Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors

Hutchinson-Gilford progeria syndrome (HGPS), reportedly a model for normal aging, is a genetic disorder in children marked by dramatic signs suggestive for premature aging. It is usually caused by de novo mutations in the nuclear envelope protein lamin A. Lamins are essential to maintaining nuclear integrity, and loss of lamin A/C results in increased cellular sensitivity to mechanical strain and defective mechanotransduction signaling. Since increased mechanical sensitivity in vascular cells could contribute to loss of smooth muscle cells and the development of arteriosclerosis--the leading cause of death in HGPS patients--we investigated the effect of mechanical stress on cells from HGPS patients. We found that skin fibroblasts from HGPS patients developed progressively stiffer nuclei with increasing passage number. Importantly, fibroblasts from HGPS patients had decreased viability and increased apoptosis under repetitive mechanical strain, as well as attenuated wound healing, and these defects preceded changes in nuclear stiffness. Treating fibroblasts with farnesyltransferase inhibitors restored nuclear stiffness in HGPS cells and accelerated the wound healing response in HGPS and healthy control cells by increasing the directional persistence of migrating cells. However, farnesyltransferase inhibitors did not improve cellular sensitivity to mechanical strain. These data suggest that increased mechanical sensitivity in HGPS cells is unrelated to changes in nuclear stiffness and that increased biomechanical sensitivity could provide a potential mechanism for the progressive loss of vascular smooth muscle cells under physiological strain in HGPS patients.     

Absence of arterial phenotype in mice with homozygous slc2A10 missense substitutions

Arterial tortuosity syndrome (ATS, MIM# 208050) is a rare autosomal recessive connective tissue disease, mainly characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries (Callewaert et al., 2008, Hum Mutat 29:150-158). Recently, mutations were identified in the SLC2A10 gene encoding the facilitative glucose transporter GLUT10 (Coucke et al., 2006, Nat Genet 38:452-457). It was hypothesized that loss-of-function of the transporter results in upregulation of the transforming growth factor beta (TGFbeta) signaling pathway (Coucke et al., 2006, Nat Genet 38:452-457). We anticipated that a mouse model would help to gain more insight in the complex pathophysiological mechanism of human ATS. Here, we report that two mouse models, homozygous respectively for G128E and S150F missense substitutions in glut10 do not present any of the vascular, anatomical, or immunohistological abnormalities as encountered in human ATS patients. We conclude that these mouse strains do not phenocopy human ATS and cannot help the further elucidation of pathogenetic mechanisms underlying this disease.     

Behavioural phenotype affects social interactions in an animal network

Animal social networks can be extremely complex and are characterized by highly non-random interactions between group members. However, very little is known about the underlying factors affecting interaction preferences, and hence network structure. One possibility is that behavioural differences between individuals, such as how bold or shy they are, can affect the frequency and distribution of their interactions within a network. We tested this using individually marked three-spined sticklebacks (Gasterosteus aculeatus), and found that bold individuals had fewer overall interactions than shy fish, but tended to distribute their interactions more evenly across all group members. Shy fish, on the other hand, tended to associate preferentially with a small number of other group members, leading to a highly skewed distribution of interactions. This was mediated by the reduced tendency of shy fish to move to a new location within the tank when they were interacting with another individual; bold fish showed no such tendency and were equally likely to move irrespective of whether they were interacting or not. The results show that animal social network structure can be affected by the behavioural composition of group members and have important implications for understanding the spread of information and disease in social groups.     

Sources of individual variation in plasma testosterone levels

The steroid hormone testosterone (T) plays a central role in the regulation of breeding in males, because many physiological, morphological and behavioural traits related to reproduction are T dependent. Moreover, in many seasonally breeding vertebrates, male plasma T levels typically show a pronounced peak during the breeding season. While such population-level patterns are fairly well worked out, the sources and the implications of the large variability in individual T levels within the seasonal cycle remain surprisingly little understood. Understanding the potential sources of individual variation in T levels is important for behavioural and evolutionary ecologists, for at least two reasons. First, in 'honest signalling' theory, T is hypothesized to play a critical role as the assumed factor that enforces honesty of the expression of sexually selected quality indicators. Second, T is often considered a key mediator of central life-history trade-offs, such as investment in survival versus reproduction or in mating versus parental care. Here, we discuss the patterns of within- and between-individual variation in male plasma T levels in free-living populations of birds. We argue that it is unclear whether this variability mainly reflects differences in underlying individual quality (intrinsic factors such as genetic or maternal effects) or in the environment (extrinsic factors including time of day, individual territorial status and past experience). Research in avian behavioural endocrinology has mainly focused on the effects of extrinsic factors, while other sources of variance are often ignored. We suggest that studies that use an integrative approach and investigate the relative importance of all potential sources of variation are essential for the interpretation of data on individual plasma T levels.     

Directional sensitivity of the retina: 75 years of Stiles-Crawford effect

The reduction of the brightness when a light beam's entry into the eye is shifted from the centre to the edge of the pupil has from the outset been shown to be due to a change in luminous efficiency of radiation when it is incident obliquely on the retina. The phenomenon is most prominent in photopic vision and this has concentrated attention on the properties of retinal cones, where responsibility has yet to be assigned to factors such as differences in shape, fine structure and configuration, and membrane anchoring of photopigment molecules. Geometrical optics and waveguide formulations have been applied to the question of how light is guided in receptors, but details of their geometry and optical parameters even if they become available will make calculations complex and of only moderate generality. In practice, the diminution of oblique light helps visual performance by reducing deleterious influence of ocular aberrations and of glare caused by light scattering when the pupil is wide. Receptor orientation can come into play in ocular conditions due to mechanical disturbance and has been shown to have potentiality as a tool for clinical diagnosis. Currently, open questions include microanatomical and molecular differences between rods and cones, the coupling of the optical image of the eye with the transducing apparatus in the photoreceptors, possible phototropism and more convincing methods of estimating the actual spatial distribution of photon events as it affects visual resolution.     

Apolipoprotein E gene polymorphism and dyslipidaemia in adult Asian Indians: A population based study from Calcutta, India

AIM:

The study was aimed to determine the association of Apolipoprotein E (apo E) gene polymorphisms on lipid levels in Asian Indian population.

METHODS:

A total of 350 (184 males and 166 females) adult (30 years and above) Asian Indians of Calcutta and suburb participated in the study. Anthropometric measures, lipids profiles, and blood glucose measures were collected. Out of 350 subjects, a sample of 70 individuals was selected randomly for genotyping after adjusting for age and sex. The apo E gene polymorphisms were determined by agarose gel electrophoresis.

RESULTS:

The apo E polymorphism showed significant association with dyslipidaemia (P=0.0135) with ε3/4 combination has had the highest occurrence of dyslipidaemia and metabolic syndrome (MS) followed by ε4/4 <ε3/3 <ε2/4 <ε2/3 in decreasing order.

CONCLUSIONS:

The ε4 allele of apo E gene independent of other risk factors is associated with dyslipidaemia in particular with low HDLc and high TC: HDLc ratio.     

Brugada syndrome manifested by the typical electrocardiographic pattern both in the right precordial and the high lateral leads

We identified a patient with the Brugada syndrome and frequent episodes of the traumatic syncope. This patient presented with alternating ST-segment elevation in the right precordial and the high lateral leads. The signal-averaged ECG was positive for the late potentials and electrophysiology study revealed no inducible supraventricular or ventricular tachycardias. Because of the frequent traumatic syncope, a dual-chamber implantable cardioverter-defibrillator was implanted. This report suggests that the Brugada syndrome may have different electrocardiographic presentations within a single individual over a short period of time. The significance of these changes needs to be assessed in a prospective long term study.     

Troponin elevation in patients with various tachycardias and normal epicardial coronaries

Troponin elevation is usually synonymous with acute coronary syndrome (ACS). Although sensitive for ACS, the elevation of serum troponin, in the absence of clinical evidence of ischemia, should prompt a search for other etiologies of myocardial necrosis. In fact, elevated values of troponin are correlated with myocardial necrosis even though it does not discriminate the mechanism involved. We report a series of seven patients (age range 18-67 years), who presented with complaints of chest discomfort and were found to have regular supraventricular tachycardia (5 patients) and one patient each with atrial fibrillation and ventricular tachycardia. All these patients had elevated troponin I and underwent coronary angiography that revealed normal epicardial coronary arteries. This is first case series in which all patients underwent coronary angiography and none of the patients was hemodynamically unstable at the time of presentation. Patients with elevated troponin due to conditions other than ACS can receive inappropriate and delayed definitive diagnosis and treatment.     

Stability of behavioral syndromes but plasticity in individual behavior: consequences for rockfish stock enhancement

This study investigated behavioral syndromes, which are defined as correlations between behaviors. Behavioral syndromes can lead to the unintentional alteration of a wide range of behavioral traits of hatchery fish if unintentional selection on one behavior leads to selection on a correlated behavior. Specifically, this study used brown rockfish, Sebastes auriculatus, to test the hypothesis that a fish that feeds at high rates in the absence of a predator also takes more risks when a predator is present, and that through such a correlation, unintentional hatchery selection for high feeding rates may also lead to changes in risk taking behavior (here defined as behavior that increases predation risk). Behavioral syndromes were found—feeding behavior in the absence of a predator tended to correlate positively with both feeding behavior in the presence of a predator model and time near the model. These syndromes were stable through time—that is, the same correlations appeared 10 days later when the behavioral assays were repeated. However individual behavior was inconsistent (plastic). A fish could both feed and take risks at high rates on Day 1, but then both feed and take risks at low rates on Day 10. Thus, while behavioral syndromes were stable (i.e. present in both rounds 1 and 2), individuals were plastic in their behavior (i.e. inconsistent between rounds 1 and 2). After 16 weeks of hatchery rearing, neither growth nor survival were predicted by behavior. It is suggested that the behavioral plasticity within individuals through time makes consistent selection for strong feeders less likely, and that species with more plastic behavior may be less susceptible to unintentional selection on behavioral syndromes than species with behavior that is more fixed.     

Facilitating sympatric species coexistence via pollinator partitioning in endemic tropical trees of Madagascar

Summary The island of Madagascar ranks second to the neotropics in diversity of Bignoniaceae. Tribe Coleeae (Bignoniaceae) is a monophyletic group of tropical trees endemic to Madagascar and surrounding islands. The Masoala assemblage of Coleeae, in northeastern Madagascar, utilizes four mechanisms for avoiding competition via niche specialization: (1) morphologically via characters that comprise syndromes, explaining part of the pattern in this system – although the syndrome concept is not perfect; (2) spatially via vertical stratification and potentially pollen placement; (3) temporally via phenological stagger; (4) ethologically via flowering duration and display. The 13 sympatric species of understory treelets and canopy trees did receive low flower visitor numbers. Contrary to the prevailing view of pollination systems where generalized systems predict equivalency between floral traits and pollinators, I found that different pollinators pollinated the 13 species of trees, that floral characters of different trees did not overlap in multidimensional phenotype space, and that few species of trees were visited by more than two pollinator groups. The use of multiple niches is potentially important in understanding both the origin and maintenance of tropical tree diversity.