The new biology of ageing

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.     

NP7 protects from cell death induced by oxidative stress in neuronal and glial midbrain cultures from parkin null mice

Parkin mutations produce Parkinson’s disease (PD) in humans and nigrostriatal dopamine lesions related to increased free radicals in mice. We examined the effects of NP7, a synthetic, marine derived, free radical scavenger which enters the brain, on H₂O₂ toxicity in cultured neurons and glia from wild-type (WT) and parkin null mice (PK-KO).NP7, 5-10 μM, prevented the H₂O₂ induced apoptosis and necrosis of midbrain neuronal and glial cultures from WT and PK-KO mice. NP7 suppressed microglial activation and the H₂O₂ induced drop-out of dopamine neurons_. Furthermore, NP7 prevented the increased phosphorylation of ERK and AKT induced by H₂O₂. NP7 may be a promising neuroprotector against oxidative stress in PD.     

溶血磷脂酸在皮肤损伤疾病中的作用及其分子机制

皮肤作为人体最大器官覆盖于全身,能阻挡有害物质的侵入,保护人体内环境稳态,参与人体代谢过程。皮肤损伤、炎症和纤维化等,都会导致皮肤屏障功能的减退,影响正常的生命活动。溶血磷脂酸(lysophosphatidic acid,LPA)是十分活跃的磷脂信号分子,参与多种生理和病理生理过程。LPA是维持体内平衡所必需的生物活性脂质介质,在皮肤中通过不同的信号通路发挥多功能磷脂信使作用。本文综述了皮肤中溶血磷脂酸受体(lysophosphatidic acid receptor,LPA1-6)及其细胞信号通路的作用及机制,综述了LPA在皮肤创面愈合、皮肤瘢痕、皮肤黑色素瘤、硬皮病、皮肤瘙痒、过敏性皮炎、皮肤屏障、皮肤疼痛,皮肤毛发生长中的作用及分子机制,有助于了解LPA在皮肤中的生理和病理生理作用。深入研究LPA的作用机制将有助于挖掘其在皮肤治疗中的作用,开发以LPA为靶点的药物。     

Striking convergence in the mouthpart evolution of stream-living algae grazers

This scanning-electron microscopic study demonstrates the convergent evolution of the mouthparts of various herbivorous stream animals (insects from different orders, an isopod, snails, fish, and a tadpole) feeding on epilithic algal pastures. This food source is rich but is often difficult to harvest. Nevertheless, a large number of species can live on it because they have evolved highly specialized mouthparts. There are four functional problems that an algae grazer has to solve: the algae must be removed from the stone, they have to be collected and crushed, and a current shield is needed to prevent the water flow sweeping away the food. Among the 30 algae grazers examined in this study, a limited number of morphological solutions have been found for each of these adaptational problems. There are multiple evolutionary pathways for mouthpart adaptation and even closely related species have often evolved different types of tools for the same function. This refects the existence of a certain amount of evolutionary scope. Such freedom of evolution is present, however, only at the beginning of the adaptiogenesis of an algae grazer. Once one of the evolutionary pathways is taken, further improvement of the mouthparts is possible only by the refinement of the ‘chosen’ type of tools. The consequence of this is that a large number of astonishing convergences have occurred in algae grazers that have independently trodden the same evolutionary pathway.     

Are the carbon costs of seed production related to the quantitative and qualitative performance? An appraisal for legumes and other crops

In the past great efforts have been made to gain a thorough understanding of the processes involved in carbon fixation but the fate of the acquired carbon has been somewhat neglected, although this aspect is crucial for improving yield performance without diminishing the quality of the harvested organs. To contribute to the crucial debate on that topic the aim of the present study was to propose some unbiased components concerning in particular grain legumes: ‘Is there any antagonism between high yield and increased nutritional quality, with a focus on protein content?’ An original approach has been used to study the impact of the modification of seed composition on the crop production, which combines theoretical calculations of energetic cost and field yield data. When applied to a wide range of species with varying seed composition, a plurispecific negative relationship between the theoretical carbon costs of seed production and the observed yields was demonstrated. The high-throughput of genetic markers could result in large-scale screening of seed quality parameters and such studies, while evaluating the impact of seed composition on crop yield, could also be used to provide data to forecast the economic impact of a new line with an original composition compared with its economically enhanced value.     

Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat

Summary The lumen of the small intestine in anesthetized rats was recirculated with 50 ml perfusion fluid containing normal salts, 25mm glucose and low concentrations of hydrophilic solutes ranging in size from creatinine (mol wt 113) to Inulin (mol wt 5500). Ferrocyanide, a nontoxic, quadrupally charged anion was not absorbed; it could therefore be used as an osmotically active solute with reflection coefficient of 1.0 to adjust rates of fluid absorption,J _v , and to measure the coefficient of osmotic flow,L _p . The clearances from the perfusion fluid of all other test solutes were approximately proportional toJ _v . FromL _p and rates of clearances as a function ofJ _v and molecular size we estimate (a) the fraction of fluid absorption which passes paracellularly (approx. 50%), (b) coefficients of solvent drag of various solutes within intercellular junctions, (c) the equivalent pore radius of intercellular junctions (50 Å) and their cross sectional area per unit path length (4.3 cm per cm length of intestine). Glucose absorption also varied as a function ofJ _v . From this relationship and the clearances of inert markers we calculate the rate of active transport of glucose, the amount of glucose carried paracellularly by solvent drag or back-diffusion at any givenJ _v and luminal glucose concentration and the concentration of glucose in the absorbate. The results indicate that solvent drag through paracellular channels is the principal route for intestinal transport of glucose or amino acids at physiological rates of fluid absorption and concentration. In the absence of luminal glucose the rate of fluid absorption and the clearances of all inert hydrophilic solutes were greatly reduced. It is proposed that Na-coupled transport of organic solutes from lumen to intercellular spaces provides the principal osmotic force for fluid absorption and triggers widening of intercellular junctions, thus promoting bulk absorption of nutrients by solvent drag. Further evidence for regulation of channel width is provided in accompanying papers on changes in electrical impedance and ultrastructure of junctions during Na-coupled solute transport.     

The effect of glucose-6-phosphate isomerase genotype onin vitro specific activity andin vivo flux inMytilus edulis

Four samples of the musselMytilus edulis were taken between 1984 and 1987 from Stony Brook, New York, and used to study the glucose-6-phosphate isomerase (GPI) polymorphism in this species.In vitro specific activity andin vivo flux measured in the same animals were found to be significantly correlated. A significant effect of GPI genotype on flux was observed in one of the samples; overall, significant evidence of effect of genotype on enzyme activity was also obtained. GPI activities of common genotypes tend to deviate less from the population mean than those of rare (frequency less than 5%) genotypes. This suggests the possibility that rare GPI genotypes are rare as a consequence of having biochemical properties that deviate from an optimum level and, therefore, having a lower fitness. In support of this hypothesis, we found in one of our samples that shell length is a concave function of GPI activity with an intermediate optimum activity level. The financial support provided to P.J.N.S. by the Luso-American Educational Commission (Fulbright Program), the Instituto Nacional de Investigacao Científica (Portugal), and the Faculdade de Ciências da Universidade de Lisboa during several stages of this research is gratefully acknowledged. Financial support from the Ministerio de Educatión y Ciencia (Spain) in the form of a postdoctoral Fulbright/MEC fellowship to M.S. is also gratefully acknowledged. Research was supported by National Science Foundation Grant BSR-8415060 to R.K.K. This is contribution No. 736 from the Program in Ecology and Evolution, State University of New York at Stony Brook. On leave from Departamento de Biologia Vegetal, Faculdade de Ciências, Universidade de Lisboa, Campo Grande C2, Lisboa, Portugal.     

Genetic variation and distances of five Italian native sheep breeds

Genetic distances among five of the most important Italian native sheep breeds were estimated by using gene frequencies of four blood group and seven blood protein loci and by three different computing methods. The values of the three distance matrices were highly correlated. Genetic distances were found within the range values reported in the literature for local breeds. Shorter distances fitted the historical evidence of migrations.     

Flavonoid aglycones from the leaf surfaces of someLabiatae species

The distribution of excreted flavonoid aglycones within the familyLabiatae was studied and differences were found, especially in the A-ring substitution patterns. Thus, 5,7-dihydroxy-6-methoxyflavones with substituted B-rings are characteristic of species ofSalvia (sect.Salvia),Rosmarinus andOcimum; 5,7-dihydroxy-6,8-dimethoxyflavones occur only inOcimum and 5,6-dihydroxy-7,8-dimethoxyflavones inThymus and related species. Members of the two subfamiliesLamioideae andNepetoideae produce exudate flavonoids, but some genera are devoid of these compounds. There is a correlation between the habitat where the plant grows and production of these compounds, the species from (semi-)arid habitats being those which generally accumulate external flavonoids.     

Mechanisms of fusicoccin action: A dominant role for secondary transport in a higher-plant cell

Fusicoccin (FC) is commonly thought to promote electrogenic H⁺ extrusion through its action on the H⁺-ATPase of the plant plasma membrane. Nonetheless, essential support from rigorous electrophysiological analysis has remained largely absent. The present investigation surveys the effects of FC on the charge transport properties at the membrane of a higher-plant cell — stomatal guard cells of Vicia faba L. — for which the electrical geometry is defined, and from which the voltage-dependent kinetic characteristic for the pump has been identified. Current-voltage (I-V) relations of the guard cells were determined before and during treatments with FC, and during brief exposures to NaCN plus salicylhydroxamic acid. Responses of the pump and of the ensemble of secondary transport processes were identified in the whole-membrane conductance-voltage relations and in the difference-current-voltage (dI-V) characteristic for the pump. In 0.1 mM K⁺, exposure to 10 M FC shifted guard-cell potentials negative by 29–61 mV. Current-and conductance-voltage profiles indicated limited changes in the pump I-V characteristic, an observation which was confirmed through explicit kinetic analysis of pump dI-V relations. However, the voltage response was accompanied by a 1.5-to 2.6-fold fall in membrane conductance. These results challenge conventional views of fusicoccin action by ascribing the electrical responses to reduced current passage through secondary transport pathways as well as to enhanced electrogenic ion pumping.Abbreviations and symbols Hepes 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - SHAM salicylhydroxamic acid - FC fusicoccin - V _m free-running membrane potential - G _m membrane slope conductance at V _m - (d)I-V (difference) current-voltage (relation) - G-V slope conductance-voltage (relation)