Mitochondrial dysfunction and possible treatments in Parkinson's disease--a review

Mitochondria are central not only to the bioenergetics of the cell but also to the process of apoptotic cell death. Substantial data indicate mitochondrial dysfunction, particularly of complex I of the electron transport chain, in some patients with Parkinson's disease (PD), and it appears likely that mitochondria contribute to the pathogenic processes that occurs in this disorder. Treatments targeted at mitochondrial function hold promise to slow the progression of PD.     

Two distinct mechanisms for induction of dendritic cell apoptosis in response to intact Streptococcus pneumoniae

Apoptotic dendritic cells (DCs) are ineffective at inducing immunity. Thus, parameters that regulate DC viability during a primary infection will help to determine the outcome of the subsequent immune response. In this regard, pathogens have developed strategies to promote DC apoptosis to counterbalance the nascent primary immune response. We demonstrate, using cultured bone marrow-derived DCs, that Streptococcus pneumoniae can induce DC apoptosis through two distinct mechanisms: 1) a rapid, caspase-independent mechanism of apoptosis induction, critically dependent on bacterial expression of pneumolysin, and 2) a delayed-onset, caspase-dependent mechanism of apoptosis induction associated with terminal DC maturation. Delayed-onset apoptosis does not require bacterial internalization, but rather is triggered by the interaction of bacterial subcapsular components and bone marrow-derived DC (likely Toll-like) receptors acting in a myeloid differentiation factor 88-dependent manner. In this regard, heavy polysaccharide encapsulation interferes with both DC maturation and apoptosis induction. In contrast, neither CD95/CD95 ligand interactions nor TNF-alpha appear to play a role in the delayed onset of apoptosis. These data are the first to define two mechanistically distinct pathways of DC apoptosis induction in response to an extracellular bacterium that likely have important consequences for the establishment of antibacterial immunity.     

The effect of tautomeric constant on the specificity of nucleotide incorporation during DNA replication: support for the rare tautomer hypothesis of substitution mutagenesis

The nucleoside analogue dP (6-(2-deoxy-beta-D-ribofuranosyl)-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-2-one) displays ambivalent hydrogen bonding characteristics whereby the imino tautomer of P can base-pair with adenine and its amino tautomer can base-pair with guanine. Fixed imino and amino tautomers of 6-methyl-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-2-one (N-methyl P) have been synthesised and their structures obtained by X-ray crystallography. The tautomeric constant of N-methyl P has been calculated from pK(a) values of the fixed tautomers and the kinetic parameters for the incorporation of its 5'-triphosphate (dPTP) by exonuclease-free Klenow fragment of DNA polymerase I have been determined. A strong correlation between the tautomeric constant and the incorporation specificity of dPTP is found. These results lend support to the proposal that the minor tautomeric forms of the natural bases may play an important role in substitution mutagenesis during DNA replication. Furthermore, they imply that DNA polymerases impose specific steric requirements on the base-pair during nucleotide incorporation.     

Loss of naïve cells accompanies memory CD4+ T-cell depletion during long-term progression to AIDS in Simian immunodeficiency virus-infected macaques

Human immunodeficiency virus and simian immunodeficiency virus (SIV) induce a slow progressive disease, characterized by the massive loss of memory CD4+ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4+ T-cell dynamics and disease progression in 12 SIV-infected rhesus monkeys for nearly 2 years. Three macaques exhibiting a rapid progressor phenotype experienced rapid and irreversible loss of memory, but not na?ve, CD4+ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first 6 months of virus inoculation. In contrast, SIV-infected conventional progressor animals sustained marked but incomplete depletions of memory CD4+ T cells and continuous activation/proliferation of this T-lymphocyte subset. This was associated with a profound loss of na?ve CD4+ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4(+)T cells, which are being eliminated by direct virus killing and activation-induced cell death, requires the continuous differentiation of na?ve into memory CD4+ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the na?ve CD4+T-cell pool and the development of disease.     

In vivo knee moments and shear after total knee arthroplasty

Tibiofemoral loading is very important in cartilage degeneration as well as in component survivorship after total knee arthroplasty. We have previously reported the axial knee forces in vivo. In this study, a second-generation force-sensing device that measured all six components of tibial forces was implanted in a 74-kg, 83-year-old male. Video motion analysis, ground reaction forces, and knee forces were measured during walking, stair climbing, chair-rise, and squat activities. Peak total force was 2.3 times body weight (BW) during walking, 2.5 x BW during chair rise, 3.0 x BW during stair climbing, and 2.1 x BW during squatting. Peak anterior shear force at the tibial tray was 0.30 x BW during walking, 0.17 x BW during chair rise, 0.26 x BW during stair climbing, and 0.15 x BW during squatting. Peak flexion moment at the tray was 1.9% BW x Ht (percentage of body weight multiplied by height) for chair-rise activity and 1.7% BW x Ht for squat activity. Peak adduction moment at the tray was -1.1% BW x Ht during chair-rise, -1.3% BW x Ht during squatting. External knee flexion and adduction moments were substantially greater than flexion and adduction moments at the tray. The axial component of forces predominated especially during the stance phase of walking. Shear forces and moments at the tray were very modest compared to total knee forces. These findings indicate that the soft tissues around the knee absorbed most of the external shear forces. Our results highlight the importance of direct measurements of knee forces.     

GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin alpha5beta1-fibronectin interaction

Carcinoembryonic antigen (CEA) and CEA family member CEACAM6 are glycophosphatidyl inositol (GPI)-anchored, intercellular adhesion molecules that are up-regulated in a wide variety of human cancers, including colon, breast, and lung. When over-expressed in a number of cellular systems, these molecules are capable of inhibiting cellular differentiation and anoikis, as well as disrupting cell polarization and tissue architecture, thus increasing tumorigenicity. The present study shows that perturbation of the major fibronectin receptor, integrin alpha5beta1, underlies some of these biological effects. Using confocal microscopy and specific antibodies, CEA and CEACAM6 were demonstrated to co-cluster with integrin alpha5beta1 on the cell surface. The presence of CEA and CEACAM6 was shown to lead to an increase in the binding of the integrin alpha5beta1 receptor to its ligand fibronectin, without changing its cell surface levels, resulting in increased adhesion of CEA/CEACAM6-expressing cells to fibronectin. More tenacious binding of free fibronectin to cells led to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. Disruption of this process with specific monoclonal antibodies against either fibronectin or integrin alpha5beta1 led to the restoration of cellular differentiation and anoikis in CEA/CEACAM6 producing cells.     

The impact of arm-crank position on the drag of a paralympic hand-cyclist

The aerodynamic features associated with the rotation of a cyclist’s legs have long been a research topic for sport scientists and engineers, with studies in recent years shedding new light on the flow structures and drag trends. While the arm-crank rotation cycle of a hand-cyclist bears some resemblance to the leg rotation of a traditional cyclist, the aerodynamics around the athlete are fundamentally different due to the proximity and position of the athlete’s torso with respect to their arms, especially since both arm-cranks move in phase with each other. This research investigates the impact of arm-crank position on the drag acting on a hand-cyclist and is applied to a hill descent position where the athlete is not pedalling. Four primary arm-crank positions, namely 3, 6, 9, and 12 o’clock of a Paralympic hand-cyclist were investigated with CFD for five yaw angles, namely 0°, 5°, 10°, 15°, and 20°. The results demonstrated that the 3 and 12 o’clock positions (when observed from the left side of the hand-cyclist) yielded the highest drag area at 0° yaw, while the 9 o’clock position yielded the lowest drag area for all yaw angles. This is in contrast to the 6 o’clock position traditionally held by hand-cyclists during a descent to reduce aerodynamic drag.     

Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent

Female 129:Stat1-null mice (129S6/SvEvTac-Stat1^tm1Rds homozygous) uniquely develop estrogen-receptor (ER)-positive mammary tumors. Herein we report that the mammary glands (MG) of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP) fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment.     

A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology

IntroductionThe two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand.AimTo determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology–surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology.MethodsBetween April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 monthsResultsCNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17).ConclusionCNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients.

Trial Registration

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