Citations

Humans show considerable interindividual variation in susceptibility to weight gain in response to overeating. The physiological basis of this variation was investigated by measuring changes in energy storage and expenditure in 16 nonobese volunteers who were fed 1000 kilocalories per day in excess of weight-maintenance requirements for 8 weeks. Two-thirds of the increases in total daily energy expenditure was due to increased nonexercise activity thermogenesis (NEAT), which is associated with fidgeting, maintenance of posture, and other physical activities of daily life. Changes in NEAT accounted for the 10-fold differences in fat storage that occurred and directly predicted resistance to fat gain with overfeeding (correlation coefficient = 0.77, probability < 0.001). These results suggest that as humans overeat, activation of NEAT dissipates excess energy to preserve leanness and that failure to activate NEAT may result in ready fat gain.

ErbB-4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding of its ligand heregulin (HRG) or activation of protein kinase C (PKC) by 12- O -tetradecanoylphorbol-13-acetate (TPA), the ErbB-4 ectodomain is cleaved by a metalloprotease. We now report a subsequent cleavage by γ-secretase that releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus. γ-Secretase cleavage was prevented by chemical inhibitors or a dominant negative presenilin. Inhibition of γ-secretase also prevented growth inhibition by HRG. γ-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase–mediated signaling.

p53 acts as a tumor suppressor by inducing both growth arrest and apoptosis. p53-induced apoptosis can occur without new RNA synthesis through an unknown mechanism. In human vascular smooth muscle cells, p53 activation transiently increased surface Fas (CD95) expression by transport from the Golgi complex. Golgi disruption blocked both p53-induced surface Fas expression and apoptosis. p53 also induced Fas-FADD binding and transiently sensitized cells to Fas-induced apoptosis. In contrast, lpr and gld fibroblasts were resistant to p53-induced apoptosis. Thus, p53 can mediate apoptosis through Fas transport from cytoplasmic stores.

The T cell receptor (TCR) inherently has dual specificity. T cells must recognize self-antigens in the thymus during maturation and then discriminate between foreign pathogens in the periphery. A molecular basis for this cross-reactivity is elucidated by the crystal structure of the alloreactive 2C TCR bound to self peptide–major histocompatibility complex (pMHC) antigen H-2K b –dEV8 refined against anisotropic 3.0 angstrom resolution x-ray data. The interface between peptide and TCR exhibits extremely poor shape complementarity, and the TCR β chain complementarity-determining region 3 (CDR3) has minimal interaction with the dEV8 peptide. Large conformational changes in three of the TCR CDR loops are induced upon binding, providing a mechanism of structural plasticity to accommodate a variety of different peptide antigens. Extensive TCR interaction with the pMHC α helices suggests a generalized orientation that is mediated by the V α domain of the TCR and rationalizes how TCRs can effectively “scan” different peptides bound within a large, low-affinity MHC structural framework for those that provide the slight additional kinetic stabilization required for signaling.

An ultrasound method based on radiation force is presented for imaging the acoustic response of a material to mechanical excitation. Acoustic energy was emitted from solids and tissues in response to an oscillatory radiation force produced by interfering focused beams of ultrasound. Frequency spectra of ultrasound-stimulated acoustic emission exhibited object resonances. Raster-scanning the radiation force over the object and recording the amplitude and phase of the emitted sound resulted in data from which images related to the elastic compositions of the acoustically emitting objects could be computed. Acoustic emission signals distinguished tuning-fork resonances, submillimeter glass spheres, and calcification in excised arteries and detected object motions on the order of nanometers.

A methodology was developed for determining the compressive properties of the supraspinatus tendon, based on finite element principles. Simplified three-dimensional models were created based on anatomical thickness measurements of unloaded supraspinatus tendons over 15 points. The tendon material was characterized as a composite structure of longitudinally arranged collagen fibers within an extrafibrillar matrix. The matrix was formulated as a hyperelastic material described by the Ogden form of the strain energy potential. The hyperelastic material parameters were parametrically manipulated until the analytical load-displacement results were similar to the results obtained from indentation testing. In the geometrically averaged tendon, the average ratio of experimental to theoretical maximum indentation displacement was 1.00 (SD: 0.01). The average normalization of residuals was 2.1g (SD: 0.9g). Therefore, the compressive material properties of the supraspinatus tendon extrafibrillar matrix were adequately derived with a first-order hyperelastic formulation. The initial compressive elastic modulus ranged from 0.024 to 0.090 MPa over the tendon surface and increased nonlinearly with additional compression. Using these material properties, the stresses induced during acromional impingement can be analyzed.

The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of rejection responses. Hyperacute rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute vascular rejection and cellular rejection, however, may present important opportunities for immunological tolerance, and humoral rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.

ABSTRACT Although immune responses are generally considered to be systemic, local events such as interaction of complement products with blood vessels and with inflammatory cells play a pivotal role in determining the nature and manifestations of immune responses. This paper will discuss how blood vessel physiology and immunity influence one another to reach homeostasis upon exposure to an infectious agent. We review new insights into the mechanisms by which the microenvironment of tissues protects against microbial invasion yet facilitates migration of leukocytes and ‘decides’ whether immunity or tolerance ensues and whether, in the face of immunity, protective responses or tissue injury ensues. These ‘decisions’ are made based on interaction of components of normal tissues such as proteoglycans and injured tissues such as cell‐associated cytokines with receptors on immune cells and blood vessels.—Saadi, S., Wrenshall, L. E., Platt, J. L. Regional manifestations and control of the immune system. FASEB J. 16, 849–856 (2002)

ABSTRACT Atherosclerotic arteries frequently become calcified, and these calcium deposits are associated with a high risk of adverse clinical events. Descriptive studies suggest calcification is an organized and regulated process with many similarities to osteogenesis, yet the mechanism and its relationship to atherosclerosis remain largely unknown. In bone development and homeostasis, mineral deposition by osteoblasts and mineral resorption by osteoclasts are delicately balanced such that there is no overall gain or loss in bone mass. We hypothesize that there exists in arteries a mechanism that similarly balances mineral deposition with resorption. We propose that the cellular mediators of arterial mineral resorption are osteoclast‐like cells (OLCs) derived from hematopoietic precursors of the mononuclear phagocytic lineage. In arterial microenvironments, mononuclear precursors are induced to differentiate toward OLCs by macrophage‐colony stimulating factor and receptor activator of NF‐κB ligand, both of which are necessary and sufficient for osteoclastogenesis and mineral resorption in bone. OLCs may participate in normal mineral homeostasis within the arterial wall or, alternatively, may be recruited to specific sites within developing plaque. Net calcium deposition occurs as a result of focal perturbation of the balance between the activity of osteoblast‐like cells and OLCs. Our proposed mechanism thus views arterial mineral deposition not so much as an active pathological process, but as a localized failure of protective mechanisms that actively oppose mineral deposition within the disordered metabolic milieu of developing atherosclerotic plaque.—Doherty, T. M., Uzui, H., Fitzpatrick, L. A., Tripathi, P. V., Dunstan, C. R., Asotra, K., Rajavashisth, T. B. Rationale for the role of osteoclast‐like cells in arterial calcification. FASEB J. 16, 577–582 (2002)