The aged: medical and social aspects

Physical health is affected by physiological aging that impacts on all tissues and organs, notably sensorial systems (hearing, sight), the locomotory and the immunological systems (lowering of resistance to infections). There is an increase with age in the incidence of many cancers (particularly breast, prostate, and colon cancers) and cardiovascular diseases. Regular check-ups are useful in order to take appropriate measures in time. It is important that people maintain regular physical activity and a balanced diet even up to an advanced age and the elderly must learn to adapt themselves to the ever-changing abilities of their organism. It is possible to slow down the aging process through good hygiene and often to maintain autonomy until the end of life. Mental health is threatened by impairment of mental functions, depressive tendencies, and the risk of senile dementia that cannot be foreseen or avoided. It appears that keeping intellectually active and having a good level of education impact favorably on mental aging. Social health depends, for a large part, on the way society accepts and treats the elderly. They must be kept integrated into society and allowed to live at home for as long as possible. Any measures of rejection, discrimination, and exclusion should be opposed. The dignity of the elderly must be respected and activities giving them a feeling of usefulness should be encouraged. It is important to help families who care for their parents at home, to develop and evaluate healthcare networks, and encourage medical professionals and social services to work together. The change in the demographic structure of France is a considerable phenomenon requiring a long-term strategy and not only superficial and cosmetic measures.     

A paradigm for therapy-induced microenvironmental changes in solid tumors leading to drug resistance

Intrinsic alterations in the tumor microenvironment are known to contribute to various forms of drug resistance. For example, tumor hypoxia, due to abnormal or sluggish blood flow within areas of solid tumors, can result in both microenvironment-mediated radiation and chemotherapeutic drug resistance. In contrast, acquired resistance to chemotherapy is generally considered to be the result of the gradual selection of mutant subpopulations having genetic mutations and biochemical alterations responsible for the resistant phenotype. Here we present a paradigm for therapyinduced microenvironment-mediated acquired drug resistance. It is based on the results showing that tumor cells appear to be heterogeneous in their relative dependence on adjacent tumor-associated vasculature for survival. Some tumor cells are highly vessel dependent, whereas some are significantly less so, and thus can survive in more hypoxic regions of tumors, distal from such tumor vessels. Hence, it is possible that variant tumor cells that are less vessel dependent may therefore be selected for over time by successful antiangiogenic drug therapies. This results in loss of response or attenuated responses to the therapy. Preliminary evidence is summarized in support of this hypothesis, using paired human colon cancer (HCT116) cell lines that contain two copies of either the wild-type or the disrupted p53 tumor suppressor gene. The mutant cells were found to be less responsive to antiangiogenic therapy, compared to the wild-type cells, and could be progressively selected for in mixed cell populations. Because p53 inactivation can lead to resistance to hypoxia-mediated apoptosis, the results suggest that a protracted and successful antiangiogenic therapy may create more hypoxic tumor microenvironments, thereby creating the necessary conditions to accelerate the selection of mutant tumor cells that are more adept in surviving and growing in such environments. As such, consideration might be given to the combined use of bioreductive hypoxic cell cytotoxic drugs and angiogenesis inhibitors to prolong the efficacy of antiangiogenic therapeutics.     

Linear correlation between thermal stability and folding kinetics of lysozyme

We have studied the refolding and thermal denaturation of hen egg white lysozyme in a wide range of pH values (from 1.5 to 9.4) using stopped-flow circular dichroism (CD) and differential scanning calorimetry (DSC). A linear correlation was found between the thermal denaturation temperature (T(m)) and the logarithm of the refolding rate of the slow folding phase of hen egg white lysozyme (lnk(2)).     

Correlative coherence analysis: variation from intrinsic and extrinsic sources in competing populations

The concept of the correlation between two signals is generalized to the correlative coherence of a set of n signals by introducing a Shannon-Weaver-type measure of the entropy of the normalized eigenvalues of the n-dimensional correlation matrix associated with the set of signals. Properties of this measure are stated for canonical cases. The measure is then used to evaluate which subsets of a particular set of n signals are more or less coherent. This set of signals comprises extrinsic, stochastic resource inputs and the population trajectories obtained from simulations of a discrete time model of competing biological populations driven by these resource inputs. The analysis reveals that, at low levels of competition, the correlative coherence of the combined system of intrinsic population and extrinsic resource variables is relatively low, but increases with increasing variation in the resources. Further, at intermediate and high competition levels, the correlative coherence depends more strongly on competition than entrainment of stochasticity in the extrinsic resource variables. Density dependence has the effect of amplifying variation in noise only when this variation is relatively large. Also, chaotic systems appear to be entrained by sufficiently noisy environmental inputs.     

Stoichiometry of transjunctional voltage-gating polarity reversal by a negative charge substitution in the amino terminus of a connexin32 chimera

Gap junctions are intercellular channels formed by the serial, head to head arrangement of two hemichannels. Each hemichannel is an oligomer of six protein subunits, which in vertebrates are encoded by the connexin gene family. All intercellular channels formed by connexins are sensitive to the relative difference in the membrane potential between coupled cells, the transjunctional voltage (Vj), and gate by the separate action of their component hemichannels (Harris, A.L., D.C. Spray, and M.V. Bennett. 1981. J. Gen. Physiol. 77:95-117). We reported previously that the polarity of Vj dependence is opposite for hemichannels formed by two closely related connexins, Cx32 and Cx26, when they are paired to form intercellular channels (Verselis, V.K., C.S. Ginter, and T.A. Bargiello. 1994. Nature. 368:348-351). The opposite gating polarity is due to a difference in the charge of the second amino acid. Negative charge substitutions of the neutral asparagine residue present in wild-type Cx32 (Cx32N2E or Cx32N2D) reverse the gating polarity of Cx32 hemichannels from closure at negative Vj to closure at positive Vj. In this paper, we further examine the mechanism of polarity reversal by determining the gating polarity of a chimeric connexin, in which the first extracellular loop (E1) of Cx32 is replaced with that of Cx43 (Cx43E1). The resulting chimera, Cx32*Cx43E1, forms conductive hemichannels when expressed in single Xenopus oocytes and intercellular channels in pairs of oocytes (Pfahnl, A., X.W. Zhou, R. Werner, and G. Dahl. 1997. Pflügers Arch. 433:733-779). We demonstrate that the polarity of Vj dependence of Cx32*Cx43E1 hemichannels in intercellular pairings is the same as that of wild-type Cx32 hemichannels and is reversed by the N2E substitution. In records of single intercellular channels, Vj dependence is characterized by gating transitions between fully open and subconductance levels. Comparable transitions are observed in Cx32*Cx43E1 conductive hemichannels at negative membrane potentials and the polarity of these transitions is reversed by the N2E substitution. We conclude that the mechanism of Vj dependence of intercellular channels is conserved in conductive hemichannels and term the process Vj gating. Heteromeric conductive hemichannels comprised of Cx32*Cx43E1 and Cx32N2E*Cx43E1 subunits display bipolar Vj gating, closing to substates at both positive and negative membrane potentials. The number of bipolar hemichannels observed in cells expressing mixtures of the two connexin subunits coincides with the number of hemichannels that are expected to contain a single oppositely charged subunit. We conclude that the movement of the voltage sensor in a single connexin subunit is sufficient to initiate Vj gating. We further suggest that Vj gating results from conformational changes in individual connexin subunits rather than by a concerted change in the conformation of all six subunits.     

Chronic toxicity of rare-earth elements on human beings

Blood analyses for rare-earth element (REE)-high background regions in South Jiangxi show that the population averages of many of the biochemical indices deviate markedly from normal values in the normal region. These deviations are thought to be caused by prolonged intake of REE through food chains in view of that the toxicity of other harmful metals such as Pb and Cd can be neglected because of their insignificant amounts in the environment. In comparison with the normal region, blood biochemical indices abnormal in the REE-high regions are manifested as low total serum protein (TSP), albumin, β-globulin, glutamic pyruvic transitanase, serium triglycerides, and immunoglobulin, but high cholesterol. These deviations may be related to the REE concentration and composition of food chains, and are sex dependent. Certain blood indices (such as TSP) of different age groups in the LREE-high region indicate that the influence of REE on males is a one-way irreversible process, whereas females show a strong ability of restoration.     

The effect of local change in habitat quality on populations of migratory species

1. Habitat deterioration is a major problem world-wide as a result of processes such as change in land use, introduced species, human disturbance and exploitation of food supplies. Many studies have shown that habitat change can have considerable effect on the numbers of individuals using a site. For migratory species, however, the consequences for the total population cannot be deduced from local studies.
2. For a migratory species, the change in total population size Δ N , as a consequence of habitat change in the wintering area, can be calculated from Δ N  =  LM γ d '/( b ' +  d '), where γ is the expected proportional change in the number of birds using a site as a result of the habitat change, L is the area affected, M is the density of individuals using the site prior to habitat change, b ' is the strength of the per capita density-dependent breeding output, and d ' is the strength of the per capita density-dependent winter mortality. Similarly the consequences of habitat change in the breeding area can be calculated from Δ N  =  LM γ b '/( b ' +  d ').
3. The same approach can be used for predicting the consequences of improvements in habitat quality.
4. A worked example is given to illustrate how this approach could be used to predict the consequences for the total population of changes in the food supply of oystercatchers within one estuary.
5. There is a need for more measures of γ, the expected proportional change in the number of birds using a site as a result of various forms of habitat deterioration, and the strengths of density dependence.     

Selective Increases in Phosphoinositide Signaling Activity and G Protein Levels in Postmortem Brain from Subjects with Schizophrenia or Alcohol Dependence

Abstract: Comparisons of the activity of the G protein-mediated phosphoinositide signal transduction system and of G protein levels were made in two regions of frontal cortex from eight schizophrenic, alcohol-dependent, and control subjects. G protein-mediated phosphoinositide hydrolysis was measured by stimulating cortical membranes incubated with [³H]phosphatidylinositol with 0.3–10 µM guanosine 5′-O-(3-thio)triphosphate (GTPγS). In frontal cortex areas 8/9, GTPγS-induced phosphoinositide hydrolysis was 50% greater in schizophrenic than control or alcohol-dependent subjects, whereas there were no differences among these groups of subjects in the response to GTPγS in frontal cortex area 10. Agonists for dopaminergic, cholinergic, purinergic, serotonergic, histaminergic, and glutamatergic receptors coupled to the phosphoinositide signaling system increased [³H]phosphatidylinositol hydrolysis in a GTPγS-dependent manner. Responses to most agonists were similar in all three subject groups in both cortical regions, with the largest difference being a 40% greater response to dopaminergic receptor stimulation in frontal cortex 8/9 from schizophrenic subjects. Measurements of the levels of phospholipase C-β, and of α-subunits of G_q, G_o, G_i1, G_i2, and G_s, made by immunoblot analyses revealed no differences among the groups of subjects except for increased Gα_o in schizophrenic subjects and increased Gα_o and Gα_i1 in alcohol-dependent subjects. These results demonstrate that schizophrenia is associated with increased activity of the phosphoinositide signal transduction system and increased levels of Gα_o, whereas the phosphoinositide system was unaltered in alcohol dependence, but Gα_o and Gα_i1 were increased.     

Structural perturbation of α-crystallin and its chaperone-like activity

α-Crystallin is a multimeric lenticular protein that has recently been shown to be expressed in several non-lenticular tissues as well. It is shown to prevent aggregation of non-native proteins as a molecular chaperone. By using a non-thermal aggregation model, we could show that this process is temperature-dependent. We investigated the chaperone-like activity of α-crystallin towards photo-induced aggregation of γ-crystallin, aggregation of insulin and on the refolding induced aggregation of β- and γ-crystallins. We observed that α-crystallin could prevent photo-aggregation of γ-crystallin and this chaperone-like activity of α-crystallin is enhanced several fold at temperatures above 30°C. This enhancement parallels the exposure of its hydrophobic surfaces as a function of temperature, probed using hydrophobic fluorescent probes such as pyrene and 8-anilinonaphthalene-1-sulfonate. We, therefore, concluded that α-crystallin prevents the aggregation of other proteins by providing appropriately placed hydrophobic surfaces; a structural transition above 30°C involving enhanced or re-organized hydrophobic surfaces of α-crystallin is important for its chaperone-like activity. We also addressed the issue of conformational aspects of target proteins and found that their aggregation prone molten globule states bind to α-crystallin. We trace these developments and discuss some new lines that suggest the role of tertiary structural aspects in the chaperone process.     

风和风沙流对不同固沙植物生理状况的影响

在野外风洞条件下,对风和风沙流影响固沙植物的生理状况进行了研究。结果表明：风和风沙流对不同植物的影响不同,风对结皮和苔藓的影响在于吹蚀和干燥,对草本和灌木的影响主要是：１．通过迫使气孔关闭、降低叶温和胞间ＣＯ２浓度来抑制光合作用;２．加强蒸腾作用,减小水分利用率;３．降低叶片水势和土壤含水量,从而加强干燥作用。而风沙流对结皮和苔藓的影响主要在于剥蚀和堆积,对草本和灌木的影响主要是机械损伤作用,对光合和水分利用的影响将更加剧烈。不同类型植物对两种胁迫的适应程度不同。