Nuclear lamin functions and disease

Recent studies have shown that premature cellular senescence and normal organ development and function depend on the type V intermediate filament proteins, the lamins, which are major structural proteins of the nucleus. This review presents an up-to-date summary of the literature describing new findings on lamin functions in various cellular processes and emphasizes the relationship between the lamins and devastating diseases ranging from premature aging to cancer. Recent insights into the structure and function of the A- and B- type lamins in normal cells and their dysfunctions in diseased cells are providing novel targets for the development of new diagnostic procedures and disease intervention. We summarize these recent findings, focusing on data from mice and humans, and highlight the expanding knowledge of these proteins in both healthy and diseased cells.     

Follicular dendritic cells emerge from ubiquitous perivascular precursors

The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived cells abolished FDC, indicating that FDC originate from PDGFRβ(+) cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation.     

Exocytotic fusion pore stability and topological defects in the membrane with orientational degree of ordering

Regulated exocytosis is a process that strongly depends on the formation and stability of the fusion pore. It was indicated experimentally and theoretically that narrow and highly curved fusion pore may be stabilized by accumulation of anisotropic membrane components possessing orientational ordering. On the other hand, narrow fusion pore may also undergo repetitive opening and closing, disruption in the so called kiss and run process or become completely opened in the process of full fusion of the vesicle with the membrane. In this paper we attempt to elucidate the subtle interplay between the stabilizing and destabilizing processes in the fusion neck. A possible physical mechanism which may lead to disruption of the stable fusion pore or complete fusion of the vesicle with the membrane is discussed. It is indicated that topologically driven defects of the in-plane orientational membrane ordering in the region of the fusion pore may disrupt the fusion. Alternatively, it may facilitate repetitive opening and closing of the fusion pore or induce full fusion of the vesicle with the target membrane.     

Myrigalone A inhibits Lepidium sativum seed germination by interference with gibberellin metabolism and apoplastic superoxide production required for embryo extension growth and endosperm rupture

Myrica gale L. (sweet gale) fruit leachate contains myrigalone A (MyA), a rare C-methylated dihydrochalcone and putative allelochemical, which is known to be a phytotoxin impeding seedling growth. We found that MyA inhibited Lepidium sativum L. seed germination in a dose-dependent manner. MyA did not affect testa rupture, but inhibited endosperm rupture and the transition to subsequent seedling growth. MyA inhibited micropylar endosperm cap (CAP) weakening and the increase in the growth potential of the radical/hypocotyl region (RAD) of the embryo, both being key processes required for endosperm rupture. We compared the contents of abscisic acid (ABA) and gibberellins in the tissues and found that the major bioactive forms of gibberellin in L. sativum seed tissues were GA(4) and GA(6), while GA(8) and GA(13) were abundant inactive metabolites. MyA did not appreciably affect the ABA contents, but severely interfered with gibberellin metabolism and signaling by inhibiting important steps catalyzed by GA3 oxidase, as well as by interfering with the GID1-type gibberellin signaling pathway. The hormonally and developmentally regulated formation of apoplastic superoxide radicals is important for embryo growth. Specific zones within the RAD were associated with accumulation of apoplastic superoxide radicals and endoreduplication indicative of embryo cell extension. MyA negatively affected both of these processes and acted as a scavenger of apoplastic reactive oxygen species. We propose that MyA is an allelochemical with a novel mode of action on seed germination.     

An alternative theoretical approach to escape decision-making: the role of visual cues

Escape enables prey to avoid an approaching predator. The escape decision-making process has traditionally been interpreted using theoretical models that consider ultimate explanations based on the cost/benefit paradigm. Ultimate approaches, however, suffer from inseparable extra-assumptions due to an inability to accurately parameterize the model's variables and their interactive relationships. In this study, we propose a mathematical model that uses intensity of predator-mediated visual stimuli as a basic cue for the escape response. We consider looming stimuli (i.e. expanding retinal image of the moving predator) as a cue to flight initiation distance (FID; distance at which escape begins) of incubating Mallards (Anas platyrhynchos). We then examine the relationship between FID, vegetation cover and directness of predator trajectory, and fit the resultant model to experimental data. As predicted by the model, vegetation concealment and directness of predator trajectory interact, with FID decreasing with increased concealment during a direct approach toward prey, but not during a tangential approach. Thus, we show that a simple proximate expectation, which involves only visual processing of a moving predator, may explain interactive effects of environmental and predator-induced variables on an escape response. We assume that our proximate approach, which offers a plausible and parsimonious explanation for variation in FID, may serve as an evolutionary background for traditional, ultimate explanations and should be incorporated into interpretation of escape behavior.     

Relationship between Audiometric slope and tinnitus pitch in tinnitus patients: insights into the mechanisms of tinnitus generation

Background

Different mechanisms have been proposed to be involved in tinnitus generation, among them reduced lateral inhibition and homeostatic plasticity. On a perceptual level these different mechanisms should be reflected by the relationship between the individual audiometric slope and the perceived tinnitus pitch. Whereas some studies found the tinnitus pitch corresponding to the maximum hearing loss, others stressed the relevance of the edge frequency. This study investigates the relationship between tinnitus pitch and audiometric slope in a large sample.

Methodology

This retrospective observational study analyzed 286 patients. The matched tinnitus pitch was compared to the frequency of maximum hearing loss and the edge of the audiogram (steepest hearing loss) by t-tests and correlation coefficients. These analyses were performed for the whole group and for sub-groups (uni- vs. bilateral (117 vs. 338 ears), pure-tone vs. narrow-band (340 vs. 115 ears), and low and high audiometric slope (114 vs. 113 ears)).

Findings

For the right ear, tinnitus pitch was in the same range and correlated significantly with the frequency of maximum hearing loss, but differed from and did not correlate with the edge frequency. For the left ear, similar results were found but the correlation between tinnitus pitch and maximum hearing loss did not reach significance. Sub-group analyses (bi- and unilateral, tinnitus character, slope steepness) revealed identical results except for the sub-group with high audiometric slope which revealed a higher frequency of maximum hearing loss as compared to the tinnitus pitch.

Conclusion

The study-results confirm a relationship between tinnitus pitch and maximum hearing loss but not to the edge frequency, suggesting that tinnitus is rather a fill-in-phenomenon resulting from homeostatic mechanisms, than the result of deficient lateral inhibition. Sub-group analyses suggest that audiometric steepness and the side of affected ear affect this relationship. Future studies should control for these potential confounding factors.     

A role for intracellular calcium downstream of G-protein signaling in undifferentiated human embryonic stem cell culture

Multiple signalling pathways maintain human embryonic stem cells (hESC) in an undifferentiated state. Here we sought to define the significance of G protein signal transduction in the preservation of this state distinct from other cellular processes. Continuous treatment with drugs targeting G(αs)-, G(α-i/o)- and G(α-q/11)-subunit signalling mediators were assessed in independent hESC lines after 7days to discern effects on normalised alkaline phosphatase positive colony frequency vs total cell content. This identified PLCβ, intracellular free calcium and CAMKII kinase activity downstream of G(α-q/11) as of particular importance to the former. To confirm the significance of this finding we generated an agonist-responsive hESC line transgenic for a G(α-q/11) subunit-coupled receptor and demonstrated that an undifferentiated state could be promoted in the presence of an agonist without exogenously supplied bFGF and that this correlated with elevated intracellular calcium. Similarly, treatment of unmodified hESCs with a range of intracellular free calcium-modulating drugs in biologically defined mTESR culture system lacking exogenous bFGF promoted an hESC phenotype after 1week of continuous culture as defined by co-expression of OCT4 and NANOG. At least one of these drugs, lysophosphatidic acid significantly elevates phosphorylation of calmodulin and STAT3 in this culture system (p<0.05). These findings substantiate a role for G-protein and calcium signalling in undifferentiated hESC culture.     

Theories of willpower affect sustained learning

Building cognitive abilities often requires sustained engagement with effortful tasks. We demonstrate that beliefs about willpower-whether willpower is viewed as a limited or non-limited resource-impact sustained learning on a strenuous mental task. As predicted, beliefs about willpower did not affect accuracy or improvement during the initial phases of learning; however, participants who were led to view willpower as non-limited showed greater sustained learning over the full duration of the task. These findings highlight the interactive nature of motivational and cognitive processes: motivational factors can substantially affect people's ability to recruit their cognitive resources to sustain learning over time.