Is bacterial persistence a social trait?

The ability of bacteria to evolve resistance to antibiotics has been much reported in recent years. It is less well-known that within populations of bacteria there are cells which are resistant due to a non-inherited phenotypic switch to a slow-growing state. Although such 'persister' cells are receiving increasing attention, the evolutionary forces involved have been relatively ignored. Persistence has a direct benefit to cells because it allows survival during catastrophes-a form of bet-hedging. However, persistence can also provide an indirect benefit to other individuals, because the reduced growth rate can reduce competition for limiting resources. This raises the possibility that persistence is a social trait, which can be influenced by kin selection. We develop a theoretical model to investigate the social consequences of persistence. We predict that selection for persistence is increased when: (a) cells are related (e.g. a single, clonal lineage); and (b) resources are scarce. Our model allows us to predict how the level of persistence should vary with time, across populations, in response to intervention strategies and the level of competition. More generally, our results clarify the links between persistence and other bet-hedging or social behaviours.     

Is Alzheimer's disease a systemic disease?

Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.     

Is Huntington disease a developmental disorder?

The recently discovered roles of huntingtin in non-differentiated cells indicate that it is a key molecule in brain development. Humbert argues that the haploinsufficiency of wild-type huntingtin in Huntington disease might lead to various cellular alterations well before the onset of symptoms and ultimately cause disease.The construction of an organism is a complex process that involves a developmental challenge: the orchestrated proliferation, migration and differentiation of cells, leading to the assembly of organs. Huntingtin—the protein that is mutated in the neurodegenerative disorder Huntington disease—is widely expressed in the early developing mouse embryo, in which it has an essential role. The most compelling proof that huntingtin is essential for early development is that inactivation of the murine gene results in defects in extra-embryonic tissues and embryonic death at embryonic day 7.5 (Dragatsis et al, 1998). My group has recently directly linked a cellular function of huntingtin to brain development (Godin et al, 2010a). Indeed, huntingtin regulates cortical neurogenesis through, at least in part, its role during spindle pole orientation.The growing evidence that huntingtin functions during development opens the door to viewing Huntington disease as a developmental disorder. Development could be abnormal in carriers of the mutant protein and precede the manifestation of the disease by decades. Changes during development might not have phenotypical consequences until the mature cells are required to function later in life. Indeed, a given protein will not function in the same context during development and adulthood, and the resulting phenotypes of these functions will not be the same. Furthermore, compensatory mechanisms that respond to abnormal development might be overwhelmed when the organism is ageing. We have not yet identified all of the neurodevelopmental defects—both functional and morphological—involved in Huntington disease. However, there are changes in the brain before the onset of disease, including a smaller intracranial adult brain volume in pre-manifest Huntington disease carriers (Nopoulos et al, 2010). It is tempting to consider that this might be a consequence of altered brain development.A complex molecular picture of the biology of huntingtin is emerging, suggesting that it is a scaffold protein that could couple many cellular events. Huntingtin regulates the assembly of the dynein–dynactin complex for axonal transport and Golgi apparatus organization (Caviston et al, 2007; Gauthier et al, 2004). During cell division, this role extends to a complex that also contains NuMA, a component that is essential for the organization of microtubules at the spindle pole (Godin et al, 2010a). Furthermore, NuMA and the Goloco-containing protein LGN form a complex that regulates the interaction between astral microtubules and the cell cortex (Du & Macara, 2004). Therefore, huntingtin could also participate in the distribution of the dynein–dynactin complex at the cell cortex and, as a consequence, regulate mitosis at several points. Similarly, huntingtin could regulate the assembly of other supramolecular complexes that are involved in various cell pathways, as suggested by the diverse nature of its interactors (Kaltenbach et al, 2007). For example, huntingtin interacts with the β-catenin destruction complex and thus participates in the tight regulation of the steady-state levels of β-catenin (Godin et al, 2010b; Kaltenbach et al, 2007). This might be crucial to regulate the Wingless/Wnt signalling pathway, known for its central role during development and adulthood. Thus, the functions attributed to huntingtin so far are important cellular processes in the early stages of development and adulthood, and contribute as initial or secondary disease mechanisms to several neurodegenerative disorders. This might not be a coincidence!Finally, the scaffold nature of huntingtin might be important for histogenesis in general and explain the widespread abnormalities observed in Huntington disease. A high level of huntingtin is found in the testes and one of the peripheral manifestations of the disease is testicular pathology, with a reduced number of germ cells and abnormal seminiferous tubule morphology (van Raamsdonk et al, 2007). Testes require functional intracellular transport for their normal development, and asymmetrical division is particularly important for germline stem-cell maintenance. Thus, an abnormal developmental programme induced by defective huntingtin function would alter cells and, thereby, the homeostasis of the tissues expressing this protein.Several other disorders are caused by the toxic presence of an abormal polyglutamine expansion. These ‘polyglutamine diseases'' have this mutation in common; however, the mutated proteins are unrelated and the disorders are phenotypically distinct, affecting different brain regions and neurons. A defect in the function of the mutated proteins explains the separate mechanisms of neuronal degeneration observed. Huntington disease is a dominant disorder, but the vision of it as a gain-of-function disease with loss-of-function manifestations could be outdated. The situation seems to be more complicated, and most patients express not only one copy of the mutant huntingtin, but also half the amount of the wild-type protein. It is time to rethink the idea that studying huntingtin protein is irrelevant to Huntington disease. In the light of recent advances in the understanding of its function, one might even suggest that taking developmental biology into account could provide new insight into the pathological mechanisms of this so far incurable adult-onset disorder.     

Is multiple sclerosis a mitochondrial disease?

Multiple sclerosis (MS) is a relatively common and etiologically unknown disease with no cure. It is the leading cause of neurological disability in young adults, affecting over two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability. Recently, MS has become increasingly viewed as a neurodegenerative disorder in which axonal injury, neuronal loss, and atrophy of the central nervous system leads to permanent neurological and clinical disability. In this article, we discuss the latest developments on MS research, including etiology, pathology, genetic association, EAE animal models, mechanisms of neuronal injury and axonal transport, and therapeutics. In this article, we also focus on the mechanisms of mitochondrial dysfunction that are involved in MS, including mitochondrial DNA defects, and mitochondrial structural/functional changes.     

Is RecG a general guardian of the bacterial genome?

The RecG protein of Escherichia coli is a double-stranded DNA translocase that unwinds a variety of branched DNAs in vitro, including Holliday junctions, replication forks, D-loops and R-loops. Coupled with the reported pleiotropy of recG mutations, this broad range of potential targets has made it hard to pin down what the protein does in vivo, though roles in recombination and replication fork repair have been suggested. However, recent studies suggest that RecG provides a more general defence against pathological DNA replication. We have postulated that this is achieved through the ability of RecG to eliminate substrates that the replication restart protein, PriA, could otherwise exploit to re-replicate the chromosome. Without RecG, PriA triggers a cascade of events that interfere with the duplication and segregation of chromosomes. Here we review the studies that led us to this idea and to conclude that RecG may be both a specialist activity and a general guardian of the genome.     

Is the bacterial ferrous iron transporter FeoB a living fossil?

The cytoplasmic membrane protein FeoB of Escherichia coli, Helicobacter pylori, Legionella pneumophila and Synechocystis sp. strain PCC 6803 is necessary for Fe(2+) uptake. The C-terminal part of FeoB is predicted to contain 8-12 membrane-spanning helices. The N-terminal domain shows much similarity to eukaryotic and prokaryotic G proteins and, indeed, GTPase activity is necessary for Fe(2+) transport. Four of the five characteristic conserved G protein motifs have been identified in FeoB proteins. Whether FeoB is involved directly, via its Me(2+) binding site, or indirectly in Fe(2+) transport, remains to be investigated.     

Is infertility a disease and does it matter?

Claims about whether or not infertility is a disease are sometimes invoked to defend or criticize the provision of state‐funded treatment for infertility. In this paper, I suggest that this strategy is problematic. By exploring infertility through key approaches to disease in the philosophy of medicine, I show that there are deep theoretical disagreements regarding what subtypes of infertility qualify as diseases. Given that infertility’s disease status remains unclear, one cannot uncontroversially justify or undermine its claim to medical treatment by claiming that it is or is not a disease. Instead of focusing on disease status, a preferable strategy to approach the debate about state‐funded treatment is to explicitly address the specific ethical considerations raised by infertility. I show how this alternative strategy can be supported by a recent theoretical framework in the philosophy of medicine which avoids the problems associated with the concepts of health and disease.     

Is ammonia a pathogenetic factor in Alzheimer's disease?

An attempt was made to review experimental evidence in favor of the idea that ammonia plays a role in dementia of the Alzheimer type (DAT). Hyperammonemia causes biochemical and cellular dysfunctions in the brain, which can be found in brains of DAT patients. The most conspicuous among these findings are astrocytosis, impairment of glucose utilization, and a decreased rate of energy metabolism, and the impairment of neurotransmission, with a net increase in excitability and glutamate release. The derangement of lysosomal processing of proteins is another potential site of ammonia action. This aspect is especially important in view of the growing evidence for the role of the endosomal-lysosomal system in the formation of amyloidogenic fragments from -amyloid precursor protein. Ammonia is not considered a primary factor of the disease. However, since hyperammonemia and release of ammonia from the brains of DAT patients is well supported by published observations, ammonia should be taken into account as a factor that contributes to manifestations and the progression of DAT. If elevated ammonia concentrations turn out to be indeed as important in DAT, as is suggested in this review, rational therapeutic avenues can be envisaged that lead to the amelioration of symptoms and progression of the disease.Abbreviations -AP -amyloid protein - -APP -amyloid precursor protein - CNS central nervous system - DAT dementia of the Alzheimer type - GABA -aminobutyrate - MAO monoamine oxidase - NAD nicotinamide adenine dinucleotide This paper is dedicated to Rudi Vrba, a pioneer of the neurochemistry of ammonia, and a friend, at the occasion of his 68th birthday.     

Is modification sufficient to protect a bacterial chromosome from a resident restriction endonuclease?

It has been generally accepted that DNA modification protects the chromosome of a bacterium encoding a restriction and modification system. But, when target sequences within the chromosome of one such bacterium (Escherichia coli K-12) are unmodified, the cell does not destroy its own DNA; instead, ClpXP inactivates the nuclease, and restriction is said to be alleviated. Thus, the resident chromosome is recognized as 'self' rather than 'foreign' even in the absence of modification. We now provide evidence that restriction alleviation may be a characteristic of Type I restriction-modification systems, and that it can be achieved by different mechanisms. Our experiments support disassembly of active endonuclease complexes as a potential mechanism. We identify amino acid substitutions in a restriction endonuclease, which impair restriction alleviation in response to treatment with a mutagen, and demonstrate that restriction alleviation serves to protect the chromosome even in the absence of mutagenic treatment. In the absence of efficient restriction alleviation, a Type I restriction enzyme cleaves host DNA and, under these conditions, homologous recombination maintains the integrity of the bacterial chromosome.     

Is there a role for quorum sensing signals in bacterial biofilms?

Bacteria form multicellular biofilm communities on most surfaces. Genetic analysis of biofilm formation has led to the proposal that extracellular signals and quorum-sensing regulatory systems are essential for differentiated biofilms. Although such a model fits the concept of density-driven cell-cell communication and appear to describe biofilm development in several bacterial species and conditions, biofilm formation is multifactorial and complex. Hydrodynamics, nutrient load and intracellular carbon flux have major impacts, presumably by altering the expression of cellular traits essential for bacterial adaptation during the different stages of biofilm formation. Hence, differentiated biofilms may also be the net result of many independent interactions, rather than being determined by a particular global quorum sensing system.     

Is oxytocin a therapeutic factor for ischemic heart disease?

Ischemic heart disease (IHD) is among the most important and top ranked causes of death in the world, and its preventive and interventional mechanisms are actively being investigated. Preconditioning may still be beneficial in some situations such as IHD. Development of cardioprotective agents to improve myocardial function, to decrease the incidence of arrhythmias, to delay the onset of necrosis, and to limit the total extent of infarction during IHD is of great clinical importance. In order to reduce morbidity, a new treatment modality must be developed, and oxytocin may indeed be one of the candidates. There is increasing experimental evidence indicating that oxytocin may have cardioprotective effects either by decreasing the extent of reperfusion injury or by pharmacologic preconditioning activity. This review shows that in the presence of oxytocin, the cardioprotective effects may be increased to some extent. The presented board of evidence focuses on the valuable effects of oxytocin on myocardial function and candidates it for future clinical studies in the realm of ischemic heart diseases.     

Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery?

The emergence of resistance against most current drugs emphasizes the need to develop new approaches to control bacterial pathogens, particularly Staphylococcus aureus. Bacterial fatty acid synthesis is one such target that is being actively pursued by several research groups to develop anti-Staphylococcal agents. Recently, the wisdom of this approach has been challenged based on the ability of a Gram-positive bacterium to incorporate extracellular fatty acids and thus circumvent the inhibition of de novo fatty acid synthesis. The generality of this conclusion has been challenged, and there is enough diversity in the enzymes and regulation of fatty acid synthesis in bacteria to conclude that there is not a single organism that can be considered typical and representative of bacteria as a whole. We are left without a clear resolution to this ongoing debate and await new basic research to define the pathways for fatty acid uptake and that determine the biochemical and genetic mechanisms for the regulation of fatty acid synthesis in Gram-positive bacteria. These crucial experiments will determine whether diversity in the control of this important pathway accounts for the apparently different responses of Gram-positive bacteria to the inhibition of de novo fatty acid synthesis in presence of extracellular fatty acid supplements.     

Interpreting the epidemiology and natural history of bacterial vaginosis: are we still confused?

Bacterial vaginosis (BV) is a common cause of vaginitis and increases women's risk of pelvic inflammatory disease, adverse pregnancy outcomes, and risk of STD/HIV acquisition. The etiology of BV is unclear, though it is believed to involve loss of vaginal hydrogen peroxide-producing lactobacilli and acquisition of complex bacterial communities that include many fastidious BV-associated bacteria (BVAB) that have recently been detected using PCR methods. Treatment failure (persistence) is common, and may be facilitated by unprotected sex. Potential contributions to BV and BV persistence include (1) sexual partners as a reservoir for BVAB; (2) specific sexual practices, including male partners' condom use; and (3) the composition of the vaginal microbiota involved in BV. Specific BVAB in the Clostridiales order may predict BV persistence when detected pre-treatment, and have been detected in men whose female partners have BV. BVAB may be associated with unprotected sexual behavior and failure of BV to resolve in women, supporting the hypothesis that BVAB colonization of male genitalia may serve as a reservoir for re-infection of female partners. Moreover, specific sexual practices may favor vaginal colonization with certain BVAB that have been associated with persistence. This review provides background on BV, and discusses the epidemiologic and microbiologic data to support a role for acquisition of BVAB and how this process might differ among subsets of women.     

Is cancer a disease set up by cellular stress responses?

For several decades, the somatic mutation theory (SMT) has been the dominant paradigm on cancer research, leading to the textbook notion that cancer is fundamentally a genetic disease. However, recent discoveries indicate that mutations, including “oncogenic” ones, are widespread in normal somatic cells, suggesting that mutations may be necessary but not sufficient for cancer to develop. Indeed, a fundamental but as yet unanswered question is whether or not the first step in oncogenesis corresponds to a mutational event. On the other hand, for some time, it has been acknowledged the important role in cancer progression of molecular processes that participate in buffering cellular stress. However, their role is considered secondary or complementary to that of putative oncogenic mutations. Here we present and discuss evidence that cancer may have its origin in epigenetic processes associated with cellular adaptation to stressful conditions, and so it could be a direct consequence of stress-buffering mechanisms that allow cells with aberrant phenotypes (not necessarily associated with genetic mutations) to survive and propagate within the organism. We put forward the hypothesis that there would be an inverse correlation between the activation threshold of the cellular stress responses (CSRs) and the risk of cancer, so that species or individuals with low-threshold CSRs will display a higher incidence or risk of cancer.