Input-dependent structural identifiability of nonlinear systems

A dynamic model is structurally identifiable if it is possible to infer its unknown parameters by observing its output. Structural identifiability depends on the system dynamics, output, and input, as well as on the specific values of initial conditions and parameters. Here we present a symbolic method that characterizes the input that a model requires to be structurally identifiable. It determines which derivatives must be non-zero in order to have a sufficiently exciting input. Our approach considers structural identifiability as a generalization of nonlinear observability and incorporates extended Lie derivatives. The methodology assesses structural identifiability for time-varying inputs and, additionally, it can be used to determine the input profile that is required to make the parameters structurally locally identifiable. Furthermore, it is sometimes possible to replace an experiment with time-varying input with multiple experiments with constant inputs. We implement the resulting method as a MATLAB toolbox named STRIKE-GOLDD2. This tool can assist in the design of new experiments for the purpose of parameter estimation

In Vitro Reactivation of Replication-Competent and Infectious HIV-1 by Histone Deacetylase Inhibitors.

UNLABELLED: The existence of long-lived HIV-1-infected resting memory CD4 T cells is thought to be the primary obstacle to HIV-1 eradication. In the search for novel therapeutic approaches that may reverse HIV-1 latency, inhibitors of histone deacetylases (HDACis) have been tested to reactivate HIV-1 replication with the objective of rendering HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In the present study, we evaluated the efficiency of HDACis to reactivate HIV-1 replication from resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. We demonstrate that following prolonged/repeated treatment of resting memory CD4 T cells with HDACis, HIV-1 replication may be induced from primary resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. More importantly, we demonstrate that HIV-1 reactivated in the cell cultures was not only replication competent but also infectious. Interestingly, givinostat, an HDACi that has not been investigated in clinical trials, was more efficient than vorinostat, panobinostat, and romidepsin in reversing HIV-1 latency in vitro. Taken together, these results support further evaluation of givinostat as a latency-reversing agent (LRA) in aviremic long-term-treated HIV-1-infected subjects. IMPORTANCE: The major barrier to HIV cure is the existence of long-lived latently HIV-1-infected resting memory CD4 T cells. Latently HIV-1-infected CD4 T cells are transcriptionally silent and are therefore not targeted by conventional antiretroviral therapy (ART) or the immune system. In this context, one strategy to target latently infected cells is based on pharmacological molecules that may force the virus to replicate and would therefore render HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In this context, we developed an experimental strategy that would allow the evaluation of latency-reversing agent (LRA) efficiency in vitro using primary CD4 T cells. In the present study, we demonstrate that HDACis are potent inducers of replication-competent and infectious HIV-1 in resting memory CD4 T cells of long-term ART-treated patients and identify givinostat as the most efficient LRA tested

Validation of the modified Berlin questionnaire to identify patients at risk for the obstructive sleep apnoea syndrome

Background & Objectives: Awareness regarding obstructive sleep apnoea (OSA) among general public as well as practicing physicians is low in India. The present study was undertaken to test the utility of modified Berlin questionnaire for risk categorization of OSA in Indian setting. Methods: The modified Berlin questionnaire was administered in 180 middle aged adults (of 320 screened), of whom, 104 underwent overnight polysomnograhy, in a cross-sectional study at a tertiary care, referral center in north India. Questionnaire addressed the presence of frequency of snoring, wake time sleepiness, fatigue, obesity and hypertension. Subjects with persistent and frequent symptoms in any two of these three domains were considered in high risk category for obstructive sleep apnoea. Overnight polysomnograhy was performed to measure apnoea and hypopnoea index (AHI). Results: Questions about the symptoms demonstrated internal consistency (Cronbach alpha correlations 0.92-0.96). Of the 180 respondents to the screening questions, 80 were in the high risk and the rest were in low risk group. For 104 subjects who underwent polysomnograhy, risk grouping was useful in prediction of AHI. High risk category predicted an AHI > 5 with a sensitivity of 86 per cent, specificity of 95 per cent, positive and negative predictive values of 96 and 82 per cent respectively. These results were comparable to Berlin questionnaire study done in the western population for validation. Interpretation & Conclusion: On the basis of the findings of present study it is concluded that administration of modified Berlin questionnaire prior to a polysomnography study can identify high risk subjects and can thus avoid unnecessary polysomnography studies especially in resource-limited settings. To identify subjects at risk for OSA syndrome in general population, this questionnaire can be applied. However, the findings of the present study need to be confirmed further in a large number of subjects in a community-based setting

CD32⁺ and PD-1⁺ Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals.

A recent study conducted in blood has proposed CD32 as the marker identifying the "elusive" HIV reservoir. We have investigated the distribution of CD32 <sup>+</sup> CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1 <sup>+</sup> CD4 T cells. The frequency of CD32 <sup>+</sup> CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32 <sup>+</sup> cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32 <sup>+</sup> CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32 <sup>+</sup> and PD-1 <sup>+</sup> CD4 T cells compared to CD32 <sup>-</sup> and PD-1 <sup>-</sup> cells in both viremic and treated individuals, but there was no difference between CD32 <sup>+</sup> and PD-1 <sup>+</sup> cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32 <sup>+</sup> versus PD-1 <sup>+</sup> cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32 <sup>+</sup> PD-1 <sup>+</sup> CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32 <sup>-</sup> PD-1 <sup>-</sup> (averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32 <sup>+</sup> PD-1 <sup>-</sup> (2.2-fold in treated individuals and 4.3-fold in viremics), and CD32 <sup>-</sup> PD-1 <sup>+</sup> (2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32 <sup>+</sup> PD-1 <sup>-</sup> and CD32 <sup>-</sup> PD-1 <sup>+</sup> CD4 T cells. Interestingly, the proportion of CD32 <sup>+</sup> and PD-1 <sup>+</sup> CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCE The existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription

Global optimization in systems biology: stochastic methods and their applications

Mathematical optimization is at the core of many problems in systems biology: (1) as the underlying hypothesis for model development, (2) in model identification, or (3) in the computation of optimal stimulation procedures to synthetically achieve a desired biological behavior. These problems are usually formulated as nonlinear programing problems (NLPs) with dynamic and algebraic constraints. However the nonlinear and highly constrained nature of systems biology models, together with the usually large number of decision variables, can make their solution a daunting task, therefore calling for efficient and robust optimization techniques. Here, we present novel global optimization methods and software tools such as cooperative enhanced scatter search (eSS), AMIGO, or DOTcvpSB, and illustrate their possibilities in the context of modeling including model identification and stimulation design in systems biology.This work was supported by the Spanish MICINN project ”MultiSysBio” (ref. DPI2008-06880-C03-02), and by CSIC intramural project ”BioREDES” (ref. PIE-201170E018).Peer reviewe

Dentinal microcracks after root canal instrumentation using instruments manufactured with different NiTi alloys and the SAF system: A systematic review

Aim: The aim of this systematic analysis was to assess the prevalence of dentinal microcracks at various levels (3, 6, and 9mm from the apex) after using instruments made with conventional, R-Phase, and M-Wire NiTi alloys and the SAF system. Materials and Methods: Electronic searches were conducted in the databases Embase, Cochrane Library, Scopus, PubMed, andWeb of Science. To arrange search methods, “MeSH” terms and/or keywords typically associated with the subject were paired with the Boolean operators “AND” and “OR.” Additional searches were conducted on the websites of four separate endodontic journals. After reading the titles and excluding duplicates, 1000 of the 1343 documents originally found were eliminated. Upon reviewing the abstracts, 310 of the remaining 343 experiments were also eliminated. Based on qualifying requirements, only 13 of the remaining 33 articles were included in the qualitative review. Results: All systems triggered dentinal microcracks; however, when chemo-mechanical preparation was performed using Self-Adjusting File (SAF) and systems manufactured with R-phase technology—K3XF and Twisted File Adaptive (TFA)—less of these defects were found when compared to those manufactured with traditional NiTi—ProTaper Universal and Mtwo—and with M-Wire—ProTaper Next, Reciproc, and WaveOne. Conclusions: A lower prevalence of dentinal microcracks was observed after using SAF and endodontic systems manufactured with R-phase

Active PD-L1 incorporation within HIV virions functionally impairs T follicular helper cells.

The limited development of broadly neutralizing antibodies (BnAbs) during HIV infection is classically attributed to an inadequate B-cell help brought by functionally impaired T follicular helper (Tfh) cells. However, the determinants of Tfh-cell functional impairment and the signals contributing to this condition remain elusive. In the present study, we showed that PD-L1 is incorporated within HIV virions through an active mechanism involving p17 HIV matrix protein. We subsequently showed that in vitro produced PD-L1high but not PD-L1low HIV virions, significantly reduced Tfh-cell proliferation and IL-21 production, ultimately leading to a decreased of IgG1 secretion from GC B cells. Interestingly, Tfh-cell functions were fully restored in presence of anti-PD-L1/2 blocking mAbs treatment, demonstrating that the incorporated PD-L1 proteins were functionally active. Taken together, the present study unveils an immunovirological mechanism by which HIV specifically exploits the regulatory potential of PD-L1 to suppress the immune system during the course of HIV infection

Evaluation de l’Alimentation Séquentielle à Base d’Une Ration Contenant des Feuilles de Manioc Post -Récolte (Manihot esculenta ) sur les Performances Zootechniques des Poulets de Chair en Phase de Finition

Après la récolte des tubercules, les feuilles de manioc sont disponibles dans les champs en République du Congo. Elles sont une source en protéines brutes pour l’alimentation des animaux domestiques. Expérimentées dans un mode séquentiel, elles sont susceptibles d’améliorer les rendements des poulets de chair. Cette technique consiste à fractionner un ou plusieurs ingrédient(s) et la présentation des fractions est faite en respectant un intervalle de temps en fonction des besoins des animaux. L’objectif du travail était d’évaluer les performances des poulets de chair nourris avec un aliment à base de ces feuilles dans un mode de distribution séquentiel sur les performances des poulets de chair. Pour atteindre cet objectif, un échantillon de 50 poulets de souche COBB 500 âgés de 26 jours ont été répartis en deux lots (témoin et traité). Les oiseaux du lot témoin ont été nourris avec un aliment contenant 5% de farine de manioc dans une seule mangeoire alors que ceux du lot traité ont reçu un aliment dont les ingrédients riches en énergies étaient séparés de ceux riches en protéines et en minéraux distribués dans deux mangeoires différentes avec 04 heures de temps d’intervalle pour les deux fractions. Les résultats ont montré que la différence n’est pas significative (p ˂ 0,05) sur le GMQ, le poids vif et l’indice de consommation. Cependant, la consommation de la fraction énergétique est plus élevée chez les témoins que les traités (102,88 contre 82,72g). L’économie des matières azotées en phase de finition a permis un gain de 112,13 F CFA/sujet chez les traités. L’incorporation des feuilles de manioc en mode séquentiel apporte une plus-value en aviculture tropicale.   After harvesting the tubers, cassava leaves are available in the fields in the Republic of Congo. They are a source of crude protein for domestic animal feed. Experimented with in a sequential mode, they are likely to improve broiler yields. This technique consists in fractionating one or more ingredients, and presenting the fractions at time intervals to suit the animals' needs. The aim of the study was to evaluate the performance of broilers fed a feed based on these leaves in a sequential distribution mode. To achieve this objective, a sample of 50 26-day-old COBB 500 chickens was divided into two batches (control and treated). Birds in the control batch were fed a feed containing 5% cassava flour in a single feed trough, while those in the treated batch were fed a feed in which energy-rich ingredients were separated from protein- and mineral-rich ones, distributed in two different feed troughs at 04-hour intervals for the two fractions. The results showed that the difference was not significant (p ˂ 0, 05) on GMQ, live weight and feed conversion ratio. However, consumption of the energy fraction was higher in controls than in treatments (102, 88 vs. 82,72g). Nitrogen savings in the finishing phase resulted in a gain of 112, 13 F CFA/subject in the treated group. The incorporation of cassava leaves in sequential mode provides added value in tropical poultry farming

A prospective study of risk factor profile & incidence of deep venous thrombosis among medically-ill hospitalized patients at a tertiary care hospital in Northern India

Background & Objective: Hospitalization for medical-illness is associated with an increased risk of deep venous thrombosis (DVT). However, there are no published data from India addressing at this issue. We sought to study the risk factor profile and the incidence of DVT among hospitalized medically-ill patients, a tertiary care hospital in northern India. Methods: All adults admitted to the medical wards and intensive care unit with level 1 or 2 mobility over a period of two years (July 2006 to July 2008) at the All India Institute of Medical Sciences hospital, New Delhi, were prospectively studied. Patients having DVT at admission or an anticipated hospital stay less than 48 h were excluded. The presence of clinical risk factors for DVT was recorded and laboratory evaluation was done for hypercoagulable state. A routine surveillance venous compression Doppler ultrasonography was performed 12 ± 8 days after hospital admission. Results: Of the 163 patients, 77 (47%) had more than one risk factor for DVT. Five (3%) patients developed DVT; none of them had symptomatic DVT. None of these patients received anticoagulation prior to the development of DVT. The mean age of those who developed DVT was 40 ± 13 (25-50) yr; two of five were male. The incidence rate of DVT was 2.7 per 1000 person-days of hospital stay [95% confidence interval (CI): 0.87 to 6.27]. None of the factors was found to be significantly associated with the risk of DVT. Interpretation & Conclusion: In our setting, although many hospitalized medically-ill patients had risk factors for DVT, the absolute risk of DVT was low compared to the western population but clearly elevated compared to non hospitalized patients. Large studies from India are required to confirm our findings