each other within IA-2 juxtamembrane amino acids 611-620 (epitope JM1) and 621-630 (epitope JM2). JM1 and JM2 are recognized by sera from 67% of patients with IA-2 Abs, and relatives of patients with type 1 diabetes having Abs to either JM epitope had a >50% risk for developing type 1 diabetes within 6 years, even in the absence of diabetes-associated HLA genotypes. Remarkably, the presence of Abs to one of these two epitopes was mutually exclusive of the other; JM2 Abs and not JM1 Abs were found in relatives with HLA DR3/4, DR4/13, or DR1/4 genotypes; and the binding of autoantibodies to the JM2 epitope, but not the JM1 epitope, markedly affected proteolysis of IA-2. This is a unique demonstration of HLA-associated B cell responses to epitopes within a single autoantigen in humans and is consistent with modification of Ag processing by specific Ab-influencing peptide presentation by HLA molecules.     

A novel role for Gq alpha in alpha-thrombin-mediated mitogenic signalling pathways

alpha-Thrombin activates several G-proteins including members of the Gq, Gi, and G12/13 families, although the physiological importance of these proteins is still not completely understood. We specifically investigated the role of Gq alpha in modulating alpha-thrombin-induced mitogenesis. In Gqa1 cells, a stable cell line expressing reduced amounts of Gq alpha, concentrations of alpha-thrombin (1 NIH unit/ml), which induce cell cycle reentry and progression into S phase in wild-type IIC9 cells, do not stimulate phosphatidylinositol (PI) hydrolysis, the rapid early phase of ERK activity, and transit through G1 into S phase as quantified by cyclin-dependent kinase (CDK)4-cyclin D activity and [3H]thymidine incorporation. Interestingly, high concentrations of alpha-thrombin restore these activities and cell cycle progression into S phase. While, it is well documented that alpha-thrombin-induced sustained ERK activity mediates important responses for transit through G1 into S phase, the importance of the rapid, Gq-dependent phase as a prerequisite for alpha-thrombin-mediated mitogenesis has not been appreciated.