Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Brain Rhythms Reveal a Hierarchical Network Organization

Recordings of ongoing neural activity with EEG and MEG exhibit oscillations of specific frequencies over a non-oscillatory background. The oscillations appear in the power spectrum as a collection of frequency bands that are evenly spaced on a logarithmic scale, thereby preventing mutual entrainment and cross-talk. Over the last few years, experimental, computational and theoretical studies have made substantial progress on our understanding of the biophysical mechanisms underlying the generation of network oscillations and their interactions, with emphasis on the role of neuronal synchronization. In this paper we ask a very different question. Rather than investigating how brain rhythms emerge, or whether they are necessary for neural function, we focus on what they tell us about functional brain connectivity. We hypothesized that if we were able to construct abstract networks, or “virtual brains”, whose dynamics were similar to EEG/MEG recordings, those networks would share structural features among themselves, and also with real brains. Applying mathematical techniques for inverse problems, we have reverse-engineered network architectures that generate characteristic dynamics of actual brains, including spindles and sharp waves, which appear in the power spectrum as frequency bands superimposed on a non-oscillatory background dominated by low frequencies. We show that all reconstructed networks display similar topological features (e.g. structural motifs) and dynamics. We have also reverse-engineered putative diseased brains (epileptic and schizophrenic), in which the oscillatory activity is altered in different ways, as reported in clinical studies. These reconstructed networks show consistent alterations of functional connectivity and dynamics. In particular, we show that the complexity of the network, quantified as proposed by Tononi, Sporns and Edelman, is a good indicator of brain fitness, since virtual brains modeling diseased states display lower complexity than virtual brains modeling normal neural function. We finally discuss the implications of our results for the neurobiology of health and disease

Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki = 1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1∶2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation

Decision making under uncertainty in environmental projects using mathematical simulation modeling

The final publication is available at Springer via http://dx.doi.org/10.1007/s12665-016-6135-yIn decision-making processes, reliability and risk aversion play a decisive role. The aim of this study is to perform an uncertainty assessment of the effects of future scenarios of sustainable groundwater pumping strategies on the quantitative and chemical status of an aquifer. The good status of the aquifer is defined according to the terms established by the EU Water Framework Directive (WFD). A decision support systems (DSS) is presented, which makes use of a stochastic inverse model (GC method) and geostatistical approaches to calibrate equally likely realizations of hydraulic conductivity (K) fields for a particular case study. These K fields are conditional to available field data, including hard and soft information. Then, different future scenarios of groundwater pumping strategies are generated, based on historical information and WFD standards, and simulated for each one of the equally likely K fields. The future scenarios lead to different environmental impacts and levels of socioeconomic development of the region and, hence, to a different degree of acceptance among stakeholders. We have identified the different stakeholders implied in the decision-making process, the objectives pursued and the alternative actions that should be considered by stakeholders in a public participation project (PPP). The MonteCarlo simulation provides a highly effective way for uncertainty assessment and allows presenting the results in a simple and understandable way even for non-experts stakeholders. The methodology has been successfully applied to a real case study and lays the foundations to performa PPP and stakeholders' involvement in a decisionmaking process as required by the WFD. The results of the methodology can help the decision-making process to come up with the best policies and regulations for a groundwater system under uncertainty in groundwater parameters and management strategies and involving stakeholders with conflicting interests.Llopis Albert, C.; Palacios Marqués, D.; Merigó -Lindahl, JM. (2016). Decision making under uncertainty in environmental projects using mathematical simulation modeling. Environmental Earth Sciences. 75(19):1-11. doi:10.1007/s12665-016-6135-yS1117519Arhonditsis GB, Perhar G, Zhang W, Massos E, Shi M, Das A (2008) Addressing equifinality and uncertainty in eutrophication models. Water Resour Res 44:W01420. doi: 10.1029/2007WR005862Capilla JE, Llopis-Albert C (2009) Gradual conditioning of non-gaussian transmissivity fields to flow and mass transport data. J Hydrol 371:66–74. doi: 10.1016/j.jhydrol.2009.03.015CHJ (Júcar Water Agency) (2016) Júcar river basin authority. http://www.chj.es/CHS (Segura Water Agency) (2016) Segura river basin authority. http://www.chsegura.es/Custodio E (2002) Aquifer overexploitation: what does it mean? Hydrogeol J 10:254–277EC (2000). Directive 2000/60/EC of the European Parliament and of the Council of October 23 2000, establishing a framework for community action in the field of water policy. Official Journal of the European Communities L327/1eL327/72. 22.12.2000EC (2006) Directive 2006/118/EC of the European Parliament and of the Council of 12 December 2006 on the protection of groundwater against pollution and deteriorationGómez-Hernández JJ, Srivastava RM (1990) ISIM3D: an ANSI-C three dimensional multiple indicator conditional simulation program. Comput Geosci 16(4):395–440Harbaugh AW, Banta ER, Hill MC and McDonald MG (2000) MODFLOW- 2000, The US geological survey modular groundwater model-user guide to modularization concepts and the groundwater flow process. US Geol. Surv. Open-File Rep 00–92, 12Hu LY (2000) Gradual deformation and iterative calibration of Gaussian related stochastic models. Math Geol 32(1):87–108Jagelke J, Barthel R (2005) Conceptualization and implementation of a regional groundwater model for the Neckar catchment in the framework of an integrated regional model. Adv Geosci 5:105–111Llopis-Albert C (2008) Stochastic inverse modeling conditional to flow, mass transport and secondary information. Universitat Politècnica de València, València. ISBN 978-84-691-9796-7Llopis-Albert C, Capilla JE (2009a) Gradual conditioning of non-gaussian transmissivity fields to flow and mass transport data. Demonstration on a synthetic aquifer. J Hydrol 371:53–55. doi: 10.1016/j.jhydrol.2009.03.014Llopis-Albert C, Capilla JE (2009b) Gradual conditioning of non-gaussian transmissivity fields to flow and mass transport data. Application to the macrodispersion experiment (MADE-2) site, on Columbus air force base in Mississippi (USA). J Hydrol 371:75–84. doi: 10.1016/j.jhydrol.2009.03.016Llopis-Albert C, Capilla JE (2010a) Stochastic simulation of non-gaussian 3D conductivity fields in a fractured medium with multiple statistical populations: a case study. J Hydrol Eng 15(7):554–566. doi: 10.1061/(ASCE)HE.1943-5584.0000214Llopis-Albert C, Capilla JE (2010b) Stochastic inverse modeling of hydraulic conductivity fields taking into account independent stochastic structures: a 3D case study. J Hydrol 391:277–288. doi: 10.1016/j.jhydrol.2010.07.028Llopis-Albert C, Pulido-Velazquez D (2014) Discussion about the validity of sharp-interface models to deal with seawater intrusion in coastal aquifers. Hydrol Process 28(10):3642–3654Llopis-Albert C, Pulido-Velazquez D (2015) Using MODFLOW code to approach transient hydraulic head with a sharp-interface solution. Hydrol Process 29(8):2052–2064. doi: 10.1002/hyp.10354Llopis-Albert C, Palacios-Marqués D, Merigó JM (2014) A coupled stochastic inverse-management framework for dealing with nonpoint agriculture pollution under groundwater parameter uncertainty. J Hydrol 511:10–16. doi: 10.1016/j.jhydrol.2014.01.021Llopis-Albert C, Merigó JM, Palacios-Marqués D (2015) Structure adaptation in stochastic inverse methods for integrating information. Water Resour Manage 29(1):95–107. doi: 10.1007/s11269-014-0829-2Llopis-Albert C, Merigó JM, Xu Y (2016) A coupled stochastic inverse/sharp interface seawater intrusion approach for coastal aquifers under groundwater parameter uncertainty. J Hydrol 540:774–783. doi: 10.1016/j.jhydrol.2016.06.065McDonald MG and Harbaugh AW (1988) A modular three-dimensional finite-difference groundwater flow model. US geological survey technical manual of water resources investigation, Book 6, US geological survey, Reston, Virginia, 586Molina JL, Pulido-Velazquez M, Llopis-Albert C, Peña-Haro S (2013) Stochastic hydro-economic model for groundwater quality management using Bayesian networks. Water Sci Technol 67(3):579–586. doi: 10.2166/wst.2012.598Peña-Haro S, Llopis-Albert C, Pulido-Velazquez M (2010) Fertilizer standards for controlling groundwater nitrate pollution from agriculture: El Salobral-Los Llanos case study, Spain. J Hydrol 392:174–187. doi: 10.1016/j.jhydrol.2010.08.006Peña-Haro S, Pulido-Velazquez M, Llopis-Albert C (2011) Stochastic hydro-economic modeling for optimal management of agricultural groundwater nitrate pollution under hydraulic conductivity uncertainty. Environ Model Softw 26(8):999–1008. doi: 10.1016/j.envsoft.2011.02.010Pulido-Velazquez D, Llopis-Albert C, Peña-Haro S, Pulido-Velazquez M (2011) Efficient conceptual model for simulating the effect of aquifer heterogeneity on natural groundwater discharge to rivers. Adv Water Resour 34(11):1377–1389. doi: 10.1016/j.advwatres.2011.07.010Reichert P, Borsuk M, Hostmann M, Schweizer S, Spörri C, Tockner K, Truffer B (2005) Concepts of decision support for river rehabilitation. Environ Model Softw 22:188–201Wright SAL, Fritsch O (2011) Operationalising active involvement in the EU water framework directive: why, when and how? Ecol Econ 70(12):2268–2274Zhou H, Gómez-Hernández JJ, Li L (2014) Inverse methods in hydrogeology: evolution and recent trends. Adv Water Resour 63:22–37. doi: 10.1016/j.advwatres.2013.10.01

Clinical and echocardiographic predictors of mortality in acute pulmonary embolism

Purpose: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). Methods: Patients with a diagnosis of acute PE, based on a positive ventilation perfusion scan or computed tomography (CT) chest angiogram, were identified using the Duke University Hospital Database. Of these, 69 had echocardiograms within 24–48 h of the diagnosis that were suitable for offline analysis. Clinical features that were analyzed included age, gender, body mass index, vital signs and comorbidities. Echocardiographic parameters that were analyzed included left ventricular (LV) ejection fraction (EF), regional, free wall and global RV speckle-tracking strain, RV fraction area change (RVFAC), Tricuspid Annular Plane Systolic Excursion (TAPSE), pulmonary artery acceleration time (PAAT) and RV myocardial performance (Tei) index. Univariable and multivariable regression statistical analysis models were used. Results: Out of 69 patients with acute PE, the median age was 55 and 48 % were female. The median body mass 2 index (BMI) was 27 kg/m . Twenty-nine percent of the cohort had a history of cancer, with a significant increase in cancer prevalence in non-survivors (57 % vs 29 %, p = 0.02). Clinical parameters including heart rate, respiratory rate, troponin T level, active malignancy, hypertension and COPD were higher among non-survivors when compared to survivors (p ≤ 0.05). Using univariable analysis, NYHA class III symptoms, hypoxemia on presentation, tachycardia, tachypnea, elevation in Troponin T, absence of hypertension, active malignancy and chronic obstructive pulmonary disease (COPD) were increased in non-survivors compared to survivors (p ≤ 0.05). In multivariable models, RV Tei Index, global and free (lateral) wall RVLS were found to be negatively associated with survival probability after adjusting for age, gender and systolic blood pressure (p ≤ 0.05). Conclusion: The addition of echocardiographic assessment of RV function to clinical parameters improved the prediction of outcomes for patients with acute PE. Larger studies are needed to validate these findings

Absence of N addition facilitates B cell development, but impairs immune responses

The programmed, stepwise acquisition of immunocompetence that marks the development of the fetal immune response proceeds during a period when both T cell receptor and immunoglobulin (Ig) repertoires exhibit reduced junctional diversity due to physiologic terminal deoxynucleotidyl transferase (TdT) insufficiency. To test the effect of N addition on humoral responses, we transplanted bone marrow from TdT-deficient (TdT−/−) and wild-type (TdT+/+) BALB/c mice into recombination activation gene 1-deficient BALB/c hosts. Mice transplanted with TdT−/− cells exhibited diminished humoral responses to the T-independent antigens α-1-dextran and (2,4,6-trinitrophenyl) hapten conjugated to AminoEthylCarboxymethyl-FICOLL, to the T-dependent antigens NP19CGG and hen egg lysozyme, and to Enterobacter cloacae, a commensal bacteria that can become an opportunistic pathogen in immature and immunocompromised hosts. An exception to this pattern of reduction was the T-independent anti-phosphorylcholine response to Streptococcus pneumoniae, which is normally dominated by the N-deficient T15 idiotype. Most of the humoral immune responses in the recipients of TdT−/− bone marrow were impaired, yet population of the blood with B and T cells occurred more rapidly. To further test the effect of N-deficiency on B cell and T cell population growth, transplanted TdT-sufficient and -deficient BALB/c IgMa and congenic TdT-sufficient CB17 IgMb bone marrow were placed in competition. TdT−/− cells demonstrated an advantage in populating the bone marrow, the spleen, and the peritoneal cavity. TdT deficiency, which characterizes fetal lymphocytes, thus appears to facilitate filling both central and peripheral lymphoid compartments, but at the cost of altered responses to a broad set of antigens

Listeriolysin O Is Strongly Immunogenic Independently of Its Cytotoxic Activity

The presentation of microbial protein antigens by Major Histocompatibility Complex (MHC) molecules is essential for the development of acquired immunity to infections. However, most biochemical studies of antigen processing and presentation deal with a few relatively inert non-microbial model antigens. The bacterial pore-forming toxin listeriolysin O (LLO) is paradoxical in that it is cytotoxic at nanomolar concentrations as well as being the source of dominant CD4 and CD8 T cell epitopes following infection with Listeria monocytogenes. Here, we examined the relationship of LLO toxicity to its antigenicity and immunogenicity. LLO offered to antigen presenting cells (APC) as a soluble protein, was presented to CD4 T cells at picomolar to femtomolar concentrations- doses 3000–7000-fold lower than free peptide. This presentation required a dose of LLO below the cytotoxic level. Mutations of two key tryptophan residues reduced LLO toxicity by 10–100-fold but had no effect on its presentation to CD4 T cells. Thus there was a clear dissociation between the cytotoxic properties of LLO and its very high antigenicity. Presentation of LLO to CD8 T cells was not as robust as that seen in CD4 T cells, but still occurred in the nanomolar range. APC rapidly bound and internalized LLO, then disrupted endosomal compartments within 4 hours of treatment, allowing endosomal contents to access the cytosol. LLO was also immunogenic after in vivo administration into mice. Our results demonstrate the strength of LLO as an immunogen to both CD4 and CD8 T cells

Perturbation of the yeast mitochondrial lipidome and associated membrane proteins following heterologous expression of Artemia-ANT

Heterologous expression is a landmark technique for studying a protein itself or its effect on the expression host, in which membrane-embedded proteins are a common choice. Yet, the impact of inserting a foreign protein to the lipid environment of host membranes, has never been addressed. Here we demonstrated that heterologous expression of the Artemia franciscana adenine nucleotide translocase (ANT) in yeasts altered lipidomic composition of their inner mitochondrial membranes. Along with this, activities of complex II, IV and ATP synthase, all membrane-embedded components, were significantly decreased while their expression levels remained unaffected. Although the results represent an individual case of expressing a crustacean protein in yeast inner mitochondrial membranes, it cannot be excluded that host lipidome alterations is a more widespread epiphenomenon, potentially biasing heterologous expression experiments. Finally, our results raise the possibility that not only lipids modulate protein function, but also membrane-embedded proteins modulate lipid composition, thus revealing a reciprocal mode of regulation for these two biomolecular entities

Seroepidemiology of Toxoplasma gondii infection in pregnant women in a public hospital in northern Mexico

BACKGROUND: Toxoplasma gondii (T. gondii) infection in pregnant women represents a risk for congenital disease. There is scarce information about the epidemiology of T. gondii infection in pregnant women in Mexico. Therefore, we sought to determine the prevalence of T. gondii infection and associated socio-demographic, clinical and behavioural characteristics in a population of pregnant women of Durango City, Mexico. METHODS: Three hundred and forty three women seeking prenatal care in a public hospital of Durango City in Mexico were examined for T. gondii infection. All women were tested for anti-T. gondii IgM and IgG antibodies by using IMx Toxo IgM and IMx Toxo IgG 2.0 kits (Abbott Laboratories, Abbott Park, IL, USA), respectively. Socio-demographic, clinical and behavioural characteristics from each participant were also obtained. RESULTS: Twenty one out of the 343 (6.1%) women had IgG anti-T. gondii antibodies. None of the 343 women had IgM anti-T. gondii antibodies. Multivariate analysis using logic regression showed that T. gondii infection was associated with living in a house with soil floor (adjusted OR = 7.16; 95% CI: 1.39–36.84), residing outside of Durango State (adjusted OR = 4.25; 95% CI: 1.72–10.49), and turkey meat consumption (adjusted OR = 3.85; 95% CI: 1.30–11.44). Other characteristics as cat contact, gardening, and food preferences did not show any association with T. gondii infection. CONCLUSION: The prevalence of T. gondii infection in pregnant women of Durango City is low as compared with those reported in other regions of Mexico and the majority of other countries. Poor housing conditions as soil floors, residing in other Mexican States, and turkey meat consumption might contribute to acquire T. gondii infection