Class A β -Lactamases as Versatile Scaffolds to Create Hybrid Enzymes: Applications from Basic Research to Medicine

Designing hybrid proteins is a major aspect of protein engineering and covers a very wide range of applications frombasic research to medical applications. This review focuses on the use of class A -lactamases as versatile scaffolds to design hybrid enzymes (referred to as -lactamase hybrid proteins, BHPs) in which an exogenous peptide, protein or fragment thereof is inserted at various permissive positions.We discuss how BHPs can be specifically designed to create bifunctional proteins, to produce and to characterize proteins that are otherwise difficult to express, to determine the epitope of specific antibodies, to generate antibodies against nonimmunogenic epitopes, and to better understand the structure/function relationship of proteins.Peer reviewe

Aromatic oligoamide foldamers as versatile scaffolds for induced circularly polarized luminescence at adjustable wavelengths

International audienceQuinoline oligoamide foldamers appended with non-chiral fluorophores and derivatized with a camphanyl chiral inducer display strong chiroptical properties at tunable wavelengths as proved by CD and CPL spectroscopies. Induced CPL activity with high luminescence dissymmetry factors was observed in the visible range at wavelengths specific to the fluorophores

Introduced Drosophila subobscura populations perform better than native populations during an oviposition choice task due to increased fecundity but similar learning ability

The success of invasive species is tightly linked to their fitness in a putatively novel environment. While quantitative components of fitness have been studied extensively in the context of invasive species, fewer studies have looked at quali- tative components of fitness, such as behavioral plasticity, and their interaction with quantitative components, despite intuitive benefits over the course of an invasion. In particular, learning is a form of behavioral plasticity that makes it possible to finely tune behavior according to environmental conditions. Learn- ing can be crucial for survival and reproduction of introduced organisms in novel areas, for example, for detecting new predators, or finding mates or oviposition sites. Here we explored how oviposition performance evolved in relation to both fecundity and learning during an invasion, using native and introduced Drosophila subobscura populations performing an ecologically rele- vant task. Our results indicated that, under comparable conditions, invasive populations performed better during our oviposition task than did native pop- ulations. This was because invasive populations had higher fecundity, together with similar cognitive performance when compared to native populations, and that there was no interaction between learning and fecundity. Unexpectedly, our study did not reveal an allocation trade-off (i.e., a negative relationship) between learning and fecundity. On the contrary, the pattern we observed was more consistent with an acquisition trade-off, meaning that fecundity could be limited by availability of resources, unlike cognitive ability. This pattern might be the consequence of escaping natural enemies and/or competitors during the introduction. The apparent lack of evolution of learning may indicate that the introduced population did not face novel cognitive challenges in the new environment (i.e., cognitive "pre-adaptation"). Alternatively, the evolution of learning may have been transient and therefore not detected

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Social environment mediates cancer progression in Drosophila

The influence of oncogenic phenomena on the ecology and evolution of animal species is becoming an important research topic. Similar to host–pathogen interactions, cancer negatively affects host fitness, which should lead to the selection of host control mechanisms, including behavioral traits that best minimize the proliferation of malignant cells. Social behavior is suggested to influence tumor progression. While the ecological benefits of sociality in gregarious species are widely acknowledged, only limited data are available on the role of the social environment on cancer progression. Here, we exposed adult Drosophila, with colorectal-like tumors, to different social environments. We show how subtle variations in social structure have dramatic effects on the progression of tumor growth. Finally, we reveal that flies can discriminate between individuals at different stages of tumor development and selectively choose their social environment accordingly. Our study demonstrates the reciprocal links between cancer and social interactions and how sociality may impact health and fitness in animals and its potential implications for disease ecology.This work was supported by the ANR (Blanc project EVOCAN to F.T. and project DROSONET to F.M. and C.S.), the CNRS (INEE and INSB), Fondation ARC (1555286 to J.M. and F.M.), The French league against Cancer (M27218 to J.M.), IDEEV program (to F.M.), by an International Associated Laboratory Project France/Australia, by the French-Australian Science Innovation Collaboration Program Early Career Fellowship (B.U.), by André Hoffmann (Fondation MAVA), Fyssen Foundation (to F.M. and E.H. D.) and the French Government (fellowship 2015–155 to M.D.)

Gemini multi-conjugate adaptive optics system review II: Commissioning, operation and overall performance

The Gemini Multi-conjugate Adaptive Optics System - GeMS, a facility instrument mounted on the Gemini South telescope, delivers a uniform, near diffraction limited images at near infrared wavelengths (0.95 microns- 2.5 microns) over a field of view of 120 arc seconds. GeMS is the first sodium layer based multi laser guide star adaptive optics system used in astronomy. It uses five laser guide stars distributed on a 60 arc seconds square constellation to measure for atmospheric distortions and two deformable mirrors to compensate for it. In this paper, the second devoted to describe the GeMS project, we present the commissioning, overall performance and operational scheme of GeMS. Performance of each sub-system is derived from the commissioning results. The typical image quality, expressed in full with half maximum, Strehl ratios and variations over the field delivered by the system are then described. A discussion of the main contributor to performance limitation is carried-out. Finally, overheads and future system upgrades are described.Comment: 20 pages, 11 figures, accepted for publication in MNRA

New Insights into the Genetic Etiology of Alzheimer’s Disease and Related Dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.Fil: Dalmasso, Maria Carolina. Gobierno de la Provincia de la Pampa. Ministerio Publico. Laboratorio de Genetica Forense.; Argentina. Universitat zu Köln; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Confluencia; ArgentinaFil: de Rojas, Itziar. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Tesi, Niccolo. Vrije Universiteit Amsterdam; Países Bajos. Delft University of Technology; Países BajosFil: Grenier Boley, Benjamin. Universite Lille; FranciaFil: Andrade, Victor. Universitat zu Köln; Alemania. Universitat Bonn; AlemaniaFil: Pedersen, Nancy L.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Stringa, Najada. University of Amsterdam; Países BajosFil: Zettergren, Anna. University of Gothenburg; SueciaFil: Hernández, Isabel. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Montrreal, Laura. Universitat Internacional de Catalunya; EspañaFil: Antúnez, Carmen. Hospital Clínico Universitario Virgen de la Arrixaca; EspañaFil: Antonell, Anna. Universidad de Barcelona; EspañaFil: Tankard, Rick M.. Murdoch University; AustraliaFil: Bis, Joshua C.. University of Washington; Estados UnidosFil: Sims, Rebecca. Cardiff University; Reino UnidoFil: Bellenguez, Céline. Universite Lille; FranciaFil: Quintela, Inés. Universidad de Santiago de Compostela; EspañaFil: González Perez, Antonio. Centro Andaluz de Estudios Bioinformáticos; EspañaFil: Calero, Miguel. Instituto de Salud Carlos Iii (isciii); España. Fundación Reina Sofia; EspañaFil: Franco Macías, Emilio. Universidad de Sevilla; EspañaFil: Macías, Juan. Hospital Universitario de Valme; EspañaFil: Blesa, Rafael. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Cervera Carles, Laura. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Menéndez González, Manuel. Universidad de Oviedo; EspañaFil: Frank García, Ana. Instituto de Salud Carlos Iii (isciii); España. Universidad Autónoma de Madrid; España. Instituto de Investigacion del Hospital de la Paz.; España. Hospital Universitario La Paz; EspañaFil: Royo, Jose Luís. Universidad de Málaga; EspañaFil: Moreno, Fermin. Instituto de Salud Carlos Iii (isciii); España. Hospital Universitario Donostia; España. Instituto Biodonostia; EspañaFil: Huerto Vilas, Raquel. Hospital Universitari Santa Maria de Lleida; España. Institut de Recerca Biomedica de Lleida; EspañaFil: Baquero, Miquel. Hospital Universitari i Politècnic La Fe; Españ

Severe Compromise of Preosteoblasts in a Surgical Mouse Model of Bisphosphonate-Associated Osteonecrosis of the Jaw.

Objectives: The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ. Material and Methods: Thirty-two mice were treated twice a week with either 100 μg/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi-quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT. Results: Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment. Conclusion: The severe imbalance between bone-forming cells and bone-resorbing cells showed in this study could contribute to the pathogenesis of BONJ