To clear,or not to clear (senescent cells)? That is the question

Cellular senescence is an anti‐proliferative program that restricts the propagation of cells subjected to different kinds of stress. Cellular senescence was initially described as a cell‐autonomous tumor suppressor mechanism that triggers an irreversible cell cycle arrest that prevents the proliferation of damaged cells at risk of neoplastic transformation. However, discoveries during the last decade have established that senescent cells can also impact the surrounding tissue microenvironment and the neighboring cells in a non‐cell‐autonomous manner. These non‐cell‐autonomous activities are, in part, mediated by the selective secretion of extracellular matrix degrading enzymes, cytokines, chemokines and immune modulators, which collectively constitute the senescence‐associated secretory phenotype. One of the key functions of the senescence‐associated secretory phenotype is to attract immune cells, which in turn can orchestrate the elimination of senescent cells. Interestingly, the clearance of senescent cells seems to be critical to dictate the net effects of cellular senescence. As a general rule, the successful elimination of senescent cells takes place in processes that are considered beneficial, such as tumor suppression, tissue remodeling and embryonic development, while the chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging. Nevertheless, exceptions to this rule may exist. Now that cellular senescence is in the spotlight for both anti‐cancer and anti‐aging therapies, understanding the precise underpinnings of senescent cell removal will be essential to exploit cellular senescence to its full potential.     

To sample or not to sample? That is the question ... for the vegetation scientist

Lájer (2007) raised the problem of using a non-random sample for statistical testing of plant community data. He argued that this violates basic assumptions of the tests, resulting thus in non-significant results. However, a huge part of present-day knowledge of vegetation science is still based on non-random, preferentially collected data of plant communities. I argue that, given the inherent limits of preferential sampling, a change of approach is now necessary, with the adoption of sampling based on random principles seeming the obvious choice. However, a complete transition to random-based sampling designs in vegetation science is limited by the yet undefined nature of plant communities and by the still diffused opinion that plant communities have a discrete nature. Randomly searching for such entities is almost impossible, given their dependence on scale of observation, plot size and shape, and the need for finding well-defined types. I conclude that the only way to solve this conundrum is to consider and study plant communities as operational units. If the limits of the plant communities are defined operationally, they can be investigated using proper sampling techniques and the collected data analyzed using adequate statistical tools.     

To NO or not to NO: 'where?' is the question

Nitric oxide (NO) is a gaseous radical with unique biological functions essential for the cardiovascular system, host defense and neuro-transmission. For two decades it was thought that NO was able to diffuse freely across relatively long distances and to traverse major parts of the cell, if not multiple cell layers. However, NO has been proven to be extremely reactive: it reacts with other reactive oxygen species, heavy metals, as well as with cysteine and tyrosine residues in proteins. In accordance, it is now widely accepted that once NO is generated, it is very short-lived and diffuses only over a short distance. This urges for the local production of NO and the localization of NO synthases in the proximity of their downstream targets. This review discusses the highly organized localization of NO synthases, with the endothelial isoform (eNOS) as its main focus, since from this synthase most is known about its subcellular localization and regulation.     

To flush or not to flush … that is a question

The human gut microflora has drawn a lot of attention as a potent therapeutic tool for many decades. More recently, efforts have been developed to devise efficient ways of complementing or replacing deficient intestinal microflora associated with intestinal diseases that are resistant to conventional medical treatments. Aside from the medical and industrial applications that emerged from the use of gut microbiota, the complex constitution of this ecosystem raises fascinating questions regarding host-cell communication and host response mechanisms to the ever changing environment. This brief comment also points to questions raised by some unexpected applications that have recently emerged from this field.     

MUC genes: mucin or not mucin? That is the question

Mucins are macromolecules lying the cells in contact with external environment and protect the epithelium against constant attacks such as digestive fluids, microorganisms, pollutants, and toxins. Mucins are the main components of mucus and are synthesized and secreted by specialized cells of the epithelium (goblet cells, cells of mucous glands) or non mucin-secreting cells. Human mucin genes show common features: large size of their mRNAs, large nucleotide tandem repeat domains, complex expression both at tissular and cellular level. Since 1987, 21 MUC symbols have been used to designate genes encoding O-glycoproteins containing tandem repeat domains rich in serine, threonine and proline. Some of these genes encode true mucins while others encode non mucin adhesion O-glycoproteins. In this paper, we propose a classification based on sequence similarities and expression areas. Two main families can be distinguished: secreted mucins or gel-forming mucins (MUC2, MUC5AC, MUC5B, MUC6), and membrane-bound mucins (MUC1, MUC3, MUC4, MUC12, MUC17). Muc-deficient mice will provide important models in the study of functional relationships between these two mucin families.     

Amyloids or prions? That is the question

ABSTRACT

Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.     

Oviparity or viviparity? That is the question…

The modes of reproduction undoubtedly represent one of the most critical life-history traits because they profoundly affect fitness and survival. The parent–offspring conflict over the degree of parental investment may be the main selective factor in the evolution of reproduction. Although the modes of sexual reproduction are remarkably diversified in animals, the traditional typology spanning three classes does not seem to be adequate to clarify the level of parental investment. Thus, lecithotrophy does not provide any information on the retention of the zygotes inside the parent's body and matrotrophy only indicates that nutrients are provided by mother but does not make any distinction between various types of maternal care. I here present a scientific typology of the reproductive modes comprising five classes: ovuliparity, oviparity, ovo-viviparity, histotrophic viviparity and hemotrophic viviparity. Based on the development stage of the zygote and on its interrelation with the parent, my classification details the degree of contrivances by which animals provide alternative parental investment in their offspring. Hence, this typology possesses a great heuristic value, both in reproduction and evolutionary biology. These different modes of reproduction do represent a sequence, with ovuliparity being the most primitive and hemotrophic viviparity the most advanced mode. Lastly, the comparative analysis of different reproductive modes in vertebrates suggests that climatic conditions (cold) could be one of the strongest selection pressures for extending egg retention and the establishment of viviparity.     

Whether to target single or multiple CDKs for therapy? That is the question

Complexes consisting of cyclin‐dependent kinases (CDKs) and their regulatory subunits (the cyclins) control the progression of normal mammalian cells through the cell cycle. However, during malignant transformation this regulatory apparatus malfunctions, allowing cells to undergo unchecked proliferation. In many cases, the high mitotic potential of malignant cells is due to the constitutive activation of CDK–cyclin complexes, facilitated by the inactivation of cellular CDK inhibitors, such as p16^INK4A or p27^Kip1, and the loss of functional tumor suppressors, such as the p53 and pRb proteins. It has recently been suggested that pharmacological intervention based on remedying the deficiency or loss of activity of these negative regulators of the cell cycle could be a very effective therapeutic option in the treatment of cancer. Multiple CDK inhibitors have been synthesized over the last two decades, spanning at least five classes of compounds. While these inhibitors can be classified on the basis of their chemical structure, it may be more interesting to categorize them according to their pharmacological nature, as broad ‐ spectrum unspecific, pan‐specific, or very selective antagonists. This review offers a critical assessment of the advantages and disadvantages of both pan‐specific and highly selective CDK inhibitors in therapy. J. Cell. Physiol. 226: 341–349, 2011. © 2010 Wiley‐Liss, Inc.     

TonB or not TonB: is that the question?

Bacteria are able to survive in low-iron environments by sequestering this metal ion from iron-containing proteins and other biomolecules such as transferrin, lactoferrin, heme, hemoglobin, or other heme-containing proteins. In addition, many bacteria secrete specific low molecular weight iron chelators termed siderophores. These iron sources are transported into the Gram-negative bacterial cell through an outer membrane receptor, a periplasmic binding protein (PBP), and an inner membrane ATP-binding cassette (ABC) transporter. In different strains the outer membrane receptors can bind and transport ferric siderophores, heme, or Fe3+ as well as vitamin B12, nickel complexes, and carbohydrates. The energy that is required for the active transport of these substrates through the outer membrane receptor is provided by the TonB/ExbB/ExbD complex, which is located in the cytoplasmic membrane. In this minireview, we will briefly examine the three-dimensional structure of TonB and the current models for the mechanism of TonB-dependent energy transduction. Additionally, the role of TonB in colicin transport will be discussed.     

To keep or not to keep? the question of crystallographic waters for enzyme simulations in organic solvent

The use of enzymes in non-aqueous solvents expands the use of biocatalysts to hydrophobic substrates, with the ability to tune selectivity of reactions through solvent selection. Non-aqueous enzymology also allows for fundamental studies on the role of water and other solvents in enzyme structure, dynamics, and function. Molecular dynamics simulations serve as a powerful tool in this area, providing detailed atomic information about the effect of solvents on enzyme properties. However, a common protocol for non-aqueous enzyme simulations does not exist. If you want to simulate enzymes in non-aqueous solutions, how many and which crystallographic waters do you keep? In the present work, this question is addressed by determining which crystallographic water molecules lead most quickly to an equilibrated protein structure. Five different methods of selecting and keeping crystallographic waters are used in order to discover which crystallographic waters lead the protein structure to reach an equilibrated structure more rapidly in organic solutions. It is found that buried waters contribute most to rapid equilibration in organic solvent, with slow-diffusing waters giving similar results.     

To fear or not to fear: what was the question? A potential role for Ras-GRF in memory

Learning, making memories, and forgetting are thought to require changes in the strengths of connections between neurons. Such changes in synaptic strength occur in two phases: an early phase that is likely mediated by covalent modifications to existing proteins, and a delayed phase that depends on new gene expression and protein synthesis. However, the biochemical mechanisms by which neuronal activity leads to changes in synaptic strength are poorly understood. Recently, it has been shown that animals that lack Ras guanine nucleotide releasing factor (Ras-GRF), a Ca²⁺-dependent activator of the small GTP-binding protein, Ras, do not learn fear responses normally, although other types of learning appear normal. These animals show defects in the delayed phase of memory formation within the neuronal circuit that mediates fear conditioning. This paper suggests that Ras-GRF couples synaptic activity to the molecular mechanisms that consolidate changes in synaptic strength within specific neuronal circuits.^(1–3) BioEssays 20 :691–695, 1998. © 1998 John Wiley & Son, Inc.