Error-prone replication for better or worse

Precise genome duplication requires accurate copying by DNA polymerases and the elimination of occasional mistakes by proofreading exonucleases and mismatch repair enzymes. The commonly held belief that 'if something is worth doing, then it's worth doing well' normally applies to DNA replication and repair, however, there are exceptions. This review describes elements that are crucial to cell fitness, evolution and survival in the recently discovered error-prone DNA polymerases. Large numbers of errant DNA polymerases, spanning microorganisms to humans, are used to rescue stalled replication forks by copying damaged DNA and even undamaged DNA to generate 'purposeful' mutations that generate genetic diversity in times of stress. Here we focus on low-fidelity polymerases from bacteria, comparing Escherichia coli, archeabacteria and those most recently discovered in Gram-positive Bacilli, Streptococcus, pathogenic Mycobacterium and intein-containing cyanobacteria.     

Autophagy: for better or for worse

Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.     

Biofuels – for better or worse?

The present world population is largely fed by ‘industrialised agriculture’. This, in turn, depends on massive inputs of fossil fuels. While this energy expenditure is inescapable, it is an expensive way of ‘converting oil into potatoes'. Arguably, in view of global climate change, ever increasing population, ever increasing oil prices, ever diminishing availability of water and arable land, this is not sustainable. Despite the fact that biofuels inevitably compete for resources that might otherwise be used to grow, store and distribute food, they are frequently held to be desirable and feasible ‘green’ substitutes for fossil fuels and even that they spare carbon emissions to the atmosphere. This article challenges the absurdity of such ‘retro-agriculture’ (i.e. except in a few local circumstances) incurring yet more energy expenditure. It seeks to illustrate the misinformation on which some of the advocacy of biofuels has been based.     

Osteoporosis: combination therapy for better or worse

Osteoporosis is a condition that is associated with an increased susceptibility for fractures. In the past few years, several drugs have become available that can reduce the incidence of fractures in patients with osteoporosis. Since these drugs work through different cellular mechanisms, combining agents of different classes may have an additive or multiplicative effect on fracture risk reduction. Combination treatments that have been evaluated in clinical trials include bisphosphonates with estrogen, raloxifene or PTH/ bisphosphonates and PTH/ estrogen. In general, these trials have shown increases in bone mineral density over that observed with each agent alone. However, whether anti-fracture efficacy is improved, or worsened remains to be established. This article reviews the combination treatments that have been evaluated in clinical trials, with a discussion of the potential benefits and risks that those treatments entail. Integrating safety and cost issues will eventually determine whether those combinations will become the standard of care.     

How cells change their phenotype

Recent attention has focused on the remarkable ability of adult stem cells to produce differentiated cells from embryologically unrelated tissues. This phenomenon is an example of metaplasia and shows that embryological commitments can be reversed or erased under certain circumstances. In some cases, even fully differentiated cells can change their phenotype (transdifferentiation). This review examines recently discovered cases of metaplasia, and speculates on the potential molecular and cellular mechanisms that underlie the switches, and their significance to developmental biology and medicine.     

Fluid shear stress and the vascular endothelium: for better and for worse

As blood flows, the vascular wall is constantly subjected to physical forces, which regulate important physiological blood vessel responses, as well as being implicated in the development of arterial wall pathologies. Changes in blood flow, thus generating altered hemodynamic forces are responsible for acute vessel tone regulation, the development of blood vessel structure during embryogenesis and early growth, as well as chronic remodeling and generation of adult blood vessels. The complex interaction of biomechanical forces, and more specifically shear stress, derived by the flow of blood and the vascular endothelium raise many yet to be answered questions:How are mechanical forces transduced by endothelial cells into a biological response, and is there a "shear stress receptor"?Are "mechanical receptors" and the final signaling pathways they evoke similar to other stimulus-response transduction systems?How do vascular endothelial cells differ in their response to physiological or pathological shear stresses?Can shear stress receptors or shear stress responsive genes serve as novel targets for the design of diagnostic and therapeutic modalities for cardiovascular pathologies?The current review attempts to bring together recent findings on the in vivo and in vitro responses of the vascular endothelium to shear stress and to address some of the questions raised above.     

For better or for worse: complexins regulate SNARE function and vesicle fusion

In contrast to constitutive secretion, SNARE-mediated synaptic vesicle fusion is controlled by multiple regulatory proteins, which determine the Ca²⁺ sensitivity of the vesicle fusion process and the speed of excitation–secretion coupling. Complexins are among the best characterized SNARE regulators known to date. They operate by binding to trimeric SNARE complexes consisting of the vesicle protein synaptobrevin and the plasma membrane proteins syntaxin and SNAP-25. The question as to whether complexins facilitate or inhibit SNARE-mediated fusion processes is currently a matter of significant controversy. This is mainly because of the fact that biochemical experiments in vitro and studies on vertebrate complexins in vivo have yielded apparently contradictory results. In this review, I provide a summary of available data on the role of complexins in SNARE-mediated vesicle fusion and attempt to define a model of complexin function that incorporates evidence for both facilitatory and inhibitory roles of complexins in SNARE-mediated fusion.     

Specific interactions of serpins in their native forms attenuate their conformational transitions

Plasminogen activator inhibitor-1 (PAI-1) belongs to the serine protease inhibitor (serpin) protein superfamily. Serpins are unique in that their native forms are not the most thermodynamically stable conformation; instead, a more stable, latent conformation exists. During the transition to the latent form, the first strand of beta-sheet C (s1C) in the serpin is peeled away from the beta-sheet, and the reactive center loop (RCL) is inserted into beta-sheet A, rendering the serpin inactive. To elucidate the contribution of specific interactions in the metastable native form to the latency transition, we examined the effect of mutations at the s1C of PAI-1, specifically in positions P4' through P10'. Several mutations strengthened the interactions between these residues and the core protein, and slowed the transition of the protein from the metastable native form to the latent form. In particular, anchoring of the strand to the protein's hydrophobic core at the beginning (P4' site) and center of the strand (P8' site) greatly retarded the latency transition. Mutations that weakened the interactions at the s1C region facilitated the conformational conversion of the protein to the latent form. PAI-1's overall structural stability was largely unchanged by the mutations, as evaluated by urea-induced equilibrium unfolding monitored via fluorescence emission. Therefore, the mutations likely exerted their effects by modulating the height of the energy barrier from the native to the latent form. Our results show that interactions found only in the metastable native form of serpins are important structural features that attenuate folding of the proteins into their latent forms.     

For better or worse: Relationship status and body mass index

Recent increases in the incidence of obesity and declines in marriage have prompted policymakers to implement policies to mitigate these trends. This paper examines the link between these two outcomes. There are four hypotheses (selection, protection, social obligation and marriage market) that might explain the relationship between marital status transitions and changes in Body Mass Index (BMI). The selection hypothesis suggests that those with a lower BMI are more likely to be selected into marriage. The protection hypothesis states that married adults will have better physical health as a result of the increased social support and reduced incidence of risky behavior among married individuals. The social obligation hypothesis states that those in relationships may eat more regular meals and/or richer and denser foods due to social obligations which may arise because of marriage. Finally, the marriage market hypothesis indicates that when adults are no longer in the marriage market they may not maintain a healthy BMI because doing so is costly and they are in a stable union—or on the other hand, adults may enhance their prospects in the marriage market by losing weight. Taking advantage of longitudinal data and complete marriage histories in the National Longitudinal Survey of Youth 1979, we estimate individual fixed effects models to examine associations between the change in log BMI and the incidence of overweight and obesity, and changes in relationship status controlling for the effects of aging and other respondent characteristics. We find no support for the marriage protection hypothesis. Rather we find evidence supporting the social obligation and marriage market hypotheses—BMI increases for both men and women during marriage and in the course of a cohabiting relationship. Separate analyses by race and ethnicity reveal substantial differences in the response of BMI to relationship status across these groups.     

For better or worse: genomic consequences of intracellular mutualism and parasitism

Bacteria that replicate within eukaryotic host cells include a variety of pathogenic and mutualistic species. Early genome data for these intracellular associates suggested they experience continual gene loss, little if any gene acquisition, and minimal recombination in small, isolated populations. This view of reductive evolution is itself evolving as new genome sequences clarify mechanisms and outcomes of diverse intracellular associations. Recently sequenced genomes have confirmed a trajectory of gene loss and exceptional genome stability in long-term, nutritional mutualists and certain pathogens. However, new genome data for the Rickettsiales and Chlamydiales indicate more repeated DNA, a greater abundance of mobile DNA elements, and more labile genome dynamics than previously suspected for ancient intracellular lineages. Surprising discoveries of conjugation machinery in the parasite Rickettsia felis and the amoebae symbiont Parachlamydia sp. suggest that DNA transfer might play key roles in some intracellular taxa.     

Autophagy: for better or for worse, in good times or in bad times

Autophagy is a bulk cytosolic degradative process which in the last few years has become a key pathway for the advancement of molecular medicine. Autophagy (cellular self-eating) has several implications in human disorders involving accumulation of cytosolic protein aggregates such as Alzheimer, Parkinson, Huntington diseases, as well as in myopathies caused by deficient lysosomal functions and in cancer. Moreover, autophagy affects intracellular microorganism lifespan, acting either as a cellular defense mechanism or, on the contrary, promoting pathogen replication. Furthermore, autophagy also participates in antigen presentation, as a part of the adaptive immune response. Therefore, autophagy association with cell survival or cell death would depend on cell nutrition conditions, presence of cell intruders, and alterations in oncogene or suppressor gene expression. In this review we will focus on the wide spectra of disease-related topics where autophagy is involved, particularly, in those processes concerning microorganism infections.     

Activation of serpins and their cognate proteases in muscle after crush injury

Direct muscle injury was induced in rats in order to evaluate alterations in the balance of serine proteases and inhibitors (serpins) as a response to tissue damage. It was previously found that certain proteases, specifically urokinase-like plasminogen activator (uPA) and others, required activation in order to effect regeneration. We hypothesized that the magnitude and temporal sequence of serpin activation would follow, pari passu, activation of their cognate proteases. In addition to uPA, tissue PA (tPA) and tissue kallikrein were the proteases studied. The serpins we analyzed were protease nexin I (PNI), PA inhibitor 1 (PAI-1), and the kallikrein-binding protein (KBP). uPA nearly doubled 48 h after injury, while there was no change in amidolytic activity after addition of fibrin monomer as an estimation of tPA activity. Tissue kallikrein activity, barely detectable in normal muscle, slowly increased, nearly tripling at 7 days after injury. Greater magnitude and more rapid changes in muscle serpins occurred over the same post-injury time course. By 24 h PNI increased threefold, while PAI-1 increased more slowly, reaching double the control values by 5 days after injury. Surprisingly, KBP, the serpin-class inhibitor of tissue kallikrein, had the most robust response, increasing tenfold over control 48 h after crush injury of muscle. These results further implicate the serpin:protease balance in tissue injury. Participation of complex receptors, such as the α₂-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP), various growth factors, cytokines, and other molecules, in regulating this balance is implicated by these data. © 1994 wiley-Liss, Inc.