Vegetation changes and development of agriculture at „Kerfontaine“ (Sérent,Massif Armoricain,France)

As part of a new research programme, studies of peat bogs in Brittany are being carried out to trace the changes that have occurred in the course of time, and to determine the different regional stages related to the human activities of land clearance and agriculture. In this context, a palynological study of the Kerfontaine peat bog was undertaken to consider changes in local and regional vegetation dating from after about 7800 B.P. Local vegetation history from Neolithic times until the Middle Ages involved a succession of twelve pollen zones clearly related to variations in water level resulting from natural or anthropogenic influences. The dominant vegetation was alder carr, bog-myrtle mire and birch woods. Heath vegetation, which appeared at the end of the Iron Age, developed during the Gallo-Roman period, finally invading the entire bog in the Middle Ages. Regional vegetation history was characterised, among other things, by the presence of beech woods which developed after 3000 B.P. and then declined during the Middle Ages in conjunction with an increase of cultivation between the 8th and 11th centuries A.D., an indication of great activity during the Carolingian period. Human activity reached its peak around 1800 A.D. at the time of the first pine plantations.     

Aβ的外周清除与阿尔茨海默病

脑β-淀粉样蛋白(Amyloid-β,Aβ)沉积是阿尔茨海默病(Alzheimer's disease,AD)发病的核心问题。Aβ的沉积与其生成和清除失衡有关,尤其是清除障碍是导致Aβ沉积的主要原因。Aβ经RAGE,LRP1及P-gp介导跨血脑屏障(blood-brain barrier,BBB)转运至外周和经血管旁淋巴引流途径到达局部淋巴结是脑Aβ转运至外周进而发挥外周清除效应的两条途径,亦是Aβ清除的主要途径。RAGE,LRP1及P-gp表达异常、血管旁淋巴引流途径受阻及外周清除组织功能障碍均会影响Aβ外周清除,促进AD病程的进展。因此干预BBB上转运体的功能及血管旁淋巴引流通路,实现外周组织的清除效应,有利于Aβ外周清除。随着外周Aβ清除,脑Aβ则会源源不断转运至外周,发挥外周降解效应,即外周Sink效应。基于外周Sink效应,将AD治疗重点由促进Aβ脑内清除转为外周清除将是一条有效且相对安全的途径。     

The origins of bark-stripping by blue monkeys (Cercopithecus mitis): implications for management

Blue monkeys ( Cercopithecus mitis Wolf) on the Zomba Plateau, Malawi, damage exotic softwood plantations by bark-stripping. An ecological study was carried out to investigate the causes of this. The history of forestry practice on the Plateau reveals that, though bark-stripping did not start until 1976, plantation of exotic softwoods goes back to the beginning of the century. In the last 20 years the area of plantations close to the core of blue monkey habitat has increased substantially and some significant clearance of natural habitat has occurred. Bark-stripping is practised only by the groups which are in closest contact with the plantations. Its seasonality may be related to rainfall through sap quantity. There is no indication that the persistence of bark-stripping is the result of food shortage or agonistic encounters due to overcrowding. The most likely explanation for the genesis of bark-stripping is the encroachment of large blocks of plantations, combined with some clearance of natural habitat in 1973–74. The mechanism proposed for the initiation and maintenance of bark-stripping is a combination of temporary food shortage caused by travel through young plantations and a resultant acquired taste for sweet-tasting sap. Leaving areas of indigenous scrub adjacent to the core areas used by these primates and possibly the non-destruction of indigenous food trees within exotic plantations are suggested as ways of alleviating the problem in the future.     

Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics

Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided.     

Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843)

U-89843 has been shown to undergo biotransformation, both in vitro and in vivo, to form U-97924 as a major primary metabolite. U-89843 was found to be positive in an in vitro UDS mutagenesis screen conducted with primary rat hepatocytes in serum-free media. In contrast to in vitro results, no evidence of genetic toxicity of U-89843 was observed in rats in the in vivo/in vitro version of the UDS test with single oral doses up to 1400 mg/kg. The negative results may be related to more robust in vivo detoxification mechanisms or relatively lower exposure to reactive metabolites formed by bioactivation of U-89843 as compared to that observed in the serum-free in vitro hepatocyte test system. Further studies showed rat serum suppressed the in vitro metabolism of U-89843 as well as the formation of the corresponding hydroxylated metabolite, U-97924, the putative precursor of proposed reactive electrophilic metabolite. The measured in vivo systemic clearance of U-89843 (0.53 l/h/kg) in rats was about 1000-fold slower than the in vitro intrinsic clearance (606 l/h/kg) estimated by measuring the formation of U-97924 in rat liver microsomal incubations. Since U-89843 is extensively associated with serum proteins a poor extraction ratio into the liver may account for the slower biotransformation of U-89843 in vivo as compared to that exhibited in in vitro serum-free hepatocyte incubations. Addition of bovine serum albumin (1–40 mg/ml) to the in vitro UDS assay medium decreased the UDS mean net grains per nucleus response of U-89843. These results suggest that the effect of serum protein should be considered when comparing serum-free in vitro UDS and in vivo UDS results for highly serum protein bound compounds.     

Factors affecting the distribution, abundance and diversity of fishes of small, soft-substrata tidal pools within Moreton Bay, Australia

Clearance rates of Limnoperna fortunei (Bivalvia) were investigated in laboratory experiments using monocultures of the alga Chlorella vulgaris. Experimental conditions included two mollusc sizes (15 and 23 mm), and three water temperatures (15, 20 and 25 °C) covering the normal seasonal range in the lower Paraná river and Río de la Plata estuary. Filtration rates obtained were, for the larger mussels: 9.9, 13.1 and 17.7 ml mg tissue dry weight^–1 h^–1 at 15, 20 and 25 °C, respectively; and for the smaller ones: 17.7, 20.8 and 29.5 ml mg^–1 h^–1. Differences between sizes and between temperatures (except 15 vs. 20 °C) were statistically significant. In absolute terms larger animals have higher clearance rates, but as a function of body mass smaller individuals feed more actively. Within the range of experimental values used, filtration rates were positively associated with water temperature. These clearance rates (125–350 ml individual^–1 h^–1) are among the highest reported for suspension feeding bivalves, including the invasive species Dreissena polymorpha, D. bugensis and Corbicula fluminea. High filtration rates, associated with the very high densities of this mollusc in the Paraná watershed (up to over 200,000 ind m^–2) suggest that its environmental impact may be swiftly changing ecological conditions in the areas colonized.     

Short- and medium-chain fatty acids enhance the cell surface expression and transport capacity of the bile salt export pump (BSEP/ABCB11)

The reduced expression of the bile salt export pump (BSEP/ABCB11) at the canalicular membrane is associated with cholestasis-induced hepatotoxicity due to the accumulation of bile acids in hepatocytes. We previously reported that 4-phenylbutyrate (4PBA), an approved drug for urea cycle disorders, is a promising agent for intrahepatic cholestasis because it increases both the cell surface expression and the transport capacity of BSEP. In the present study, we searched for effective compounds other than 4PBA by focusing on short- and medium-chain fatty acids, which have similar characteristics to 4PBA such as their low-molecular-weight and a carboxyl group. In transcellular transport studies using Madin–Darby canine kidney (MDCK) II cells, all short- and medium-chain fatty acids tested except for formate, acetate, and hexanoic acid showed more potent effects on wild type (WT) BSEP-mediated [³H]taurocholate transport than did 4PBA. The increase in WT BSEP transport with butyrate and octanoic acid treatment correlated with an increase in its expression at the cell surface. Two PFIC2-type variants, E297G and D482G BSEP, were similarly affected with both compounds treatment. The prolonged half-life of cell surface-resident WT BSEP was responsible for this increased octanoic acid-stimulated transport, but not for that of butyrate. In conclusion, short- and medium-chain fatty acids have potent effects on the increase in WT and PFIC2-type BSEP-mediated transport in MDCK II cells. Although both short- and medium-chain fatty acids enhance the transport capacity of WT and PFIC2-type BSEP by inducing those expressions at the cell surface, the underlying mechanism seems to differ between fatty acids.     

The ecology and genetics of fitness in Chlamydomonas. XIII. Fitness of long-term sexual and asexual populations in benign environments

We measured the mean fitness of populations of Chlamydomonas reinhardtii maintained in the laboratory as obligately sexual or asexual populations for about 100 sexual cycles and about 1000 asexual generations. Sexuality (random gamete fusion followed by meiosis) is expected to reduce mutational load and increase mean fitness by combining deleterious mutations from different lines of descent. We found no evidence for this process of mutation clearance: the mean fitness of sexual populations did not exceed that of asexual populations, whether measured through competition or in pure culture. We found instead that sexual progeny suffer an immediate loss in fitness, and that sexual lines maintain genetic variance for fitness. We suggest that sexual populations at equilibrium with selection in a benign environment may be mixtures of several or many epistatic genotypes with nearly equal fitness. Recombination between these genotypes reduces mean fitness and creates genetic variance for fitness. This may provide fuel for continued selection should the environment change.     

The predominance of one of the SR-BI isoforms is associated with increased esterified cholesterol levels not apoptosis in mink testis

Scavenger receptor class B type I (SR-BI) contributes to HDL-mediated cellular cholesterol efflux and is a phagocytosis-inducing phospholipid phosphatidylserine receptor in rat Sertoli cells, whereas the spliced variant of the SR-B gene, SR-BII, is implicated in the efflux of free cholesterol in macrophages. This study aimed to assess whether spontaneous autoimmune orchitis (AIO), which causes impaired clearance of apoptotic germ cells and spermatogenic arrest, involves SR-BI, SR-BII, and/or cholesterol. The levels measured during development and the annual reproductive cycle in normal mink were compared with those in mink with spontaneous AIO. Time periods with lowest tubular esterified cholesterol (EC) levels showed maximal SR-BI and SR-BII levels, and the periods when one or the other SR-BI isoform predominated showed increased EC levels and spermatogenic arrest in normal mink seminiferous tubules. In tubules with AIO, the predominance of only one or the other SR-BI isoform was the reverse of that measured in normal tubules, and it was associated with an increase in EC levels but not with apoptosis levels. SR-BI and SR-BII levels were not correlated with serum testosterone levels. SR-BI mainly localized to the Leydig cell, germ cell, and Sertoli cell surface, where its distribution was stage-specific. SR-BII was principally intracellular. Tubules from testes with AIO showed a deregulation of cholesterol homeostasis and SR-BI expression but relatively unchanged apoptosis levels. These results suggest that the expression of both SR-BI isoforms is required for the maintenance of low EC levels and that the predominance of only one isoform is associated with the accumulation of EC but not with apoptosis in the tubules.