Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection

HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kinases (TBK1) as a novel pathway to reverse HIV-1 latency in latently infected non-clonal lymphoid and myeloid cell in vitro models. IKK inhibitors (IKKis) triggered up to a 1.8-fold increase in HIV reactivation in both, myeloid and lymphoid cell models. The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKβ (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo. More importantly, although none of the compounds tested showed antiviral activity, the combination of the distinct IKKis with ART did not affect the latency reactivation nor blockade of HIV infection by ART. Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection.     

From general state-space to VARMAX models

We propose two new algorithms to go from any state-space model to an output equivalent and invertible Vector AutoRegressive Moving Average model with eXogenous regressors (VARMAX). As the literature shows how to do the inverse transformation, these results imply that both representations, state-space and VARMAX, are equally general and freely interchangeable. These algorithms are useful to solve three practical problems: (i) discussing the identifiability of a state-space model, (ii) performing its diagnostic checking, and (iii) calibrating its parameters so that it realizes, exactly or approximately, a given reduced-form VARMAX. These applications are illustrated by means of practical examples with real data.     

Improving the Performance of Input Interfaces Through Scaling and Human Motor Models

The performance of interfaces is affected by human factors, which vary from one person to another, and by the inherent characteristics of the various devices involved. A set of techniques has been studied in order to improve the efficiency and efficacy of input interface devices. These techniques are based on the modification of the motor scaling factor, a transformation similar to the known Control-Display ratio (CD ratio). Operation time, the accuracy of the task and user workload are the indicators used in this work. By means of models based on the various human motor behaviors, the improvement of such indicators has been demonstrated. Using some common input interface devices, a number of experiments have been carried out to evaluate the presented methodology. The results show that the overall performance of input interfaces is significantly improved by applying such methodology.     

Prognostic factors in uterine sarcomas: a 21-year retrospective study at the Clinic and Provincial Hospital of Barcelona

BACKGROUND: Uterine sarcomas show low incidence and poor outcome despite the treatment. The prognostic factors for the survival were determined in this study. PATIENTS AND METHODS: Thirty-nine females with sarcoma of the uterus have been studied retrospectively from January 1975 to December 1996. They were treated in the Gynecology and Radiation Oncology Departments at Hospital Clínic i Provincial of Barcelona. Thirty-seven patients had surgery, 22 radiotherapy and 4 chemotherapy. The influence on the disease-specific survival, disease-free survival, local relapse disease-free survival and metastasis disease-free survival from the following pronostic factors was studied: age, pathologic subtype, miometrial invasion, mitosis, vascular and lymphatic invasion, tumor size, stage, radiotherapy and local relapse. RESULTS: 1) The disease-specific survival at 2 and 5 years was 51.5% and 42.5% respectively, and the disease-free survival at 2 and 5 years was 39%; the incidence of local and distant relapses--was 28 and 33%. 2) The multivariate analysis showed that the overall survival and the disease free survival were affected by the vascular invasion (odds ratio [OR] 12 and 32.6, respectively) and the local failure (OR = 3 and 25.5, respectively); the only factor that affected the local relapse-free survival and metastasis free survival was the III and IV stages (OR = 5.6 in both cases). CONCLUSIONS: In uterine sarcomas, the vascular invasion and the local relapse were prognostic factors for overall survival and for disease-free survival. In stages III and IV there was a decrease in the local relapse-free survival and metastasis-free survival. A correlation between vascular invasion and advanced stages was found. The outcome of the uterine sarcomas is poor, local and distant failure being responsible for this bad prognosis.     

Effect of acidic pH on the structure and lipid binding properties of porcine surfactant protein A. Potential role of acidification along its exocytic pathway

Pulmonary surfactant protein A (SP-A) is synthesized by type II cells and stored intracellularly in secretory granules (lamellar bodies) together with surfactant lipids and hydrophobic surfactant proteins B and C (SP-B and SP-C). We asked whether the progressive decrease in pH along the exocytic pathway could influence the secondary structure and lipid binding and aggregation properties of porcine SP-A. Conformational analysis from CD spectra of SP-A at various pH values indicated that the percentage of alpha-helix progressively decreased and that of beta-sheet increased as the pH was reduced. The protein underwent a marked self-aggregation at mildly acidic pH in the presence of Ca2+, conditions thought to resemble those existing in the trans-Golgi network. Protein aggregation was greater as the pH was reduced. We also found that both neutral and acidic vesicles either with or without SP-B or SP-C bound to SP-A at acidic pH as demonstrated by co-migration during centrifugation. However, the binding of acidic but not neutral vesicles to SP-A led to 1) a striking change in the CD spectra of the protein, which was interpreted as a decrease of the level of SP-A self-aggregation, and 2) a protection of the protein from endoproteinase Glu-C degradation at pH 4.5. SP-A massively aggregated acidic vesicles but poorly aggregated neutral vesicles at acidic pH. Aggregation of dipalmitoylphosphatidylcholine (DPPC) vesicles either with or without SP-B and/or SP-C strongly depended on pH, being progressively decreased as the pH was reduced and markedly increased when pH was shifted back to 7.0. At the pH of lamellar bodies, SP-A-induced aggregation of DPPC vesicles containing SP-B or a mixture of SP-B and SP-C was very low, although SP-A bound to these vesicles. These results indicate that 1) DPPC binding and DPPC aggregation are different phenomena that probably have different SP-A structural requirements and 2) aggregation of membranes induced by SP-A at acidic pH is critically dependent on the presence of acidic phospholipids, which affect protein structure, probably preventing the formation of large aggregates of protein.     

GIS approach to the definition of capacity and generation ceilings of renewable energy technologies

There are no discrepancies about the advantages of achieving a sustainable energy system based on locally available natural resources. However, supporters of green energy generation system were lacking some scientific and consistent study to defend their proposals. In order to have such a study, Greenpeace commissioned Technology Research Institute at the Pontificia Comillas University to carry out a study to assess ceilings for the potential and generation of renewable technologies in Spain. It demonstrates firstly a far greater renewable potential than the targets set by long term policies, and secondly, the viability of meeting the entire electricity demand projected for 2050. GIS was used to add the geographical dimension to the original project in order to generate a technical analysis linked to the specific constrictions imposed by territory (natural and anthropogenic) and not just designed to cover a certain demand. Therefore, GIS spatial analysis took into account local conditions producing a more accurate assessment than evaluations made upon “virtual” electrical spaces. This approach could be applied to other small scale general studies in order to assess the maximum contribution of renewable energy sources to particular energy generation mix and to help set development policies supporting high participation of renewable technologies.     

Worst-case traffic in a tree network of ATM multiplexers

We study tree networks of discrete-time queues loaded with periodic traffic sources. By using the so-called Benes method, exact closed-form expressions are obtained for the queue length distributions. The models developed can be used to study the superposition of periodic sources emitting bursts of cells in ATM networks. The results obtained show the significant effect that this kind of traffic can have on the performance of these systems