Le Corbusier et les relations avec le Brésil

[EN] The preofessionelles relationships established by Swiss-French architect Le Corbusier with Brazil was huge and varied. Having been initiated in the 1920s, they have been extended until his death in 1965, when the project of the Embassy of France in Brasilia was being developed (1964). The information available on all projects, works provided and events that show the relationship Le Corbusier with Brazil were dispersed by several sources, and they are studied by several rechercheurs. This study collects and presents an organized and systematic way, key information about events, seeking to clarify the cases where the information is different or contradictory, presenting a summary of information in a compact graphical form. The article also offers a premiere approach to the study of a case, that the original project by Le Corbusier for the Embassy of France in Brazil. One of the last works provided the architect will be studied in the light of its previous relationship with Brazil, taking into account its position to projective strategic relationship proposed by the architect throughout his work, and considering a specifically but not exclusively, realized or unrealized projects, which were developed by the architect during his last creative period in the 1960s[FR] Les relations preofessionelles établies par l’architecte suisse-français Le Corbusier avec le Brésil ont été énormes et variées. Ayant été initiées dans les années 1920, elles ont été étendues jusqu’à sa mort en 1965, lorsque son projet de l’Ambassade de la France à Brasilia était en train de se développer (1964). Les informations disponibles sur l’ensemble des projets, des œvres et des événements qui montrent la relation de Le Corbusier avec le Brésil ont été dispersés par plusieurs sources, et ils sont étudiés par plusieurs rechercheurs. Cet étude recueille et présente, de façon organisée et systématique, les informations clés sur les événements, en cherchant à élucider les cas où les informations soient différentes ou contradictoires, en présentant un résumé de ses informations sous une forme graphique compacte. L’article propose également une premiàre approche de l’étude d’un cas, celui du projet original de Le Corbusier pour l’Ambassade de la France au Brésil. Une des dernières œvres de l’architecte sera étudiée à la lumière de ses relations antérieures avec le Brésil, en tenant compte de sa position face aux relations stratégiques projectives proposées par l’architecte tout au long de son œuvre, et en considérant d’une façon spécifique mais pas exclusive, les projets realisés ou non, qui ont été élaborés par l’architecte au cours de sa dernière période créative dans les années 1960.Chiarelli, S.; Verde Zein, R. (2016). Le Corbusier et les relations avec le Brésil. En LE CORBUSIER. 50 AÑOS DESPUÉS. Editorial Universitat Politècnica de València. 384-406. https://doi.org/10.4995/LC2015.2015.285OCS38440

Discovery of new diketopiperazines inhibiting Burkholderia cenocepacia quorum sensing in vitro and in vivo

Burkholderia cenocepacia, an opportunistic respiratory pathogen particularly relevant for cystic fibrosis patients, is difficult to eradicate due to its high level of resistance to most clinically relevant antimicrobials. Consequently, the discovery of new antimicrobials as well as molecules capable of inhibiting its virulence is mandatory. In this regard quorum sensing (QS) represents a good target for anti-virulence therapies, as it has been linked to biofilm formation and is important for the production of several virulence factors, including proteases and siderophores. Here, we report the discovery of new diketopiperazine inhibitors of the B. cenocepacia acyl homoserine lactone synthase CepI, and report their anti-virulence properties. Out of ten different compounds assayed against recombinant CepI, four were effective inhibitors, with IC50 values in the micromolar range. The best compounds interfered with protease and siderophore production, as well as with biofilm formation, and showed good in vivo activity in a Caenorhabditis elegans infection model. These molecules were also tested in human cells and showed very low toxicity. Therefore, they could be considered for in vivo combined treatments with established or novel antimicrobials, to improve the current therapeutic strategies against B. cenocepacia

Spatiotemporal dynamics of attentional orienting and reorienting revealed by fast optical imaging in occipital and parietal cortices

The mechanisms of visuospatial attention are mediated by two distinct fronto-parietal networks: a bilateral dorsal network (DAN), involved in the voluntary orientation of visuospatial attention, and a ventral network (VAN), lateralized to the right hemisphere, involved in the reorienting of attention to unexpected, but relevant, stimuli. The present study consisted of two aims: 1) characterize the spatio-temporal dynamics of attention and 2) examine the predictive interactions between and within the two attention systems along with visual areas, by using fast optical imaging combined with Granger causality. Data were collected from young healthy participants performing a discrimination task in a Posner-like paradigm. Functional analyses revealed bilateral dorsal parietal (i.e. dorsal regions included in the DAN) and visual recruitment during orienting, highlighting a recursive predictive interplay between specific dorsal parietal regions and visual cortex. Moreover, we found that both attention networks are active during reorienting, together with visual cortex, highlighting a mutual interaction among dorsal and visual areas, which, in turn, predicts subsequent ventral activity. For attentional reorienting our findings indicate that dorsal and visual areas encode disengagement of attention from the attended location and trigger reorientation to the unexpected location. Ventral network activity could instead reflect post-perceptual maintenance of the internal model to generate and keep updated task-related expectations

Long-term auxological and endocrinological evaluation of patients with 9p trisomy: a focus on the growth hormone-insulin-like growth factor-I axis

BACKGROUND: Trisomy 9p is an uncommon anomaly characterised by mental retardation, head and facial abnormalities, congenital heart defects, kidney abnormalities, and skeletal malformations. Affected children may also show growth and puberty retardation with delayed bone age. Auxological and endocrinological data are lacking for this syndrome. METHODS: We describe three girls and one boy with 9p trisomy showing substantial growth failure, and we evaluate the main causes of their short stature. RESULTS: The target height was normal in all families, ranging from 0.1 and -1.2 standard deviation scores (SDS). The patients had a low birth-weight (from -1.2 to -2.4 SDS), birth length (from -1.1 to -3.2 SDS), and head circumference (from -0.5 to -1.6 SDS). All patients presented with substantial growth (height) retardation at the time of 9p trisomy diagnosis (from -3.0 to -3.8 SDS).The growth hormone stimulation test revealed a classic growth hormone (GH) deficiency (GHD) in patients 1, 3, and 4. In contrast, patient 2 was determined to have a GH neurosecretory dysfunction (GHNSD). The plasma concentrations of IGF-I and IGFBP-3 were low in all patients for their ages and sexes (from -2.0 to -3.4 SDS, and from -1.9 to -2.8 SDS, respectively).The auxological follow-up showed that those patients who underwent rhGH treatment exhibited a very good response to the GH therapy, whereas patients 3 and 4, whose families chose not to use rhGH treatment, did not experience any significant catch-up growth. CONCLUSIONS: GH deficiency appears to be a possible feature of patients with 9p trisomy syndrome. These patients, particularly those with growth delays, should be evaluated for GH secretion

Mycobacterium tuberculosis Phosphoribosylpyrophosphate Synthetase: Biochemical Features of a Crucial Enzyme for Mycobacterial Cell Wall Biosynthesis

The selection and soaring spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Currently, there is an urgent need for new drugs for tuberculosis treatment, with novel mechanisms of action and, moreover, the necessity to identify new drug targets. Mycobacterial phosphoribosylpyrophosphate synthetase (MtbPRPPase) is a crucial enzyme involved in the biosynthesis of decaprenylphosphoryl-arabinose, an essential precursor for the mycobacterial cell wall biosynthesis. Moreover, phosphoribosylpyrophosphate, which is the product of the PRPPase catalyzed reaction, is the precursor for the biosynthesis of nucleotides and of some amino acids such as histidine and tryptophan. In this context, the elucidation of the molecular and functional features of MtbPRPPase is mandatory. MtbPRPPase was obtained as a recombinant form, purified to homogeneity and characterized. According to its hexameric form, substrate specificity and requirement of phosphate for activity, the enzyme proved to belong to the class I of PRPPases. Although the sulfate mimicked the phosphate, it was less effective and required higher concentrations for the enzyme activation. MtbPRPPase showed hyperbolic response to ribose 5-phosphate, but sigmoidal behaviour towards Mg-ATP. The enzyme resulted to be allosterically activated by Mg2+ or Mn2+ and inhibited by Ca2+ and Cu2+ but, differently from other characterized PRPPases, it showed a better affinity for the Mn2+ and Cu2+ ions, indicating a different cation binding site geometry. Moreover, the enzyme from M. tuberculosis was allosterically inhibited by ADP, but less sensitive to inhibition by GDP. The characterization of M. tuberculosis PRPPase provides the starting point for the development of inhibitors for antitubercular drug design

Rv0579 Is Involved in the Resistance to the TP053 Antitubercular Prodrug

Tuberculosis remains one of the leading causes of death from a single pathogen globally. It is estimated that 1/4 of the world’s population harbors latent tuberculosis, but only a 5–10% of patients will develop active disease. During latent infection, Mycobacterium tuberculosis can persist unaffected by drugs for years in a non-replicating state with low metabolic activity. The rate of the successful tuberculosis treatment is curbed by the presence of these non-replicating bacilli that can resuscitate after decades and also by the spread of M. tuberculosis drug-resistant strains. International agencies, including the World Health Organization, urge the international community to combat this global health emergency. The thienopyrimidine TP053 is a promising new antitubercular lead compound highly active against both replicating and non-replicating M. tuberculosis cells, with an in vitro MIC of 0.125 mg/ml. TP053 is a prodrug activated by the reduced form of the mycothiol-dependent reductase Mrx2, encoded by Rv2466c gene. After its activation, TP053 releases nitric oxide and a highly reactive metabolite, explaining its activity also against M. tuberculosis non-replicating cells. In this work, a new mechanism of TP053 resistance was discovered. M. tuberculosis spontaneous mutants resistant to TP053 were isolated harboring the mutation L240V in Rv0579, a protein with unknown function, but without mutation in Rv2466c gene. Recombineering method demonstrated that this mutation is linked to TP053 resistance. To better characterize Rv0579, the protein was recombinantly produced in Escherichia coli and a direct interaction between the Mrx2 activated TP053 and Rv0579 was shown by an innovative target-fishing experiment based on click chemistry. Thanks to achieved results, a possible contribution of Rv0579 in M. tuberculosis RNA metabolism was hypothesized, linked to toxin antitoxin system. Overall, these data confirm the role of Rv0579 in TP053 resistance and consequently in the metabolism of this prodrug

"All-in-one mesh" hernioplasty: A new procedure for primary inguinal hernia open repair.

Summary: Background: We propose a new open mesh hernia repair procedure for the treatment of inguinal hernias in adults aiming to improve patients' comfort and to reduce the incidence of chronic neuralgia. Methods: From September 2012 to August 2015, 250 consecutive patients were treated with "all in-one" mesh hernioplasty procedure in our Institution. According to the devised technique, a new smaller prosthesis was placed on the floor of the inguinal canal in order to strengthen all areas of weakness from which hernias may originate. The mesh was enveloped by a fibro-cremasteric sheath avoiding contact with neural structures. Follow-up was carried out at 3, 6, 12, 18 and 24 months for evaluation of postoperative pain using Visual Analogue Scale score, need of medication, patients' comfort and short or long-term complications. Results: All patients were discharged within 24 h from surgery. Slight pain was reported by the majority of patients and 47.6% of them did not require pain medication at home. After the 1st postoperative week 96.8% reported no pain and no other symptoms. No relevant limitation of normal activities was reported. There has been no postoperative neuralgia. One recurrence was observed. Conclusions: This new hernioplasty technique respects the anatomy of the inguinal canal, uses a smaller mesh, and seems to avoid neuralgia with maximum comfort for the patients. Keywords: Inguinal hernioplasty, Tension free hernia repair, Hernioplasty technique, Mesh for groin hernia, Neuralgia post-hernioplast

Various Evolutionary Trajectories Lead to Loss of the Tobramycin-Potentiating Activity of the Quorum-Sensing Inhibitor Baicalin Hydrate in Burkholderia cenocepacia Biofilms

Combining antibiotics with potentiators that increase their activity is a promising strategy to tackle infections caused by antibiotic-resistant bacteria. As potentiators do not interfere with essential processes, it has been hypothesized that they are less likely to induce resistance. However, evidence supporting this hypothesis is lacking. In the present study, we investigated whether Burkholderia cenocepacia J2315 biofilms develop reduced susceptibility toward one such adjuvant, baicalin hydrate (BH). Biofilms were repeatedly and intermittently treated with tobramycin (TOB) alone or in combination with BH for 24 h. After treatment, the remaining cells were quantified using plate counting. After 15 cycles, biofilm cells were less susceptible to TOB and TOB + BH compared to the start population, and the potentiating effect of BH toward TOB was lost. Whole-genome sequencing was performed to probe which changes were involved in the reduced effect of BH, and mutations in 14 protein-coding genes were identified (including mutations in genes involved in central metabolism and in BCAL0296, encoding an ABC transporter). No changes in the MIC or MBC of TOB or changes in the number of persister cells were observed. However, basal intracellular levels of reactive oxygen species (ROS) and ROS levels found after treatment with TOB were markedly decreased in the evolved populations. In addition, in evolved cultures with mutations in BCAL0296, a significantly reduced uptake of TOB was observed. Our results indicate that B. cenocepacia J2315 biofilms rapidly lose susceptibility toward the antibiotic-potentiating activity of BH and point to changes in central metabolism, reduced ROS production, and reduced TOB uptake as mechanisms