Two-component regulatory systems (TCS) are among the most widespread mechanisms that bacteria use to sense and respond to environmental changes. In the human pathogen Streptococcus pneumoniae, a ...total of 13 TCS have been identified and many of them have been linked to pathogenicity. Notably, TCS01 strongly contributes to pneumococcal virulence in several infection models. However, it remains one of the least studied TCS in pneumococci and its functional role is still unclear. In this study, we demonstrate that TCS01 cooperates with a BceAB-type ABC transporter to sense and induce resistance to structurally-unrelated antimicrobial peptides of bacterial origin that all target undecaprenyl-pyrophosphate or lipid II, which are essential precursors of cell wall biosynthesis. Even though tcs01 and bceAB genes do not locate in the same gene cluster, disruption of either of them equally sensitized the bacterium to the same set of antimicrobial peptides. We show that the key function of TCS01 is to upregulate the expression of the transporter, while the latter appears the main actor in resistance. Electrophoretic mobility shift assays further demonstrated that the response regulator of TCS01 binds to the promoter region of the bceAB genes, implying a direct control of these genes. The BceAB transporter was overexpressed and purified from E. coli. After reconstitution in liposomes, it displayed substantial ATPase and GTPase activities that were stimulated by antimicrobial peptides to which it confers resistance to, revealing new functional features of a BceAB-type transporter. Altogether, this inducible defense mechanism likely contributes to the survival of the opportunistic microorganism in the human host, in which competition among commensal microorganisms is a key determinant for effective host colonization and invasive path.
Drawing on twenty months of fieldwork conducted with Emberá Dobidá women in the city of Medellín, Colombia, this article aims to examine the detailed components of their recent urbanization. I trace ...how “weaving beads” in the city affects the ways in which Emberá Dobidá women imagine and live their urban experience. I suggest that specific movements, produced in the weaving practice, generate specific transformations, both desired and uncontrolled. I show how new aspirations have led women to desire “to sit at home” and to rely on weaving to find a certain stillness. Stillness is then active, ideally transformative and transitory, and potentially allows women to build a future outside the house. I also examine how women’s aspirations are broken by the reality of the weaving industry in Medellín which effectively makes them stuck. Repetitive, painful, unhalted movements generate disappointing urban experiences and prevent desired transformations.
Drug-resistant bacteria are a serious threat to human health as antibiotics are gradually losing their clinical efficacy. Comprehending the mechanism of action of antimicrobials and their resistance ...mechanisms plays a key role in developing new agents to fight antimicrobial resistance. The lipopeptide daptomycin is an antibiotic that selectively disrupts Gram-positive bacterial membranes, thereby showing slower resistance development than many classical drugs. Consequently, it is often used as a last resort antibiotic to preserve its use as one of the least potent antibiotics at our disposal. The mode of action of daptomycin has been debated but was recently found to involve the formation of a tripartite complex between undecaprenyl precursors of cell wall biosynthesis and the anionic phospholipid phosphatidylglycerol. BceAB-type ABC transporters are known to confer resistance to antimicrobial peptides that sequester some precursors of the peptidoglycan, such as the undecaprenyl pyrophosphate or lipid II. The expression of these transporters is upregulated by dedicated two-component regulatory systems in the presence of antimicrobial peptides that are recognized by the system. Here, we investigated whether daptomycin evades resistance mediated by the BceAB transporter from the bacterial pathogen
. Although daptomycin can bind to the transporter, our data showed that the BceAB transporter does not mediate resistance to the drug and its expression is not induced in its presence. These findings show that the pioneering membrane-active daptomycin has the potential to escape the resistance mechanism mediated by BceAB-type transporters and confirm that the development of this class of compounds has promising clinical applications.IMPORTANCEAntibiotic resistance is rising in all parts of the world. New resistance mechanisms are emerging and dangerously spreading, threatening our ability to treat common infectious diseases. Daptomycin is an antimicrobial peptide that is one of the last antibiotics approved for clinical use. Understanding the resistance mechanisms toward last-resort antibiotics such as daptomycin is critical for the success of future antimicrobial therapies. BceAB-type ABC transporters confer resistance to antimicrobial peptides that target precursors of cell-wall synthesis. In this study, we showed that the BceAB transporter from the human pathogen
does not confer resistance to daptomycin, suggesting that this drug and other calcium-dependent lipopeptide antibiotics have the potential to evade the action of this type of ABC transporters in other bacterial pathogens.
Fold geometries and kinematics within foreland basins is a major issue for understanding the late evolution of thrust fronts. In the foreland of the southwestern Alps, the Vélodrome complex fold ...involves the whole Tertiary series which have recorded the evolution of the alpine front. From a geometrical and kinematic point of view, the Vélodrome is classically described as a recumbent Mio-Pliocene syncline with a strongly curved axis; interpreted either as a classic growth-fold, a post-deposit fold, or a result of coeval salt activity. The debate reveals a lack of consensus on the internal structure of the Vélodrome and the potential role of salt motion. By a detailed field analysis coupled with an implicit 3D geometrical modelling approach, we test the different hypotheses and provide a new 3D illustrated interpretation of the Vélodrome series. The Vélodrome consists in a complex non-cylindrical structure composed by several folds with different orientations together with inter- and intra-formations unconformities. Folding is partly syn-depositional and began earlier in the south, near Esclangon village, than in the north. In the north, deformation started with the marly and sandy molasse (m2, middle Burdigalian), attested by the transition from the conformable conglomeratic marine molasse (m1–2, Aquitanian and early Burdigalian) to the unconformable m2 to the Valensole formation. Deformation began earlier in the south, during the deposition of the m1–2, as shown by internal unconformities. We discuss the ingredients controlling the deformation in the Vélodrome, regional tectonics (mainly since middle Burdigalian) versus salt tectonics. This study further brings new constraints on the timing and pattern of deformation of the southwestern orogenic front of the Alps. It also highlights the power of the 3D geometrical modelling approach for testing different hypotheses and better understanding 3D complex structures.
Objective
To evaluate the postnatal outcome of children with antenatal colonic hyperechogenicity, currently considered as a sign of lysinuria‐cystinuria, but which may also be a sign of other ...disorders with a more severe prognosis.
Method
We carried out a French multi‐centric retrospective study via 15 Multidisciplinary Center for Prenatal Diagnosis from January 2011 to January 2021. We included pregnancies for which fetal colonic hyperechogenicity had been demonstrated. We collected the investigations performed during pregnancy and at birth as well as the main clinical features of the mother and the child. We then established the prevalence of pathologies such as lysinuria‐cystinuria (LC), hypotonia‐cystinuria syndrome (HC), or lysinuric protein intolerance (LPI).
Results
Among the 33 cases of colonic hyperechogenicity collected, and after exclusion of those lost to follow‐up, we identified 63% of children with lysinuria‐cystinuria, 8% with lysinuric rotein intolerance, and 4% with hypotonia‐cystinuria syndrome.
Conclusion
Management of prenatal hyperechoic colon should include a specialized consultation with a clinical geneticist to discuss further investigations, which could include invasive amniotic fluid sampling for molecular diagnosis. A better understanding of diagnoses and prognosis should improve medical counseling and guide parental decision making.
Key points
What's already known about this topic ?
Currently, colonic hyperechogenicity is a sign of lysinuria‐cystinuria, but it can also be a sign of other disorders with a more severe prognosis.
What does this study add?
In this retrospective study, among fetuses with hyperechoic colon, we identified 63% of children with lysinuria‐cystinuria, 8% with lysinuric protein intolerance, and 4% with hypotonia‐cystinuria syndrome. These data are likely to modify the management of patients in whom a hyperechogenic fetal colon is identified.
Dens are important for species that need to survive and reproduce during harsh winters. Brown bears (Ursus arctos) in Romania, listed by the European Union as a population of concern, use dens for ...several months each year. To date, few quantitative assessments of denning habitat have been carried out for this population or others in Europe. In 2008–2013 and 2015–2017, we used local knowledge and telemetry data from brown bears fitted with GPS collars to identify 115 winter dens and eight open ground nests used by bears in eastern Transylvania, Romania. We located most dens in mountainous areas (64%) and fewer in foothills (36%). Den entrances in mountainous areas were significantly narrower than entrances in foothills, likely due to the need for reduced thermal loss during more severe winters at higher elevations. We selected seven habitat characteristics (abiotic and biotic) and human-related covariates associated with known locations of dens and open nests to identify potential brown bear denning habitat using maximum entropy modeling. We found that terrain ruggedness was the single most important factor when predicting bear denning habitat. The habitat map derived from this study can be used in the future to safeguard bear denning areas from potential human disturbances.
Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, ...such as in malnourished older subjects.
Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients.
This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients 80–92 years; 18 women and 6 men in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks.
NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed-state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg).
Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM.
Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion ...of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts.
Cette monographie présente les résultats de la fouille archéologique préventive menée en 2013-2014 sur le site de l’ancienne Gare routière de Clermont-Ferrand. Le secteur concerné par l’opération ...correspond au fond de vallée de la Tiretaine du Sud, en périphérie de la ville antique d’Augustonemetum. Il s’agit d’une zone marécageuse qui est investie à la fin du ier siècle ou au tout début du iie siècle, lors d’une première phase d’expansion de l’agglomération. Deux bâtiments sont alors construits, dont une auberge, établie en rive gauche d’un bras de la Tiretaine traversant l’emprise d’est en ouest. À la fin du iie siècle, la canalisation du cours d’eau assure un meilleur drainage du quartier, qui connaît un développement spectaculaire. L’auberge est agrandie, des locaux artisanaux sont installés en rive droite et, au nord, une maison à cour centrale est construite au sein d’une parcelle allongée, dont la configuration traduit indirectement la pression foncière qui s’exerce sur le quartier. Dès la fin du iiie siècle, le tiers sud de l’emprise de fouille est abandonné suite aux crues répétées du cours d’eau. L’auberge est profondément remodelée et change probablement de fonction. Cet édifice est à nouveau modifié durant le ive siècle, mais le mauvais état de conservation des vestiges de cette période ne permet pas d’en déterminer la nature. Après une longue phase d’abandon, le secteur n’est réoccupé qu’à partir du milieu du xve siècle. Le terrain est alors divisé en parcelles cultivées qui peuvent être identifiées à des vignes qui témoignent du développement d’une agriculture spéculative aux portes de la ville. Grâce à l’importante superficie explorée (4 500 m²) et à d’excellentes conditions de conservation, les fouilles de l’ancienne Gare routière ont livré une documentation extrêmement riche. Cet ouvrage, qui rassemble les contributions de vingt chercheurs, en livre une synthèse permettant de retracer l’évolution d’un quartier dans son environnement naturel et urbain.
Purpose
To assess prospectively the prognostic value of FDG PET/CT during curative-intent radiotherapy (RT) with or without concomitant chemotherapy in patients with non-small-cell lung cancer ...(NSCLC).
Methods
Patients with histological proof of invasive localized NSCLC and evaluable tumour, and who were candidates for curative-intent radiochemotherapy (RCT) or RT were preincluded after providing written informed consent. Definitive inclusion was conditional upon significant FDG uptake before RT (PET
1
). All included patients had a FDG PET/CT scan during RT (PET
2
, mean dose 43 Gy) and were evaluated by FDG PET/CT at 3 months and 1 year after RT. The main endpoint was death (from whatever cause) or tumour progression at 1 year.
Results
Of 77 patients preincluded, 52 were evaluable. Among the evaluable patients, 77 % received RT with induction chemotherapy and 73 % RT with concomitant chemotherapy. At 1 year, 40 patients (77 %) had died or had tumour progression. No statistically significant association was found between stage (IIIB vs. other), histology (squamous cell carcinoma vs. other), induction or concomitant chemotherapy, and death/tumour progression at 1 year. The SUV
max
in the PET
2
scan was the single variable predictive of death or tumour progression at 1 year (odds ratio 1.97, 95 % CI 1.25 – 3.09,
p
= 0.003) in multivariate analysis. The area under the receiver operating characteristic curve was 0.85 (95 % CI 0.73 – 0.94,
p
< 10
−4
). A SUV
max
value of 5.3 in the PET
2
scan yielded a sensitivity of 70 % and a specificity of 92 % for predicting tumour progression or death at 1 year.
Conclusion
This prospective multicentre study demonstrated the prognostic value in terms of disease-free survival of SUV
max
assessed during the 5th week of curative-intent RT or RCT in NSCLC patients (NCT01261598; RTEP2 study).