Evolving anisotropy and degree of elastolytic insult in abdominal aortic aneurysms: Potential clinical relevance?

Accurately estimating patient-specific rupture risk remains a primary challenge in timing interventions for abdominal aortic aneurysms (AAAs). By re-analyzing published biaxial mechanical testing data from surgically repaired human AAAs, material anisotropy emerged as a potentially important determinant of patient-specific lesion progression. That is, based on a new classification scheme, we discovered that anisotropic aneurysmal specimens correlated with increased patient age at surgery when compared with more isotropic specimens (79.7 vs. 70.9 years, p<0.002), despite no significant difference in maximum diameter. Furthermore, using an idealized axisymmetric, finite-element growth and remodeling model of AAA progression, we found that both the initial axial extent of elastin loss and ongoing damage to elastin in the shoulder region of the AAA directly affected the degree of anisotropy as the lesion evolved, with more extensive insults increasing the anisotropy. This effect appeared to be mediated by alterations in axial loading and subsequent differences in orientation of deposited collagen fibers. While the observed increased age before surgical intervention may suggest a potential benefit of anisotropic remodeling, future biaxial tests coupled with pre-surgical data on expansion rates and detailed theoretical analyses of the biostability of a lesion as a function of anisotropy will be required to verify its clinical relevance to patient-specific rupture risk.     

Heparan Sulfate Regulates Hair Follicle and Sebaceous Gland Morphogenesis and Homeostasis

Hair follicle (HF) morphogenesis and cycling are a result of intricate autonomous epithelial-mesenchymal interactions. Once the first HF cycle is complete it repeatedly undergoes cyclic transformations. Heparan sulfate (HS) proteoglycans are found on the cell surface and in the extracellular matrix where they influence a variety of biological processes by interacting with physiologically important proteins, such as growth factors. Inhibition of heparanase (an HS endoglycosidase) in in vitro cultured HFs has been shown to induce a catagen-like process. Therefore, this study aimed to elucidate the precise role of HS in HF morphogenesis and cycling. An inducible tetratransgenic mouse model was generated to excise exostosin glycosyltransferase 1 (Ext1) in keratin 14-positive cells from P21. Interestingly, EXT1^{StEpiΔ/StEpiΔ} mice presented solely anagen HFs. Moreover, waxing the fur to synchronize the HFs revealed accelerated hair regrowth in the EXT1^{StEpiΔ/StEpiΔ} mice and hindered cycling into catagen. The ablation of HS in the interfollicular epidermal cells of mature skin led to the spontaneous formation of new HFs and an increase in Sonic Hedgehog expression resembling wild-type mice at P0, thereby indicating that the HS/Sonic Hedgehog signaling pathway regulates HF formation during embryogenesis and prevents HF formation in mature skin. Finally, the knock-out of HS also led to the morphogenesis and hyperplasia of sebaceous glands and sweat glands in mature mice, leading to exacerbated sebum production and accumulation on the skin surface. Therefore, our findings clearly show that an intricate control of HS levels is required for HF, sebaceous gland, and sweat gland morphogenesis and HF cycling.     

Comprehensive DNA microarray expression profiles of tumors in tenascin-C-knockout mice

Tenascin-C (TNC), an extracellular matrix glycoprotein, plays a pivotal role in tumor growth. However, the mechanism whereby TNC affects tumor biology remains unclear. To investigate the exact role of TNC in primary tumor growth, a mouse mammary tumor cell line, GLMT1, was first developed. Subsequently, global gene expression in GLMT1-derived tumors was compared between wild-type (WT) and TNC-knockout (TNKO) mice. Tumors in WT mice were significantly larger than those in TNKO mice. DNA microarray analysis revealed 447 up and 667 downregulated in the tumors inoculated into TNKO mice as compared to tumors in WT mice. Validation by quantitative gene expression analysis showed that Tnc, Cxcl1, Cxcl2, and Cxcr2 were significantly upregulated in WT mice. We hypothesize that TNC stimulates the CXCL1/2-CXCR2 pathway involved in cancer cell proliferation.     

Endoplasmic reticulum stress in insulin resistance and diabetes

The endoplasmic reticulum is the main intracellular Ca²⁺ store for Ca²⁺ release during cell signaling. There are different strategies to avoid ER Ca²⁺ depletion. Release channels utilize first Ca²⁺-bound to proteins and this minimizes the reduction of the free luminal [Ca²⁺]. However, if release channels stay open after exhaustion of Ca²⁺-bound to proteins, then the reduction of the free luminal ER [Ca²⁺] (via STIM proteins) activates Ca²⁺ entry at the plasma membrane to restore the ER Ca²⁺ load, which will work provided that SERCA pump is active. Nevertheless, there are several noxious conditions that result in decreased activity of the SERCA pump such as oxidative stress, inflammatory cytokines, and saturated fatty acids, among others. These conditions result in a deficient restoration of the ER [Ca²⁺] and lead to the ER stress response that should facilitate recovery of the ER. However, if the stressful condition persists then ER stress ends up triggering cell death and the ensuing degenerative process leads to diverse pathologies; particularly insulin resistance, diabetes and several of the complications associated with diabetes. This scenario suggests that limiting ER stress should decrease the incidence of diabetes and the mobility and mortality associated with this illness.     

Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK–NF-κB pathway

Acute lung injury (ALI) is a serious disease with unacceptably high mortality and morbidity rates. Up to now, no effective therapeutic strategy for ALI has been established. Rutin, quercetin-3-rhamnosyl glucoside, expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. Pretreatment with rutin inhibited not only histopathological changes in lung tissues but also infiltration of polymorphonuclear granulocytes into bronchoalveolar lavage fluid in lipopolysaccharide (LPS)-induced ALI. In addition, LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-κB and MAPK and degradation of IκB, an NF-κB inhibitor. Decreased activities of antioxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 caused by LPS were reversed by rutin. At the same time, we found that ALI amelioration by chelation of extracellular metal ions with rutin is more efficacious than with deferoxamine. These results indicate that the protective mechanism of rutin is through inhibition of MAPK–NF-κB activation and upregulation of antioxidative enzymes.     

How to deal with oxygen radicals stemming from mitochondrial fatty acid oxidation

Oxygen radical formation in mitochondria is an incompletely understood attribute of eukaryotic cells. Recently, a kinetic model was proposed, in which the ratio between electrons entering the respiratory chain via FADH₂ or NADH determines radical formation. During glucose breakdown, the ratio is low; during fatty acid breakdown, the ratio is high (the ratio increasing—asymptotically—with fatty acid length to 0.5, when compared with 0.2 for glucose). Thus, fatty acid oxidation would generate higher levels of radical formation. As a result, breakdown of fatty acids, performed without generation of extra FADH₂ in mitochondria, could be beneficial for the cell, especially in the case of long and very long chained ones. This possibly has been a major factor in the evolution of peroxisomes. Increased radical formation, as proposed by the model, can also shed light on the lack of neuronal fatty acid oxidation and tells us about hurdles during early eukaryotic evolution. We specifically focus on extending and discussing the model in light of recent publications and findings.     

Impact of Bacillus popilliae,Rickettsiella popilliae and entomopathogenic nematodes on a population of the scarabaeid,Cyclocephala hirta

Larvae of the scarabaeid, Cyclocephala hirta, are major pests of turfgrass in California. A field test was conducted against third instars that included the following treatments: untreated control; chemical insecticide (bendiocarb); milky disease bacterium (Bacillus popilliae); and entomopathogenic nematodes (Steinernema feltiae and Heterorhabditis bacteriophora). There were no significant differences in population reduction among the treatments, but the larval population in all plots showed a dramatic decline. The C. hirta population had a natural occurrence of milky disease and blue disease caused by Rickettsiella popilliae. The prevalence of blue disease during the course of the study averaged < 10% but that of milky disease averaged about 20%. More significantly, the soil from all treatment plots when bioassayed for B. popilliae showed that 67–90% of the larvae became infected with this bacterium. None of the larvae became infected with the blue disease organism. We conclude that B. popilliae was occurring in epizootic proportions in our field tests and was a significant mortality factor in causing the decline of the C. hirta population.     

Positioning behaviour in fish shoals: a cost–benefit analysis

Shoal position can have a strong influence on individual fitness. Individuals in front positions of shoals were observed to have higher feeding rates than individuals elsewhere. Manipulation of nutritional state showed that hungry individuals had a stronger preference for front positions and that the duration of food-deprivation was positively correlated with the degree of the position preference. On the other hand, front positions (like other peripheral positions) probably incur costs in terms of increased predation risks. Experiments with Schreckstoff showed that frightened individuals seek the central part of the shoal. This suggests that individuals rotate their shoal positions according to the tradeoff between energy intake and predation risk.