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.     

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.     

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.     

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.     

DNA from formalin-fixed tissue: extraction or repair? That is the question

Establishing effective DNA-based protocols for use on archival material fixed in formaldehyde (formalin) is a particularly challenging task. Formalin fixation induces cross-linking with nucleic acids and proteins, thereby reducing the amount and quality of the extracted DNA. Previous attempts have primarily focused on optimizing DNA extraction protocols. Here we focus on the use of enzymes capable of in vitro repair of DNA extracts prior to amplification of the nucleic acids by the polymerase chain reaction (PCR). The amplification success of mitochondrial DNA was greater using the repair enzyme assay (56%) than with the regular PCR assay (20%), and even more convincing results were obtained with the amplified nuclear ribosomal region (91% versus 21%). These results indicate that in vitro repair of DNA damage (depurinated sites, strand nicks and base modifications) increases the number of samples that amplify, amplify to a greater extent and amplify fewer ancillary bands and that DNA repair has been overlooked as a way of improving the efficiency of molecular methods used on formalin-fixed samples. Fidelity has not been specifically investigated, but preliminary results indicate that misincorporation is not a major problem.     

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 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 include or not to include (the invader in community analyses)? That is the question

An increasing number of studies report impacts from invasive species on community metrics or ecosystem functions. We draw attention to an issue arising whenever impact is measured on a community where the invader is an integrated part: should or shouldn’t the attributes of the invader itself be included in the data-analysis? We identify many examples from the published literature showing inconsistency in whether or not data for the invader is included or excluded, and discuss potential implications for ecological interpretations. We also provide a case study to show that the invasive seaweed Undaria pinnatifida can be interpreted to have strong or no impact on seaweed communities, depending on its inclusion or exclusion in the data analysis. We conclude that it is critical for studies to (1) clearly state in the methods section, if the invaders are included or excluded from the data-analysis, (2) acknowledge potential differences in outcomes when comparing results based on different methods, and (3) analyze, if possible, impacts both with and without the invader. Finally, we note that this ‘inclusion versus exclusion’ conundrum is not only relevant to invasion biology, but to any field where the test-object of interest can be an integrated part of the response, such as when impact of seaweed blooms are analysed on community productivity or community effects are quantified over time from ecological pulse-perturbation experiments.     

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.     

Self or nonself? That is the question: sensing of cytomegalovirus infection by innate immune receptors

Cytomegaloviruses (CMV) are ubiquitous, opportunistic DNA viruses that have mastered the art of immune evasion through their ability to mimic host proteins or to inhibit antiviral responses. The study of the host response against CMV infection has illuminated many facets of the complex interaction between host and pathogen. Here, we review evidence derived from the animal models and human studies that supports the central role played by innate immune receptors in the recognition of virus infection and their participation in the many layers of defense.     

Pannexin: to gap or not to gap, is that a question?

Vertebrates express two families of gap junction proteins: the well characterized connexins and the recently discovered pannexins. The latter are related to invertebrate innexins. Here we present the hypothesis that pannexins, rather than providing a redundant system to gap junctions formed by connexins, exert a physiological role as nonjunctional membrane channels. Specifically, we propose that pannexins can serve as ATP release channels. This function presumptively is also performed by innexins in invertebrates, in addition to their traditional gap junction role.     

Location of genes in chromosomes: Random or not?

The possibility is discussed that the order of genes in chromosomes is not random but determined by natural selection, i.e., is a selectively valuable character. Cases of long-term conservation of gene linkage or synteny in evolution are presented. Examples and possible mechanisms of nonrandom gene localization in prokaryotic and eukaryotic chromosomes are considered.