Microtubules are supramolecular structures that make up the cytoskeleton and strongly affect the mechanical properties of the cell. Within the cytoskeleton filaments, the microtubule (MT) exhibits by far the highest bending stiffness. Bending stiffness depends on the mechanical properties and intermolecular interactions of the tubulin dimers (the MT building blocks). Computational molecular modeling has the potential for obtaining quantitative insights into this area. However, to our knowledge, standard molecular modeling techniques, such as molecular dynamics (MD) and normal mode analysis (NMA), are not yet able to simulate large molecular structures like the MTs; in fact, their possibilities are normally limited to much smaller protein complexes. In this work, we developed a multiscale approach by merging the modeling contribution from MD and NMA. In particular, MD simulations were used to refine the molecular conformation and arrangement of the tubulin dimers inside the MT lattice. Subsequently, NMA was used to investigate the vibrational properties of MTs modeled as an elastic network. The coarse-grain model here developed can describe systems of hundreds of interacting tubulin monomers (corresponding to up to 1,000,000 atoms). In particular, we were able to simulate coarse-grain models of entire MTs, with lengths up to 350 nm. A quantitative mechanical investigation was performed; from the bending and stretching modes, we estimated MT macroscopic properties such as bending stiffness, Young modulus, and persistence length, thus allowing a direct comparison with experimental data.

Lifelong differences in adult body composition and fat distribution between the low- and high-birth-weight groups are consistent with programming in early life. The use of BMI to predict percentage body fat and the use of the trunk-to-limb skinfold thickness ratio (and waist-to-hip ratio) to predict the trunk-to-limb fat ratio measured by DXA can be misleading when low- and high-birth-weight groups are compared.

In recent years there has been an increased interest in the treatment of acquired pes planus. The breakdown of the medial longitudinal arch is most often seen at the talonaviculocalcaneal articulation. This suggests a relationship between the ligamentous complex at this articulation and acquired pes planus. This study was undertaken to gain a better understanding of the gross, histologic, and microvascular anatomy, as well as the biomechanics of the ligamentous structures surrounding the talonaviculocalcaneal articulation. Cadaver dissections of 38 fresh-frozen feet were performed. Detailed descriptions of the gross anatomy of the superomedial calcaneonavicular ligament, inferior calcaneonavicular ligament, and the superficial deltoid ligament were recorded. Their relationships to the posterior tibialis tendon and to the bones of the talonaviculocalcaneal articulation are described. The histology and microvascularity of these structures were also studied. Preliminary biomechanical testing was performed. It was found there are two definitive anatomic structures that are commonly called the spring ligament: the superomedial calcaneonavicular ligament (SMCN) and the inferior calcaneonavicular ligament (ICN). The SMCN ligament was found to have histologic properties that suggest significant load bearing. The histology of the ICN ligament suggests a pure tensile load function. The deltoid ligament and the posterior tibialis tendon had direct attachments to the SMCN ligament in all specimens. An articular facet composed of fibrocartilage was found in each SMCN ligament specimen. The microvascular structures showed an avascular articular facet present in the ligament. The biomechanical testing showed that the SMCN ligament and ICN ligament had strength similar to ankle ligaments. This study suggests this "spring ligament complex" has more of a "sling" function for the talar head. It is hoped that the better understanding of this region will add to our understanding of the etiology of pes planus and possible treatment alternatives.

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Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first-and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.pemphigus | autoantibody | protein microarray P emphigus vulgaris (PV) is a blistering autoimmune skin disease characterized by the presence of autoantibodies (autoAbs) directed against keratinocyte surface antigens (1, 2). Although early immunofluorescence studies demonstrated the presence of autoAbs in patient sera that bound to the surface of keratinocytes, a direct role of autoAbs in disease pathogenesis was not established until purified patient IgG (PVIgG) was shown to elicit blister formation upon passive transfer in mice (3). The main targets of these autoAbs were identified as Desmoglein (Dsg) 3 and 1, cadherin proteins that constitute key components of desmosomes, protein complexes responsible for maintaining cell-cell adhesion (4-7). Later experiments in which patient sera depleted of anti-Dsg3 Abs failed to produce blisters when passively transferred to mice (8) seemingly cemented the notion that these autoAbs alone were responsible for blister formation. As a result, subsequent research in the field has focused primarily on autoAbs directed against Dsgs.The assertion that anti-Dsg autoAbs alone are pathogenic was first challenged when PVIgG, lacking any anti-Dsg1 autoAbs, produced blisters when passively transferred into Dsg3-null mice (9). Additionally, several studies have shown that anti-Dsg Ab titers do not necessarily correlate with disease activity, and a subset of patients with PV do not harbor any detectable anti-Dsg Abs (10-14). The presence of pathogenic autoAbs directed against non-Dsg targets could account for th...

images in clinical medicineT h e n e w e ng l a n d j o u r na l o f m e dic i n e n engl j med 358;6 www.nejm.org february 7, 2008 625 A 55-year-old man presented with a 2-year history of painful jaw enlargement and progressively ill-fitting dentures. He had no headaches or visual-field defects and did not have hyperhidrosis, oily skin, glucose intolerance, heart failure, or an increase in glove or shoe size. The entire mandible was enlarged bilaterally to the angle of the jaw (Panels A and B), with marked misalignment of the upper and lower teeth. The serum level of insulin-like growth factor I was normal at 15.2 nmol per liter (normal range, 9 to 40), but levels of serum alkaline phosphatase and bone-specific alkaline phosphatase were elevated (154 IU per liter [normal level, <120] and 92 IU per liter [normal range, 15 to 41], respectively). A bone scan revealed increased uptake of radionuclide in the jaw (Panel C); no other bones were involved. A mandibular biopsy confirmed the diagnosis of Paget's disease; there was no evidence of osteosarcoma. Treatment with a bisphosphonate normalized the serum level of alkaline phosphatase. Earlier diagnosis and treatment might have limited further mandibular hypertrophy and pain, which the patient had for some time.

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and the Hertfordshire Study Group. Substrate-energy metabolism and metabolic risk factors for cardiovascular disease in relation to fetal growth and adult body composition. Am J Physiol Endocrinol Metab 291: E365-E371, 2006. First published March 28, 2006 doi:10.1152/ajpendo.00599.2005.-The effect of fetal programming on intermediary metabolism is uncertain. Therefore, we examined whether fetal programming affects oxidative and nonoxidative macronutrient metabolism and the prevalence of the metabolic syndrome in adult life. Healthy older men, aged 64 -72 years, with either a lower birth weight (LBW, Յ25th %ile; n ϭ 16) or higher birth weight (HBW, Ն75th %ile; n ϭ 13) had measurements of 1) net oxidative metabolism using indirect calorimetry before and for 6 h after a mixed meal (3,720 kJ) and 2) postprandial oxidation of exogenous [13 C]palmitic acid. Body composition was measured using dual-energy X-ray absorptiometry. After adjustment for current weight and height, the LBW group had a lower resting energy expenditure (REE) in the preprandial (4.01 vs. 4.54 kJ/min, P ϭ 0.015) and postprandial state (4.60 vs. 5.20 kJ/min, P ϭ 0.004), and less fat-free mass than the HBW group. The BW category was a significant, independent, and better predictor of REE than weight plus height. There were no significant differences between groups in net oxidative and nonoxidative macronutrient (protein, fat, carbohydrate) metabolism (or of exogenous [13 C]palmitate) or in the prevalence of the metabolic syndrome, which was present almost twice as commonly in the LBW than in the HBW group. The study suggests that fetal programming affects both pre-and postprandial EE in older life by mechanisms that are at least partly related to the mass of the fat-free body. BW was found to be a significant predictor of REE that was independent of adult weight plus height. energy expenditure; birth weight; body composition; fat; fat-free mass; oxidation ENVIRONMENTAL FACTORS OPERATING during fetal growth are believed to influence the risk of cardiovascular disease, diabetes, hypertension, and obesity in adult life. Despite increasing interest in this field (17,19,24), there is surprisingly little information about programming of even the most basic aspects of human metabolism, such as selection of endogenous and exogenous fuels, oxidative and nonoxidative metabolism of fat carbohydrate and protein, and lipoprotein metabolism. There is also little information about the extent to which any programmed metabolic processes are linked to body composition, fat distribution, and health risk. Although several studies have reported a link between birth weight and glucose tolerance (12,16,23), there is little information as to whether events in early life also affect the way adults handle other fuels, mixture of fuels such as those present in a mixed meal, and whether any such differences are related to percent body fat and its distribution within the body. Furthermore, despite the interest in early-life programming of adiposity and its comorbidities, there...