Tiam1 takes PARt in cell polarity

Cell polarity is an essential requirement for the proper tissue development of complex organisms. This is underscored by in vivo studies showing that loss of cell polarity contributes to the formation and progression of tumours. Evolutionary conserved multiprotein complexes, such as the Par3-Par6-aPKC or, in short, the Par polarity complex, regulate the establishment of cell polarity. The small Rho GTPases CDC42 and Rac control the activation of the Par polarity complex. Evidence now implicates the Rac activator Tiam1 as a crucial component of the Par complex in regulating neuronal (axonal) and epithelial (apical-basal) polarity. Our current knowledge places Tiam1 at the centre of a pivotal biological process, the establishment and maintenance of cell polarity, and suggests that deregulation of the Tiam1-Par complex contributes to tumourigenicity.     

Could the acid–base status of Antarctic sea urchins indicate a better‐than‐expected resilience to near‐future ocean acidification?

Increasing atmospheric carbon dioxide concentration alters the chemistry of the oceans towards more acidic conditions. Polar oceans are particularly affected due to their low temperature, low carbonate content and mixing patterns, for instance upwellings. Calcifying organisms are expected to be highly impacted by the decrease in the oceans' pH and carbonate ions concentration. In particular, sea urchins, members of the phylum Echinodermata, are hypothesized to be at risk due to their high‐magnesium calcite skeleton. However, tolerance to ocean acidification in metazoans is first linked to acid–base regulation capacities of the extracellular fluids. No information on this is available to date for Antarctic echinoderms and inference from temperate and tropical studies needs support. In this study, we investigated the acid–base status of 9 species of sea urchins (3 cidaroids, 2 regular euechinoids and 4 irregular echinoids). It appears that Antarctic regular euechinoids seem equipped with similar acid–base regulation systems as tropical and temperate regular euechinoids but could rely on more passive ion transfer systems, minimizing energy requirements. Cidaroids have an acid–base status similar to that of tropical cidaroids. Therefore Antarctic cidaroids will most probably not be affected by decreasing seawater pH, the pH drop linked to ocean acidification being negligible in comparison of the naturally low pH of the coelomic fluid. Irregular echinoids might not suffer from reduced seawater pH if acidosis of the coelomic fluid pH does not occur but more data on their acid–base regulation are needed. Combining these results with the resilience of Antarctic sea urchin larvae strongly suggests that these organisms might not be the expected victims of ocean acidification. However, data on the impact of other global stressors such as temperature and of the combination of the different stressors needs to be acquired to assess the sensitivity of these organisms to global change.     

Male-biased operational sex ratios and the Viking phenomenon: an evolutionary anthropological perspective on Late Iron Age Scandinavian raiding

In this paper, we use a combination of evolutionary theory, ethnographic data, written sources, and archaeological evidence to develop a new explanation for the origins of Viking raiding. Our argument focuses on the operational sex ratio, which is the ratio of males to females in a society who are ready to mate at a given time. We propose that a combination of two practices – polygyny and concubinage – and the increase in social inequality that occurred in Scandinavia during the Late Iron Age resulted in a male-biased operational sex ratio. This would have created a pool of unmarried men motivated to engage in risky behaviours that had the potential to increase their wealth and status, and therefore their probability of entering the marriage market. With high-status men looking to instigate expeditions to acquire plunder and develop their reputations as war leaders, raiding represented a mutually beneficial means of achieving social advancement and success.     

The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity

BACKGROUND: The establishment and maintenance of cell polarity is crucial for many biological functions and is regulated by conserved protein complexes. The Par polarity complex consisting of Par3, Par6, and PKCzeta, in conjunction with Tiam1-mediated Rac signaling, controls apical-basal cell polarity in contacting epithelial cells. Here we tested the hypothesis that the Par complex, in conjunction with Tiam1, controls "front-rear" polarity during the persistent migration of freely migrating keratinocytes. RESULTS: Wild-type (WT) epidermal keratinocytes lacking cell-cell contacts are stably front-rear polarized and migrate persistently. In contrast, Tiam1-deficient (Tiam1 KO) and (si)Par3-depleted keratinocytes are generally unpolarized and migrate randomly because front-rear polarity is short lived. Immunoprecipitation experiments show that in migrating keratinocytes, Tiam1 associates with Par3 and PKCzeta. Moreover, Par3, PKCzeta, and Tiam1 proteins are enriched at the leading edges of polarized keratinocytes. Tiam1 KO keratinocytes are impaired in chemotactic migration toward growth factors, whereaes haptotactic migration is similar to WT. Par3 depletion or the blocking of PKCzeta signaling in WT keratinocytes impairs chemotaxis but has no additional effect on Tiam1 KO cells. The migratory and morphological defects in keratinocytes with impaired Par-Tiam1 function closely resemble cells with pharmacologically destabilized microtubules (MTs). Indeed, MTs in Tiam1 KO keratinocytes and WT cells treated with a PKCzeta inhibitor are unstable, thereby negatively influencing directional but not random migration. CONCLUSIONS: We conclude that the Par-Tiam1 complex stabilizes front-rear polarization of noncontacting migratory cells, thereby stimulating persistent and chemotactic migration, whereas in contacting keratinocytes, the same complex controls the establishment of long-lasting apical-basal polarity. These findings underscore a remarkable flexibility of the Par polarity complex that, depending on the biological context, controls distinct forms of cellular polarity.     

Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors

We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.     

Mandibular size and shape variation in the hominins at Dmanisi, Republic of Georgia

The hominin fossils of Dmanisi, Republic of Georgia, present an ideal means of assessing levels of skeletal size and shape variation in a fossil hypodigm belonging to the genus Homo because they have been recovered from a spatially and temporally restricted context. We compare variation in mandible size and shape at Dmanisi to that of extant hominoids and extinct hominins. We use height and breadth measurements of the mandibular corpus at the first molar and the symphysis to assess size, and analyze shape based on size-adjusted (using a geometric mean) versions of these four variables. We compare size and shape variation at Dmanisi relative to all possible pairs of individuals within each comparative taxon using an exact resampling procedure of the ratio of D2600 to D211 and the average Euclidean distance (AED) between D2600 and D211, respectively. Comparisons to extant hominoids were conducted at both the specific and subspecific taxonomic levels and to extinct hominins by adopting both a more, and less speciose, hominin taxonomy. Results indicate that the pattern of variation for the Dmanisi hominins does not resemble that of any living species: they exhibit significantly more size variation when compared to modern humans, and they have significantly more corpus shape variation and size variation in corpus heights and overall mandible size than any extant ape species. When compared to fossil hominins they are also more dimorphic in size (although this result is influenced by the taxonomic hypothesis applied to the hominin fossil record). These results highlight the need to re-examine expectations of levels of sexual dimorphism in members of the genus Homo and to account for marked size and shape variation between D2600 and D211 under the prevailing view of a single hominin species at Dmanisi.     

Enzymatic repair of Amadori products

Protein deglycation, a new form of protein repair, involves several enzymes. Fructosamine-3-kinase (FN3K), an enzyme found in mammals and birds, phosphorylates fructosamines on the third carbon of their sugar moiety, making them unstable and causing them to detach from proteins. This enzyme acts particularly well on fructose-epsilon-lysine, both in free form and in the accessible regions of proteins. Mice deficient in FN3K accumulate protein-bound fructosamines and free fructoselysine, indicating that the deglycation mechanism initiated by FN3K is operative in vivo. Mammals and birds also have an enzyme designated ‘FN3K-related protein’ (FN3KRP), which shares ≈65% sequence identity with FN3K. Unlike FN3K, FN3KRP does not phosphorylate fructosamines, but acts on ribulosamines and erythrulosamines. As with FN3K, the third carbon is phosphorylated and this leads to destabilization of the ketoamines. Experiments with intact erythrocytes indicate that FN3KRP is also a protein-repair enzyme. Its physiological substrates are most likely formed from ribose 5-phosphate and erythrose 4-phosphate, which give rise to ketoamine 5- or 4-phosphates. The latter are dephosphorylated by ‘low-molecular-weight protein-tyrosine-phosphatase-A’ (LMW-PTP-A) before FN3KRP transfers a phosphate on the third carbon. The specificity of FN3K homologues present in plants and bacteria is similar to that of mammalian FN3KRP, suggesting that deglycation of ribulosamines and/or erythrulosamines is an ancient mechanism. Mammalian cells contain also a phosphatase acting on fructosamine 6-phosphates, which result from the reaction of proteins with glucose 6-phosphate.     

Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy

Adult skeletal muscles adapt their fiber size to workload. We show that serum response factor (Srf) is required for satellite cell-mediated hypertrophic muscle growth. Deletion of Srf from myofibers and not satellite cells blunts overload-induced hypertrophy, and impairs satellite cell proliferation and recruitment to pre-existing fibers. We reveal a gene network in which Srf within myofibers modulates interleukin-6 and cyclooxygenase-2/interleukin-4 expressions and therefore exerts a paracrine control of satellite cell functions. In Srf-deleted muscles, in vivo overexpression of interleukin-6 is sufficient to restore satellite cell proliferation but not satellite cell fusion and overall growth. In contrast cyclooxygenase-2/interleukin-4 overexpression rescue satellite cell recruitment and muscle growth without affecting satellite cell proliferation, identifying altered fusion as the limiting cellular event. These findings unravel a role for Srf in the translation of mechanical cues applied to myofibers into paracrine signals, which in turn will modulate satellite cell functions and support muscle growth.     

Body segment differences in surface area, skin temperature and 3D displacement and the estimation of heat balance during locomotion in hominins

The conventional method of estimating heat balance during locomotion in humans and other hominins treats the body as an undifferentiated mass. This is problematic because the segments of the body differ with respect to several variables that can affect thermoregulation. Here, we report a study that investigated the impact on heat balance during locomotion of inter-segment differences in three of these variables: surface area, skin temperature and rate of movement. The approach adopted in the study was to generate heat balance estimates with the conventional method and then compare them with heat balance estimates generated with a method that takes into account inter-segment differences in surface area, skin temperature and rate of movement. We reasoned that, if the hypothesis that inter-segment differences in surface area, skin temperature and rate of movement affect heat balance during locomotion is correct, the estimates yielded by the two methods should be statistically significantly different. Anthropometric data were collected on seven adult male volunteers. The volunteers then walked on a treadmill at 1.2 m/s while 3D motion capture cameras recorded their movements. Next, the conventional and segmented methods were used to estimate the volunteers' heat balance while walking in four ambient temperatures. Lastly, the estimates produced with the two methods were compared with the paired t-test. The estimates of heat balance during locomotion yielded by the two methods are significantly different. Those yielded by the segmented method are significantly lower than those produced by the conventional method. Accordingly, the study supports the hypothesis that inter-segment differences in surface area, skin temperature and rate of movement impact heat balance during locomotion. This has important implications not only for current understanding of heat balance during locomotion in hominins but also for how future research on this topic should be approached.     

Separation of human metaphase chromosomes at neutral pH by velocity sedimentation at 20 times gravity

A method for the separation of large quantities of human metaphase chromosomes at neutral pH is described. The separation was performed in a specially designed sedimentation chamber which was placed in a bucket of a speed-controlled centrifuge. Flow deflectors in the chamber allowed both the undisturbed introduction of gradient and chromosomes, as well as the undisturbed fractionation of the content of the chamber. The centrifuge was run at 20 g for 1 h taking care of slow acceleration and deceleration. The slow morphological changes of the chromosomes due to ageing at neutral pH do not affect the resolving power of the sedimentation technique within this hour. This in contrast to separation of chromosomes at neutral pH by velocity sedimentation at unit gravity during 20 h, as described before. The main advantage of chromosome sorting at neutral pH is that the fractionated chromosomes are more suitable for gene transfer and gene mapping experiments.