lca_algebraic: a library bringing symbolic calculus to LCA for comprehensive sensitivity analysis

The International Journal of Life Cycle Assessment - In this paper, we present new tools to ease the analysis of the effect of variability and uncertainty on life cycle assessment (LCA) results....     

Inhalation pressure distributions for medical gas mixtures calculated in an infant airway morphology model

A numerical pressure loss model previously used for adult human airways has been modified to simulate the inhalation pressure distribution in a healthy 9-month-old infant lung morphology model. Pressure distributions are calculated for air as well as helium and xenon mixtures with oxygen to investigate the effects of gas density and viscosity variations for this age group. The results indicate that there are significant pressure losses in infant extrathoracic airways due to inertial effects leading to much higher pressures to drive nominal flows in the infant airway model than for an adult airway model. For example, the pressure drop through the nasopharynx model of the infant is much greater than that for the nasopharynx model of the adult; that is, for the adult-versus-child the pressure differences are 0.08 cm H₂O versus 0.4 cm H₂O, 0.16 cm H₂O versus 1.9 cm H₂O and 0.4 cm H₂O versus 7.7 cm H₂O, breathing helium–oxygen (78/22%), nitrogen–oxygen (78/22%) and xenon–oxygen (60/40%), respectively. Within the healthy lung, viscous losses are of the same order for the three gas mixtures, so the differences in pressure distribution are relatively small.     

Synthesis of imidazole-containing analogues of farnesyl pyrophosphate and evaluation of their biological activity on protein farnesyltransferase

With the aim of creating new bisubstrate inhibitors of protein farnesyltransferase (FTase), new carboxylic farnesyl pyrophosphate analogues have been designed and synthesized. The original structures are built around three elements: a prenyl moiety, a 1,4-diacid motif and an imidazole ring. All the compounds were evaluated for their ability to inhibit FTase and compared with the corresponding derivatives lacking the imidazole ring, synthesized for that purpose. These new compounds are not bisubstrate inhibitors probably because the imidazole ring is not in the right position to interact with the zinc atom. However these derivatives display FPP competitive inhibition with a good activity in the carboxylic farnesyl pyrophosphate analogues series.     

Predictors of Chikungunya rheumatism: a prognostic survey ancillary to the TELECHIK cohort study

Introduction

Long-lasting relapsing or lingering rheumatic musculoskeletal pain (RMSP) is the hallmark of Chikungunya virus (CHIKV) rheumatism (CHIK-R). Little is known on their prognostic factors. The aim of this prognostic study was to search the determinants of lingering or relapsing RMSP indicative of CHIK-R.

Methods

Three hundred and forty-six infected adults (age ≥ 15 years) having declared RMSP at disease onset were extracted from the TELECHIK cohort study, Reunion island, and analyzed using a multinomial logistic regression model. We also searched for the predictors of CHIKV-specific IgG titres, assessed at the time of a serosurvey, using multiple linear regression analysis.

Results

Of these, 111 (32.1%) reported relapsing RMSP, 150 (43.3%) lingering RMSP, and 85 (24.6%) had fully recovered (reference group) on average two years after acute infection. In the final model controlling for gender, the determinants of relapsing RMSP were the age 45-59 years (adjusted OR: 2.9, 95% CI: 1.0, 8.6) or greater or equal than 60 years (adjusted OR: 10.4, 95% CI: 3.5, 31.1), severe rheumatic involvement (fever, at least six joints plus four other symptoms) at presentation (adjusted OR: 3.6, 95% CI: 1.5, 8.2), and CHIKV-specific IgG titres (adjusted OR: 3.2, 95% CI: 1.8, 5.5, per one unit increase). Prognostic factors for lingering RMSP were age 45-59 years (adjusted OR: 6.4, 95% CI: 1.8, 22.1) or greater or equal than 60 years (adjusted OR: 22.3, 95% CI: 6.3, 78.1), severe initial rheumatic involvement (adjusted OR: 5.5, 95% CI: 2.2, 13.8) and CHIKV-specific IgG titres (adjusted OR: 6.2, 95% CI: 2.8, 13.2, per one unit increase). CHIKV specific IgG titres were positively correlated with age, female gender and the severity of initial rheumatic symptoms.

Conclusions

Our data support the roles of age, severity at presentation and CHIKV specific IgG titres for predicting CHIK-R. By identifying the prognostic value of the humoral immune response of the host, this work also suggest a significant contribution of the adaptive immune response to the physiopathology of CHIK-R and should help to reconsider the paradigm of this chronic infection primarily shifted towards the involvement of the innate immune response.     

Impact of hyperthermic intraperitoneal chemotherapy on Hsp27 protein expression in serum of patients with peritoneal carcinomatosis

Despite the strong rationale for combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis, thermotolerance and chemoresistance might result from heat shock protein overexpression. The aim of the present study was thus to determine whether the heat shock protein 27 (Hsp27), a potential factor in resistance to treatment, could have a higher level in serum from patients under this combined therapy. Patients receiving CRS plus HIPEC for peritoneal carcinomatosis (group 1), patients with cancer or a history of cancer undergoing abdominal surgery (group 2), and patients without malignancies undergoing abdominal surgery (group 3) were included. Hsp27 serum levels were determined before and at different times following CRS and HIPEC using enzyme-linked immunosorbent assay. In group 1 (n = 25), the high Hsp27 levels, observed at the end of surgery compared with before (p < 0.0001), decreased during HIPEC, but remained significantly higher than before surgery (p < 0.0005). In groups 2 (n = 11) and 3 (n = 15), surgery did not significantly increase Hsp27 levels. A targeted molecular strategy, inhibiting Hsp27 expression in tumor tissue, could significantly reduce resistance to the combined CRS plus HIPEC treatment. This approach should be further assessed in a clinical phase I trial.     

Bryophyte‐cyanobacteria associations as regulators of the northern latitude carbon balance in response to global change

Ecosystems in the far north, including arctic and boreal biomes, are a globally significant pool of carbon (C). Global change is proposed to influence both C uptake and release in these ecosystems, thereby potentially affecting whether they act as C sources or sinks. Bryophytes (i.e., mosses) serve a variety of key functions in these systems, including their association with nitrogen (N₂)‐fixing cyanobacteria, as thermal insulators of the soil, and producers of recalcitrant litter, which have implications for both net primary productivity (NPP) and heterotrophic respiration. While ground‐cover bryophytes typically make up a small proportion of the total biomass in northern systems, their combined physical structure and N₂‐fixing capabilities facilitate a disproportionally large impact on key processes that control ecosystem C and N cycles. As such, the response of bryophyte‐cyanobacteria associations to global change may influence whether and how ecosystem C balances are influenced by global change. Here, we review what is known about their occurrence and N₂‐fixing activity, and how bryophyte systems will respond to several key global change factors. We explore the implications these responses may have in determining how global change influences C balances in high northern latitudes.     

Correction of Chloride Transport and Mislocalization of CFTR Protein by Vardenafil in the Gastrointestinal Tract of Cystic Fibrosis Mice

Although lung disease is the major cause of mortality in cystic fibrosis (CF), gastrointestinal (GI) manifestations are the first hallmarks in 15–20% of affected newborns presenting with meconium ileus, and remain major causes of morbidity throughout life. We have previously shown that cGMP-dependent phosphodiesterase type 5 (PDE5) inhibitors rescue defective CF Transmembrane conductance Regulator (CFTR)-dependent chloride transport across the mouse CF nasal mucosa. Using F508del-CF mice, we examined the transrectal potential difference 1 hour after intraperitoneal injection of the PDE5 inhibitor vardenafil or saline to assess the amiloride-sensitive sodium transport and the chloride gradient and forskolin-dependent chloride transport across the GI tract. In the same conditions, we performed immunohistostaining studies in distal colon to investigate CFTR expression and localization. F508del-CF mice displayed increased sodium transport and reduced chloride transport compared to their wild-type littermates. Vardenafil, applied at a human therapeutic dose (0.14 mg/kg) used to treat erectile dysfunction, increased chloride transport in F508del-CF mice. No effect on sodium transport was detected. In crypt colonocytes of wild-type mice, the immunofluorescence CFTR signal was mostly detected in the apical cell compartment. In F508del-CF mice, a 25% reduced signal was observed, located mostly in the subapical region. Vardenafil increased the peak of intensity of the fluorescence CFTR signal in F508del-CF mice and displaced it towards the apical cell compartment. Our findings point out the intestinal mucosa as a valuable tissue to study CFTR transport function and localization and to evaluate efficacy of therapeutic strategies in CF. From our data we conclude that vardenafil mediates potentiation of the CFTR chloride channel and corrects mislocalization of the mutant protein. The study provides compelling support for targeting the cGMP signaling pathway in CF pharmacotherapy.     

Adaptation of an L-Proline Adenylation Domain to Use 4-Propyl-L-Proline in the Evolution of Lincosamide Biosynthesis

Clinically used lincosamide antibiotic lincomycin incorporates in its structure 4-propyl-L-proline (PPL), an unusual amino acid, while celesticetin, a less efficient related compound, makes use of proteinogenic L-proline. Biochemical characterization, as well as phylogenetic analysis and homology modelling combined with the molecular dynamics simulation were employed for complex comparative analysis of the orthologous protein pair LmbC and CcbC from the biosynthesis of lincomycin and celesticetin, respectively. The analysis proved the compared proteins to be the stand-alone adenylation domains strictly preferring their own natural substrate, PPL or L-proline. The LmbC substrate binding pocket is adapted to accomodate a rare PPL precursor. When compared with L-proline specific ones, several large amino acid residues were replaced by smaller ones opening a channel which allowed the alkyl side chain of PPL to be accommodated. One of the most important differences, that of the residue corresponding to V306 in CcbC changing to G308 in LmbC, was investigated in vitro and in silico. Moreover, the substrate binding pocket rearrangement also allowed LmbC to effectively adenylate 4-butyl-L-proline and 4-pentyl-L-proline, substrates with even longer alkyl side chains, producing more potent lincosamides. A shift of LmbC substrate specificity appears to be an integral part of biosynthetic pathway adaptation to the PPL acquisition. A set of genes presumably coding for the PPL biosynthesis is present in the lincomycin - but not in the celesticetin cluster; their homologs are found in biosynthetic clusters of some pyrrolobenzodiazepines (PBD) and hormaomycin. Whereas in the PBD and hormaomycin pathways the arising precursors are condensed to another amino acid moiety, the LmbC protein is the first functionally proved part of a unique condensation enzyme connecting PPL to the specialized amino sugar building unit.     

A Systematic Review of Mapping Strategies for the Sonification of Physical Quantities

The field of sonification has progressed greatly over the past twenty years and currently constitutes an established area of research. This article aims at exploiting and organizing the knowledge accumulated in previous experimental studies to build a foundation for future sonification works. A systematic review of these studies may reveal trends in sonification design, and therefore support the development of design guidelines. To this end, we have reviewed and analyzed 179 scientific publications related to sonification of physical quantities. Using a bottom-up approach, we set up a list of conceptual dimensions belonging to both physical and auditory domains. Mappings used in the reviewed works were identified, forming a database of 495 entries. Frequency of use was analyzed among these conceptual dimensions as well as higher-level categories. Results confirm two hypotheses formulated in a preliminary study: pitch is by far the most used auditory dimension in sonification applications, and spatial auditory dimensions are almost exclusively used to sonify kinematic quantities. To detect successful as well as unsuccessful sonification strategies, assessment of mapping efficiency conducted in the reviewed works was considered. Results show that a proper evaluation of sonification mappings is performed only in a marginal proportion of publications. Additional aspects of the publication database were investigated: historical distribution of sonification works is presented, projects are classified according to their primary function, and the sonic material used in the auditory display is discussed. Finally, a mapping-based approach for characterizing sonification is proposed.