Perturbative study of large NN principal chiral model with twisted reduction

We compute the first four perturbative coefficients of the internal energy for the twisted reduced principal chiral model (TRPCM) using numerical stochastic perturbation theory (NSPT). This matrix model has the same large $N$ limit as the ordinary principal chiral model (PCM) at infinite volume. Indeed, we verify that the first three coefficients match the analytic result for the PCM coefficients at large $N$ with a precision of three to four significant digits. The fourth coefficient also matches our own NSPT calculation of the corresponding PCM coefficient at large $N$. The finite-$N$ corrections to all coefficients beyond the leading order are smaller for TRPCM than for PCM. We analyze the variance to determine the feasibility of extending the calculations to higher orders.Comment: 27 pages, 12 figures, using ws-ijmpa.cls style, using siunitx version

Autophagy down regulates pro-inflammatory mediators in BV2 microglial cells and rescues both LPS and alpha-synuclein induced neuronal cell death

Autophagy is a fundamental cellular homeostatic mechanism, whereby cells autodigest parts of their cytoplasm for removal or turnover. Neurodegenerative disorders are associated with autophagy dysregulation, and drugs modulating autophagy have been successful in several animal models. Microglial cells are phagocytes in the central nervous system (CNS) that become activated in pathological conditions and determine the fate of other neural cells. Here, we studied the effects of autophagy on the production of pro-inflammatory molecules in microglial cells and their effects on neuronal cells. We observed that both trehalose and rapamycin activate autophagy in BV2 microglial cells and down-regulate the production of pro-inflammatory cytokines and nitric oxide (NO), in response to LPS and alpha-synuclein. Autophagy also modulated the phosphorylation of p38 and ERK1/2 MAPKs in BV2 cells, which was required for NO production. These actions of autophagy modified the impact of microglial activation on neuronal cells, leading to suppression of neurotoxicity. Our results demonstrate a novel role for autophagy in the regulation of microglial cell activation and pro-inflammatory molecule secretion, which may be important for the control of inflammatory responses in the CNS and neurotoxicity.Fil: Bussi, Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Peralta Ramos, Javier María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Gaviglio, Emilia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Gallea, Jose Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; ArgentinaFil: Wang, Ji Ming. National Cancer Institute at Frederick; Estados UnidosFil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; ArgentinaFil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentin

Broken conformal invariance and spectrum of anomalous dimensions in QCD

Employing the operator algebra of the conformal group and the conformal Ward identities, we derive the constraints for the anomalies of dilatation and special conformal transformations of the local twist-2 operators in Quantum Chromodynamics. We calculate these anomalies in the leading order of perturbation theory in the minimal subtraction scheme. From the conformal consistency relation we derive then the off-diagonal part of the anomalous dimension matrix of the conformally covariant operators in the two-loop approximation of the coupling constant in terms of these quantities. We deduce corresponding off-diagonal parts of the Efremov-Radyushkin-Brodsky-Lepage kernels responsible for the evolution of the exclusive distribution amplitudes and non-forward parton distributions in the next-to-leading order in the flavour singlet channel for the chiral-even parity-odd and -even sectors as well as for the chiral-odd one. We also give the analytical solution of the corresponding evolution equations exploiting the conformal partial wave expansion.Comment: 45 pages, LaTeX, 6 figures; typos fixe

Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

Autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, but the exact mechanisms and causal connections are not clear and most previous work was done in neurons and not in microglial cells. Here, we report that exogenous fibrillary, but not monomeric, alpha-synuclein (AS, also known as SNCA) induces autophagy in microglial cells. We extensively studied the dynamics of this response using both live-cell imaging and correlative light-electron microscopy (CLEM), and found that it correlates with lysosomal damage and is characterised by the recruitment of the selective autophagy-associated proteins TANK-binding kinase 1 (TBK1) and optineurin (OPTN) to ubiquitylated lysosomes. In addition, we observed that LC3 (MAP1LC3B) recruitment to damaged lysosomes was dependent on TBK1 activity. In these fibrillar AS-treated cells, autophagy inhibition impairs mitochondrial function and leads to microglial cell death. Our results suggest that microglial autophagy is induced in response to lysosomal damage caused by persistent accumulation of AS fibrils. Importantly, triggering of the autophagic response appears to be an attempt at lysosomal quality control and not for engulfment of fibrillar AS.Fil: Bussi, Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Peralta Ramos, Javier María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Arroyo, Daniela Soledad. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gallea, Jose Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Ronchi, Paolo. European Molecular Biology Laboratory; AlemaniaFil: Kolovou, Androniki. European Molecular Biology Laboratory; AlemaniaFil: Wang, Ji M.. National Cancer Institute at Frederick; Estados UnidosFil: Florey, Oliver. Babraham Institute; Reino UnidoFil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Schwab, Yannick. European Molecular Biology Laboratory; AlemaniaFil: Ktistakis, Nicholas. Babraham Institute; Reino UnidoFil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; Argentin

Next-to-next-to-leading order prediction for the photon-to-pion transition form factor

We evaluate the next-to-next-to-leading order corrections to the hard-scattering amplitude of the photon-to-pion transition form factor. Our approach is based on the predictive power of the conformal operator product expansion, which is valid for a vanishing $\beta$-function in the so-called conformal scheme. The Wilson--coefficients appearing in the non-forward kinematics are then entirely determined from those of the polarized deep-inelastic scattering known to next-to-next-to-leading accuracy. We propose different schemes to include explicitly also the conformal symmetry breaking term proportional to the $\beta$-function, and discuss numerical predictions calculated in different kinematical regions. It is demonstrated that the photon-to-pion transition form factor can provide a fundamental testing ground for our QCD understanding of exclusive reactions.Comment: 62 pages LaTeX, 2 figures, 9 tables; typos corrected, some references added, to appear in Phys. Rev.

Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation

WNK1 [with no lysine (K)] and WNK4 regulate blood pressure by controlling the activity of ion co-transporters in the kidney. Groundbreaking work has revealed that the ubiquitylation and hence levels of WNK isoforms are controlled by a Cullin-RING E3 ubiquitin ligase complex (CRL3KLHL3) that utilizes CUL3 (Cullin3) and its substrate adaptor, KLHL3 (Kelch-like protein 3). Loss-of-function mutations in either CUL3 or KLHL3 cause the hereditary high blood pressure disease Gordon's syndrome by stabilizing WNK isoforms. KLHL3 binds to a highly conserved degron motif located within the C-terminal non-catalytic domain of WNK isoforms. This interaction is essential for ubiquitylation by CRL3KLHL3 and disease-causing mutations in WNK4 and KLHL3 exert their effects on blood pressure by disrupting this interaction. In the present study, we report on the crystal structure of the KLHL3 Kelch domain in complex with the WNK4 degron motif. This reveals an intricate web of interactions between conserved residues on the surface of the Kelch domain β-propeller and the WNK4 degron motif. Importantly, many of the disease-causing mutations inhibit binding by disrupting critical interface contacts. We also present the structure of the WNK4 degron motif in complex with KLHL2 that has also been reported to bind WNK4. This confirms that KLHL2 interacts with WNK kinases in a similar manner to KLHL3, but strikingly different to how another KLHL protein, KEAP1 (Kelch-like enoyl-CoA hydratase-associated protein 1), binds to its substrate NRF2 (nuclear factor-erythroid 2-related factor 2). The present study provides further insights into how Kelch-like adaptor proteins recognize their substrates and provides a structural basis for how mutations in WNK4 and KLHL3 lead to hypertension

Transverse Polarisation of Quarks in Hadrons

We review the present state of knowledge regarding the transverse polarisation (or transversity) distributions of quarks. After some generalities on transverse polarisation, we formally define the transversity distributions within the framework of a classification of all leading-twist distribution functions. We describe the QCD evolution of transversity at leading and next-to-leading order. A comprehensive treatment of non-perturbative calculations of transversity distributions (within the framework of quark models, lattice QCD and QCD sum rules) is presented. The phenomenology of transversity (in particular, in Drell-Yan processes and semi-inclusive leptoproduction) is discussed in some detail. Finally, the prospects for future measurements are outlined.Comment: small changes, references added, as finally published in Physics Report

Telomerase and Apoptosis in the Placental Trophoblasts of Growth Discordant Twins

In an effort to investigate the molecular basis of growth discordance in embryos that experience the same uterine environment, we compared telomerase activity and apoptosis in placental trophoblasts obtained from growth discordant twins. Between January 2003 and February 2005, placental tissue from twenty pairs of twins was obtained within thirty minutes of delivery. Eleven cases were classified as growth discordant, with birth weight discordance greater than 20%. Nine cases comprised the control group, with less than 20% discordance. Telomerase and apoptotic activities in placental trophoblasts were analyzed by ELISA and immunoblot. Statistical significance was analyzed by a paired t-test, chisquared test, and ANOVA (SPSS ver 11.0). The average growth discordance was 26.8% in the growth discordant group and 14.4% in the control group. There were no significant differences in maternal age, week of gestation at delivery, parity, or chorionisity between the two groups. In the growth discordant group, the larger twin showed significantly higher telomerase activity (p < 0.01), whereas no significant difference was observed in the control group (p = 0.36). In addition, there was no definitive correlation between telomerase activity and the degree of growth discordance in the larger or smaller twins (R = -0.521 and -0.399, p = 0.15 and 0.25, respectively). The apoptosis proteins Bax and Bcl 2 were detected in both the larger and smaller twins in the growth discordant and control groups. There was no statistically significant difference in Bax expression between the larger and smaller twins (p = 0.25 and 0.92, respectively) for either the growth discordant or the control groups. Bcl 2 expression also showed no significant difference between groups. In conclusion, a tendency toward reduced telomerase activity and increased apoptosis was discovered in placental trophoblasts of the smaller growth-discordant twin, possibility resulting in delayed fetal growth

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease