Beyond the ABCs of CKC and SCC. Do centromeres orchestrate sister chromatid cohesion or vice versa?

The centromere-kinetochore complex is a highly specialized chromatin domain that both mediates and monitors chromosome-spindle interactions responsible for accurate partitioning of sister chromatids to daughter cells. Centromeres are distinguished from adjacent chromatin by specific patterns of histone modification and the presence of a centromere-specific histone H3 variant (e.g. CENP-A). Centromere-proximal regions usually correspond to sites of avid and persistent sister chromatid cohesion mediated by the conserved cohesin complex. In budding yeast, there is a substantial body of evidence indicating centromeres direct formation and/or stabilization of centromere-proximal cohesion. In other organisms, the dependency of cohesion on centromere function is not as clear. Indeed, it appears that pericentromeric heterochromatin recruits cohesion proteins independent of centromere function. Nonetheless, aspects of centromere function are impaired in the absence of sister chromatid cohesion, suggesting the two are interdependent. Here we review the nature of centromeric chromatin, the dynamics and regulation of sister chromatid cohesion, and the relationship between the two.     

Sister chromatid cohesion at the centromere: confrontation between kinases and phosphatases?

Accurate chromosome segregation in mitosis and meiosis requires that the cohesin complex be protected at the centromere by the Shugoshin/MEI-S332 protein family. Recent studies show that Sgo directly binds the phosphatase PP2A, tethering it to the centromere where it can protect cohesin subunits from phosphorylation, and that localization of Sgo/MEI-S332 itself is regulated by phosphorylation.     

Heterochromatin: a meiotic matchmaker?

During meiosis, the pairing of chromosomes is crucial for a successful partitioning of the genetic material and its transmission into the developing gamete. The classical view of meiotic pairing involves recombination between homologues as an integral part of the pairing mechanism. But, in cases where no recombination occurs, how do chromosome partners find one another? And how do they pair up and then segregate appropriately? Recently, a combination of molecular genetics and fluorescence in situ hybridization appears to have provided an answer to these questions by demonstrating a crucial role for heterochromatin in chromosome pairing.     

Prion hypothesis: the end of the controversy?

Forty-three years have passed since it was first proposed that a protein could be the sole component of the infectious agent responsible for the enigmatic prion diseases. Many discoveries have strongly supported the prion hypothesis, but only recently has this once heretical hypothesis been widely accepted by the scientific community. In the past 3 years, researchers have achieved the 'Holy Grail' demonstration that infectious material can be generated in vitro using completely defined components. These breakthroughs have proven that a misfolded protein is the active component of the infectious agent, and that propagation of the disease and its unique features depend on the self-replication of the infectious folding of the prion protein. In spite of these important discoveries, it remains unclear whether another molecule besides the misfolded prion protein might be an essential element of the infectious agent. Future research promises to reveal many more intriguing features about the rogue prions.     

Heterochromatin: On the ADAR Radar?

Vigilin proteins, the absence of which is known to cause abnormalities in heterochromatin, have been found to bind edited RNAs. Molecular complexes including vigilin comprise proteins involved with RNA editing and with DNA repair, making connections between these processes and RNA-based silencing mechanisms.     

Samuel Butler and human long term memory: Is the cupboard bare?

Memory studies in biological systems distinguish three informational processes that are generally sequential—production/acquisition, storage, and retrieval/use. Identification of DNA as a storage form for hereditary information accelerated progress in that field. Assuming the path of successful elucidation in one memory field (heredity) to be heuristic for elucidation in another (brain), then progress in neuroscience should accelerate when a storage form is identified. In the 19th century Ewald Hering and Samuel Butler held that heredity and brain memory both involved the storage of information and that the two forms of storage were the same. Hering specified storage as ‘molecular vibrations’ but, while making a fuller case, Butler was less committal. In the 20th century, the ablation studies of Karl Lashley failed to identify unique sites for storage of brain information, and Donald Hebb's ‘synaptic plasticity’ hypothesis of distributed storage over a neuronal network won favor. In the 21st century this has come under attack, and the idea that brain and hereditary information are stored as DNA is advocated. Thus, albeit without attribution, Butler's idea is reinstated. Yet, while the case is still open, the synaptic plasticity and DNA hypotheses have problems. Two broad alternatives remain on the table. Long term memory is located: (1) in the brain, either in some other macromolecular form (e.g. protein, lipid) or in some sub-molecular form (e.g. quantum computing and ‘brain as holograph’ hypotheses) or (2) outside the brain. The suggestion of the medieval physician Avicenna that the brain ‘cupboard’ is bare—i.e. the brain is a perceptual, not storage, organ—is consistent with a mysterious ‘universe as holograph’ model. Understanding how Butler came to contribute could be heuristic for future progress in a field fraught with ‘fractionation and disunity’.     

Stress and the epigenetic landscape: a link to the pathobiology of human diseases?

Accumulating evidence points to a major role for chronic stress of cell renewal systems in the pathogenesis of important human diseases, including cancer, atherosclerosis and diabetes. Here we discuss emerging evidence that epigenetic abnormalities may make substantial contributions to these stress-induced pathologies. Although the mechanisms remain to be fully elucidated, we suggest that chronic stress can elicit heritable changes in the chromatin landscape that 'lock' cells in abnormal states, which then lead to disease. We emphasize the need to investigate epigenetic states in disease and links to stress and to consider how the knowledge gained through these studies may foster new means of disease prevention and management.     

Does the occurrence of Harris lines affect the morphology of human long bones?

The purpose of the study is to check the relationship between the occurrence of Harris lines and the morphological differentiation of the long bones of the human skeleton as an indicator of living conditions. The bone material (233 adult individuals, including 120 males and 113 females) was collected at a mediaeval burial ground in Cedynia, Poland. Recommended methods were applied to estimate the sex and age of the individuals (Ferembach et al 1979; Buikstra & Ubelaker 1994). The results obtained indicate that there is no clear relationship between metric characteristics of the studied long bones and the occurrence of Harris lines. Adverse environmental factors, which triggered the occurrence of Harris lines did not strongly affect the growth of long bones and did not change their morphology. Regardless of the phase of ontogenetic development in which the arrested growth lines (HL) formed, no effect of this fact on the final length of bones was observed. Similarly, no statistically significant differences were found in the proportions of bones between individuals reacting to adverse living conditions with the formation of Harris lines and those, whose bones were free of Harris lines. One may assume that Harris lines are of significance in epidemiological research and when assessing the general health profile of a population, but they are less useful in research on morphological reactions of individuals to living conditions.     

United States patent prior art rules and the neem controversy: a case of subject-matter imperialism?

A recent United States patent covering an improvement to the naturally-occurring pesticide in neem tree seed oil might have been rejected as 'obvious' if United States patent law recognized certain forms of prior inventive activity on a par with similar activity occurring within the United States' borders. But the US only recognizes prior 'knowledge, use or invention' as blocking a claim to a patent when those activities take place within US borders, or are evidenced by publications accessible in the US, or, more commonly, by foreign patents. Neither of these last forms of tangible 'prior art' is likely to be available to block patents on biodiversity inventions – most notably because of the fact that most developing nations do not allow patents on pharmaceutical or agricultural inventions, categories subsuming most biodiversity-related advances. Although the United States patent only has direct force within the United States, it is nonetheless highly significant to this global dispute, since the United States and other developed nations stand to be the major markets for the end-products of neem. This paper argues that the border-drawing distinctions in US patent law are archaic, counter to stated policy directives and are disproportionately influencing the developing world's stance towards GATT and its intellectual property rights provisions.     

Structure of a protein–detergent complex: the balance between detergent cohesion and binding

Despite the major interest in membrane proteins at functional, genomic, and therapeutic levels, their biochemical and structural study remains challenging, as they require, among other things, solubilization in detergent micelles. The complexity of this task derives from the dependence of membrane protein structure on their anisotropic environment, influenced by a delicate balance between many different physicochemical properties. To study such properties in a small protein–detergent complex, we used fluorescence measurements and molecular dynamics (MD) simulations on the transmembrane part of glycophorin A (GpAtm) solubilized in micelles of dihexanoylphosphatidylcholine (DHPC) detergent. Fluorescence measurements show that DHPC has limited ability to solubilize the peptide, while MD provides a possible molecular explanation for this. We observe that the detergent molecules are balanced between two different types of interactions: cohesive interactions between detergent molecules that hold the micelle together, and adhesive interactions with the peptide. While the cohesive interactions are detergent mediated, the adhesion to the peptide depends on the specific interactions between the hydrophobic parts of the detergent and the topography of the peptide dictated by the amino acids. The balance between these two parameters results in a certain frustration of the system and rather slow equilibration. These observations suggest how molecular properties of detergents could influence membrane protein stabilization and solubilization.     

Infanticide and effectiveness of pup protection in bank voles: does the mother recognise a killer?

Infanticide, the killing of conspecific young, has been documented in numerous species of mammals, especially rodents. In that infanticide is costly to the victim mother, natural selection should favour counter-strategies by females to protect their pups. We studied the frequency of infanticide by male and female bank voles (Clethrionomys glareolus) and the effectiveness of dams in recognising and deterring infanticide. In trials in which unprotected pups were exposed to voles of both sexes, one third of male and female intruders killed pups. When mothers were present at the nest site, not a single female and only 2 of 25 males were able to commit infanticide. Females acted aggressively towards all intruders and hence did not discern between infanticidal and non-infanticidal males and females. Aggression of dams against any intruder indicates that all strange individuals near the nest site of a territorial species form an equal threat to pups. However, the presence of the aggressive dam is sufficient to deter most intruders from harming offspring by keeping them at a distance from the nest site. Heat run before mating, in a species with postpartum oestrus and vulnerable pups in the nest, also might lure potential infanticidal males away from the nest site and obscure the nest location. Received in revised form: 17 October 2001 Electronic Publication     

Chromosome cohesion: ring around the sisters?

Sister chromatid cohesion is a key aspect of accurate chromosome transmission during mitosis, yet little is known about the structure of cohesin, the protein complex that links the two sister chromatids. Recent studies shed light on the structure of the cohesin complex, leading to intriguing models that could explain how sister chromatids are held together.     

Anatomy of rodent and human livers: What are the differences?

The size of the liver of terrestrial mammals obeys the allometric scaling law over a weight range of >3 1 10⁶. Since scaling reflects adaptive changes in size or scale among otherwise similar animals, we can expect to observe more similarities than differences between rodent and human livers. Obvious differences, such as the presence (rodents) or absence (humans) of lobation and the presence (mice, humans) or absence (rats) of a gallbladder, suggest qualitative differences between the livers of these species. After review, however, we conclude that these dissimilarities represent relatively small quantitative differences. The microarchitecture of the liver is very similar among mammalian species and best represented by the lobular concept, with the biggest difference present in the degree of connective tissue development in the portal tracts. Although larger mammals have larger lobules, increasing size of the liver is mainly accomplished by increasing the number of lobules. The increasing role of the hepatic artery in lobular perfusion of larger species is, perhaps, the most important and least known difference between small and large livers, because it profoundly affects not only interventions like liver transplantations, but also calculations of liver function.     

Arrestin-mediated signaling: Is there a controversy?

The activation of the mitogen-activated protein(MAP) kinases extracellular signal-regulated kinase(ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors(GPCRs) via arrestins, as opposed to conventional GPCR signaling via G proteins. Several recent studies using HEK293 cells where all G proteins were genetically ablated or inactivated, or both non-visual arrestins were knocked out, demonstrated that ERK1/2 phosphorylation requires G protein activity, but does not necessarily require the presence of non-visual arrestins. This appears to contradict the prevailing paradigm. Here we discuss these results along with the recent data on gene edited cells and arrestinmediated signaling. We suggest that there is no real controversy. G proteins might be involved in the activation of the upstream-most MAP3Ks, although in vivo most MAP3K activation is independent of heterotrimeric G proteins, being initiated by receptor tyrosine kinases and/or integrins. As far as MAP kinases are concerned, the best-established role of arrestins is scaffolding of the three-tiered cascades(MAP3K-MAP2 K-MAPK). Thus, it seems likely that arrestins, GPCRbound and free, facilitate the propagation of signals in these cascades, whereas signal initiation via MAP3K activation may be independent of arrestins. Different MAP3Ks are activated by various inputs, some of which are mediated by G proteins, particularly in cell culture, where we artificially prevent signaling by receptor tyrosine kinases and integrins, thereby favoring GPCR-induced signaling. Thus, there is no reason to change the paradigm: Arrestins and G proteins play distinct non-overlapping roles in cell signaling.     

What moves us? How mobility and movement are at the center of human evolution

Movement is central to the survival of all free‐living organisms. Consequently, movement and what anthropologists often refer to as mobility, which is the sum of small‐scale movements tracked across larger geographic and temporal scales, are key targets of selection. Movement and mobility also underpin many of the key features that make us human and that allowed our lineage to adapt to changing environments across the globe. The most obvious example is the evolution of humans' singular mode of locomotion. Bipedalism is arguably the most important derived anatomical trait of the hominin lineage. The mechanisms and circumstances that gave rise to this novel mode of movement remain subjects of intense research.