哺乳动物毛色调控机制及其适应性进化研究进展

哺乳动物类群呈现出的丰富毛色是引人注目的一种生物现象,是研究和理解哺乳动物适应性进化的理想模型之一。哺乳动物的毛色多态在躲避天敌、捕食、求偶及抵御紫外线等方面都具有重要作用。哺乳动物毛发的色素化过程由体内黑色素的数量、质量和分布状况所决定。黑色素的形成过程复杂,包括黑素细胞的分化、成熟,黑素体等细胞器的形态发生及黑色素在黑素细胞中的合成代谢和转运等过程;而在细胞色素化的每个阶段/时相都伴随着一些重要功能基因的参与,并通过基因之间的相互作用形成了黑色素生物代谢的复杂调控网络,进而形成不同的毛色有助于哺乳动物适应不同生存环境。对哺乳动物不同毛色形成机制的探究一直以来都是遗传学及进化生物学的重要研究领域和聚焦热点。本文综述了哺乳动物毛色色素化过程的主要分子机制以及毛色适应性进化的遗传基础,以期为哺乳动物毛色多态及其适应性进化的分子机制研究提供参考。     

The robustness of geometric morphometrics in testing the morphological equivalence hypothesis among cichlid species from East African Great Lakes

As part of an ongoing broader investigation into whether similar morphologies among cichlid species from East African Great Lakes are due to common ancestry or convergent evolution, we used geometric morphometrics to quantitatively test the hyphothesis that Lake Tanganyika's Tropheus spp. is morphologically similar to Lake Malawi's Pseudotropheus spp. and Labeotropheus fuelleborni . Landmark-based techniques were used to investigate body shape variation and the results revealed highly significant differences among these genera with the exception of L. fuelleborni vs. Pseudotropheus ( Tropheops ) spp. An ordination of all specimens along the first two canonical variate (CV) axes indicated clear interlake separation, especially along the CV I axis, whereby Tropheus moori showed a dorsoventral expansion of the mid body section with a steeper forehead relative to Lake Malawi species. Pseudotropheus ( Maylandia ) zebra was discriminated from the rest primarily on the basis of its terminally positioned gape, which differed from the inferior subterminal gape that was prevalent in the other species. Thus, the present study reveals a pattern of parallel evolution between L. fuelleborni and Pseudotropheus ( Tropheops ) spp., but does not support an interlake convergent evolution hypothesis. Contrary to previous researchers' assertions, these results emphasize the robustness of geometric morphometrics when testing morphological equivalence hypothesis among cichlid species.  © 2007 The Linnean Society of London, Biological Journal of the Linnean Society , 2007, 91 , 1–9.     

Two-stage functional mixed models for evaluating the effect of longitudinal covariate profiles on a scalar outcome

The Daily Hormone Study, a substudy of the Study of Women's Health Across the Nation (SWAN) consisting of more than 600 pre- and perimenopausal women, includes a scalar measure of total hip bone mineral density (BMD) together with repeated measures of creatinine-adjusted follicle stimulating hormone (FSH) assayed from daily urine samples collected over one menstrual cycle. It is of scientific interest to investigate the effect of the FSH time profile during a menstrual cycle on total hip BMD, adjusting for age and body mass index. The statistical analysis is challenged by several features of the data: (1) the covariate FSH is measured longitudinally and its effect on the scalar outcome BMD may be complex; (2) due to varying menstrual cycle lengths, subjects have unbalanced longitudinal measures of FSH; and (3) the longitudinal measures of FSH are subject to considerable among- and within-subject variations and measurement errors. We propose a measurement error partial functional linear model, where repeated measures of FSH are modeled using a functional mixed effects model and the effect of the FSH time profile on BMD is modeled using a partial functional linear model by treating the unobserved true subject-specific FSH time profile as a functional covariate. We develop a two-stage nonparametric regression calibration method using period smoothing splines. Using the connection between smoothing splines and mixed models, we show that a key feature of our approach is that estimation at both stages can be conveniently cast into a unified mixed model framework. A simple testing procedure for constant functional covariate effect is also proposed. The proposed methods are evaluated using simulation studies and applied to the SWAN data.     

Reduced expression of INK4a/ARF genes in stem-like sphere cells from rat sarcomas

The presence of cancer stem cells, in both hematopoietic and solid malignancies, has been recently linked to their pathogenesis. We aimed to identify the characteristics and stem-like properties of sphere-colony forming cells in rat osteosarcoma and malignant fibrous histiocytoma cell lines. The results showed that both cell lines possessed an ability to form spherical, clonally expanding colonies in anchorage-independent, serum-starved conditions in N2/1% methylcellulose medium. The sphere cells showed stem-like properties with the ability to self-renew, and expressed the stem cell-related STAT3 and Bmi1 genes. Interestingly, spheres from both sarcomas remarkably decreased the expression of INK4a/ARF locus genes, p16(INK4a) and p19(ARF), which could be related to the resistance against cell senescence and apoptosis. Spheres showed strong tumorigenicity with metastatic potential in vivo via the inoculation into syngeneic rats, suggesting the presence of these populations might contribute to the tumor development such as metastasis via the resistance to apoptotic stimuli.     

Effects of organic matter availability on the life history and production of a top vertebrate predator (Plethodontidae: Gyrinophilus palleucus) in two cave streams

1. Surface ecosystems provide the primary source of organic matter to many cave communities. Variation in the strength of connectivity to the surface suggests that some caves may be more resource‐limited than others. To test this, we examined diet, prey availability and production of an obligate cave salamander Gyrinophilus palleucus (Plethodontidae), a top predator, in two south‐eastern U.S.A. caves with different levels of organic matter (Tony Sinks cave, 165 g AFDM m^?2; Bluff River cave, 62 g AFDM m^?2). 2. We quantified density, biomass, growth rate, production and diet of G. palleucus monthly for 21 months. Diet composition, differences in prey communities and seasonal patterns in prey consumption were also analysed. 3. Salamander density, biomass and secondary production were significantly greater in the high organic matter cave (0.10 m^?2, 0.18 g AFDM m^?2, 0.12 g AFDM m^?2 year^?1) than in the low organic matter cave (0.03 m^?2, 0.03 g AFDM m^?2, 0.01 g AFDM m^?2 year^?1). Although growth rates were not statistically different between the two cave salamander populations, low recaptures probably influenced this result. 4. Isopoda prey were the major contributor to salamander production in the high organic matter cave (69%). In the low organic matter cave, production was provided by isopods (41%) and oligochaetes (20%). The lower number of prey taxa contributing to salamander production in the high organic matter cave suggests the ability to forage more selectively. 5. The differences in foraging strategy, density, biomass and secondary production were probably related to differences in the strength of surface connectivity, which controls organic matter supply. Links between basal resource level and top predator performance show the importance of bottom‐up limitation in the food webs of caves and other detritus‐based ecosystems.     

Molecular models of the Mojave rattlesnake (Crotalus scutulatus scutulatus) venom metalloproteinases reveal a structural basis for differences in hemorrhagic activities

Rattlesnake venom can differ in composition and in metalloproteinase-associated activities. The molecular basis for this intra-species variation in Crotalus scutulatus scutulatus (Mojave rattlesnake) remains an enigma. To understand the molecular basis for intra-species variation of metalloproteinase-associated activities, we modeled the three-dimensional structures of four metalloproteinases based on the amino acid sequence of four variations of the proteinase domain of the C. s. scutulatus metalloproteinase gene (GP1, GP2, GP3, and GP4). For comparative purposes, we modeled the atrolysin metalloproteinases of C. atrox as well. All molecular models shared the same topology. While the atrolysin metalloproteinase molecular models contained highly conserved substrate binding sites, the Mojave rattlesnake metalloproteinases showed higher structural divergence when superimposed onto each other. The highest structural divergence among the four C. s. scutulatus molecular models was located at the northern cleft wall and the S’₁-pocket of the substrate binding site, molecular regions that modulate substrate selectivity. Molecular dynamics and field potential maps for each C. s. scutulatus metalloproteinase model demonstrated that the non-hemorrhagic metalloproteinases (GP2 and GP3) contain highly basic molecular and field potential surfaces while the hemorrhagic metalloproteinases GP1 and atrolysin C showed extensive acidic field potential maps and shallow but less dynamic active site pockets. Hence, differences in the spatial arrangement of the northern cleft wall, the S’₁-pocket, and the physico-chemical environment surrounding the catalytic site contribute to differences in metalloproteinase activities in the Mojave rattlesnake. Our results provide a structural basis for variation of metalloproteinase-associated activities in the rattlesnake venom of the Mojave rattlesnake.     

Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores preexisting T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.     

Formulation Optimization of an Indomethacin-Containing Photocrosslinked Polyacrylic Acid Hydrogel as an Anti-inflammatory Patch

Photocrosslinked polyacrylic acid hydrogel, made from polyacrylic acid (PAA) modified with 2-hydroxyethyl methacrylate (HEMA), is a promising candidate adhesive for dermatological patches. In this study, we investigated the further availability of hydrogel as an adhesive for dermatological patches using a hydrogel containing indomethacin (IDM) as a model anti-inflammatory patch. From an orthogonal experimental study, we clarified the relationships between formulation factors and characteristics of model formulation. Formulations with a lower degree of swelling were prepared by increasing the degree of HEMA modification and the addition of Tween 80. Apparent permeation rate was increased by addition of l-menthol and Tween 80. A tendency for higher HEMA modification to be accompanied by the prolongation of the lag time of IDM was observed. To obtain an applicable anti-inflammatory patch, we conducted a formulation optimization study using a novel optimization method, a response-surface method incorporating multivariate spline interpolation (RSM-S). Consequently, a highly functional anti-inflammatory patch in terms of its adhesive properties and bioavailability was successfully obtained. Since a wide range of functions can be fully controlled by manipulating the formulation factors, photocrosslinked polyacrylic acid hydrogel is an attractive candidate adhesive for dermatological patches.