Protein Disulfide Isomerase and Host-Pathogen Interaction

Reactive oxygen species (ROS) production by immunological cells is known to cause damage to pathogens. Increasing evidence accumulated in the last decade has shown, however, that ROS (and redox signals) functionally regulate different cellular pathways in the host-pathogen interaction. These especially affect (i) pathogen entry through protein redox switches and redox modification (i.e., intra- and interdisulfide and cysteine oxidation) and (ii) phagocytic ROS production via Nox family NADPH oxidase enzyme and the control of phagolysosome function with key implications for antigen processing. The protein disulfide isomerase (PDI) family of redox chaperones is closely involved in both processes and is also implicated in protein unfolding and trafficking across the endoplasmic reticulum (ER) and towards the cytosol, a thiol-based redox locus for antigen processing. Here, we summarise examples of the cellular association of host PDI with different pathogens and explore the possible roles of pathogen PDIs in infection. A better understanding of these complex regulatory steps will provide insightful information on the redox role and coevolutional biological process, and assist the development of more specific therapeutic strategies in pathogen-mediated infections

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Endoplasmic Reticulum Stress and Nox-Mediated Reactive Oxygen Species Signaling in the Peripheral Vasculature:Potential Role in Hypertension

SIGNIFICANCE: \ud \ud Reactive oxygen species (ROS) are produced during normal endoplasmic reticulum (ER) metabolism. There is accumulating evidence showing that under stress conditions such as ER stress, ROS production is increased via enzymes of the NADPH oxidase (Nox) family, especially via the Nox2 and Nox4 isoforms, which are involved in the regulation of blood pressure. Hypertension is a major contributor to cardiovascular and renal disease, and it has a complex pathophysiology involving the heart, kidney, brain, vessels, and immune system. ER stress activates the unfolded protein response (UPR) signaling pathway that has prosurvival and proapoptotic components.\ud \ud RECENT ADVANCES: \ud \ud Here, we summarize the evidence regarding the association of Nox enzymes and ER stress, and its potential contribution in the setting of hypertension, including the role of other conditions that can lead to hypertension (e.g., insulin resistance and diabetes).\ud \ud CRITICAL ISSUES: \ud \ud A better understanding of this association is currently of great interest, as it will provide further insights into the cellular mechanisms that can drive the ER stress-induced adaptive versus maladaptive pathways linked to hypertension and other cardiovascular conditions. More needs to be learnt about the precise signaling regulation of Nox(es) and ER stress in the cardiovascular system.\ud \ud FUTURE DIRECTIONS: \ud \ud The development of specific approaches that target individual Nox isoforms and the UPR signaling pathway may be important for the achievement of therapeutic efficacy in hypertension.British Heart Foundation (RG/08/011/25922; CH/99001; RE/08/003) a Leducq Foundation Transatlantic Network of Excellence awardNational Institute for Health ResearchBiomedical Research Centre award to Guy’s & St Thomas’ NHSNHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS FoundationUK Medical Research Council Clinical Research Training Fellowship (G1100441)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP

Regular physical activity preserves the lung function in patients with ankylosing spondylitis without previous lung alterations

A espondilite anquilosante é uma doença inflamatória que influencia de maneira restritiva a mecânica respiratória por meio do acometimento das articulações da coluna, bem como das alterações posturais decorrentes desse processo como o aumento da cifose torácica. OBJETIVO: O objetivo deste estudo foi avaliar a alteração pulmonar dos pacientes portadores de espondilite anquilosante e relacioná-la à atividade física, verificando a influência na capacidade respiratória. MÉTODOS:Foram recrutados para este estudo 104 pacientes. Apenas 15 preenchiam os critérios de inclusão e exclusão, sendo divididos em dois grupos: grupo I, composto por indivíduos sedentários, e o grupo II, composto por pacientes que praticam uma atividade física regular moderada. RESULTADOS:Os dois grupos não diferiram em relação à média da idade (49,6 ± 11,6 versus 43,3 ± 13,2 anos, p = 0,19), peso (70,9 ± 9,7 versus 74,1 ± 12,1 kg, p = 0,30) e a altura (164,6 ± 3,5 versus 167,6 ± 6,9 cm, p = 0,16). Entretanto, o tempo médio de doença foi significantemente maior no grupo I comparado ao grupo de ativos (20,1 ± 6,9 vs. 9,6 ± 3,4, p = 0,004). Como tema de interesse, observou-se que o volume minuto foi significativamente maior no grupo ativo que no inativo (4,83 ± 1,07 versus 6,1 ± 1,25, p = 0,035). Por outro lado, isso não foi demonstrado em relação à frequência respiratória (14,57 ± 1,76 versus 16,25 ± 3,53 ipm, p = 0,15), ao volume corrente (0,402 ± 0,07 versus 0,342 ± 0,10 L, p = 0,13), bem como às medidas de pressão PI máx (84,29 ± 24,99 versus 93,13 ± 16,76 cmH2O), p = 0,24) e PE máx (102,2 ± 29,26 versus 105 ± 17,32 cmH2O, p = 0,42). CONCLUSÃO:Este estudo pareceu demonstrar que os volumes pulmonares são mantidos em pacientes com espondilite anquilosante que realizam atividade física regular.Ankylosing spondylitis is an inflammatory condition which causes restriction in the lung function due to column joint alterations leading to postural dysfunction and thoracic ciphosis. OBJECTIVE: The objective of this study was to evaluate the lung function in patients with ankylosing spondylitis and to associate this parameter with physical activity. METHODS:104 patients were selected and only 15 fulfilled inclusion and exclusion criteria. They were divided in two groups: group I composed by sedentary patients, and group II with patients that has a regular physical activity. Demographic features, parameters of cervical, dorsal and lumbar column mobility were collected. Measurements of minute volume, respiratory rate, maximum inspiratory and expiratory pressures and quality of life (HAQ-S) were also evaluated. RESULTS: Both groups were similar regarding mean age (49.6 ± 1.6 vs. 43.3 ± 13.2 years, p = 0.19), weight (70.9 ± 9.7 vs. 74.1 ± 12.1 kg, p = 0.30) and height (164.6 ± 3.5 vs. 167.6 ± 6.9 cm, p = 0.16). However, the mean disease duration was significantly higher in the group I compared to the active group (20.1 ± 6.9 vs. 9.6 ± 3.4 years, p = 0.004). Interestingly, a significantly higher minute volume was observed in the active group than inactive one (4.83 ± 1.07 vs. 6.1 ± 1.25 L/min, p = 0.035). On the other hand, no differences were found regarding respiratory rate (14.57 ± 1.76 vs. 16.25 ± 3.53 ipm, p = 0.15), tidal volume (0.402 ± 0.07 vs. 0.342 ± 0.10 L, p = 0.13), as well as maximum inspiratory pressure (84.29 ± 24.99 vs. 93.13 ± 16.76 cmH2O), p = 0.24) and maximum expiratory pressure (102.2 ± 29.26 vs. 105 ± 17.32 cmH2O, p = 0.42). ), CONCLUSION: This study seems to show that respiratory volumes are maintained stable in patients with ankylosing spondylitis that are under regular physical activity