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Tangier disease is characterized by low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins. ABC1, a member of the ATP-binding cassette family, recently has been identified as the defective gene in Tangier disease. We report here the organization of the human ABC1 gene and the identification of a mutation in the ABC1 gene from the original Tangier disease kindred. The organization of the human ABC1 gene is similar to that of the mouse ABC1 gene and other related ABC genes. The ABC1 gene contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length. Sequence analysis of the ABC1 gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22. The deletion results in a frameshift mutation and a premature stop codon starting at nucleotide 3375. The product is predicted to encode a nonfunctional protein of 1,084 aa, which is approximately half the size of the full-length ABC1 protein. The loss of a Mn/1 restriction site, which results from the deletion, was used to establish the genotype of the rest of the kindred. In summary, we report on the genomic organization of the human ABC1 gene and identify a frameshift mutation in the ABC1 gene of the index case of Tangier disease. These results will be useful in the future characterization of the structure and function of the ABC1 gene and the analysis of additional ABC1 mutations in patients with Tangier disease.

A two-step gene replacement procedure was developed that generates infectious adenoviral genomes through homologous recombination in Escherichia coli. As a prerequisite, a human adenovirus serotype 5 (Ad5)-derived genome was first introduced as a PacI restriction fragment into an incP-derived replicon which, in contrast to ColE1-derivatives (e.g., pBR322 or pUC plasmids), is functional in a polA mutant of E. coli. Any modification can be introduced at will following two consecutive homologous recombinations between the incP/Ad5 replicon and the ColE1 plasmid. The overall procedure requires only the in vitro engineering of the ColE1-derivative by flanking the desired modification with small stretches of identical sequences. In the first step, a cointegrate between the tetracycline-resistant incP/Ad5 replicon and the kanamycin-resistant ColE1-derivative is selected by growing the polA host in the presence of both antibiotics. Resolution of this cointegrate is further selected in sucrose growth conditions due to the loss of a conditional suicide marker (the sacB gene of Bacillus subtilis) present in the ColE1 plasmid, leading to unmodified and modified incP/Ad5 replicons that can be differentiated upon restriction analysis. Consecutive rounds of this two-step cloning procedure allowed the introduction of multiple independent modifications within the virus genome, with no requirement for an intermediate virus. The potential of this procedure is demonstrated by the recovery of several E1E3E4-deleted adenoviruses following transfection of the corresponding E. coli-derived genomes in IGRP2 cells.

Background: Therapeutic bronchoscopy (TB) is an accepted strategy for the symptomatic management of central airway malignant obstruction. Stent insertion is recommended in case of extrinsic compression, but its value in preventing airway re-obstruction after endobronchial treatment without extrinsic compression is unknown. Objective: Silicone stent Placement in symptomatic airway Obstruction due to non-small cell lung Cancer (SPOC) is the first randomized controlled trial investigating the potential benefit of silicone stent insertion after successful TB in symptomatic malignant airway obstruction without extrinsic compression. Method: We planned an inclusion of 170 patients in each group (stent or no stent) over a period of 3 years with 1-year follow-up. The 1-year survival rate without symptomatic local recurrence was the main endpoint. Recurrence rate, survival, quality of life, and stent tolerance were secondary endpoints. During 1-year follow-up, clinical events were monitored by flexible bronchoscopies and were evaluated by an independent expert committee. Results: Seventy-eight patients (mean age 65 years) were randomized into 2 arms: stents (n = 40) or no stents (n = 38) after IB. Consequently, our main endpoint could not be statistically answered. Improvement of dyspnea symptoms is noticeable in each group but lasts longer in the stent group. Stents do not change the survival curve but reduce unattended bronchoscopies. In the no stent group, 19 new TB were performed with 16 stents inserted contrasting with 10 rigid bronchoscopies and 3 stents placed in the stent group. In a subgroup analysis according to the oncologic management protocol following TB (first-line treatment and other lines or palliation), the beneficial effect of stenting on obstruction recurrence was highly significant (p < 0.002), but was not observed in the naïve group, free from first-line chemotherapy. Conclusion: Silicone stent placement maintains the benefit of TB after 1 year on dyspnea score, obstruction’s recurrence, and the need for new TB. Stenting does not affect the quality of life and is suggested for patients after failure of first-line chemotherapy. It is not suggested in patients without previous oncologic treatment.

To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs ( PPT1 , TNF , IL1B and HIST1H1E ) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.

Objective The aim of this study was to investigate the factors associated with non-adherence to medication in a large multi-center sample of homeless schizophrenia (HSZ) patients. Methods This multi-center study was conducted in four French cities: Lille, Marseille, Paris, and Toulouse. In addition to the Medication Adherence Rating Scale (MARS), sociodemographic information, history of homelessness, illness severity using the Modified Colorado Symptom Index (MCSI) and the Multnomah Community Integration Scale (MCAS), and drug information were collected. Results In total, 218 HSZ patients (16.1% women, mean age 36.8 ± 9.3 years) were included in this study. In the multivariate analysis, being a woman and having higher illness severity (MCSI score) and lower “acceptance of illness” (MCAS score) were significantly associated with lower MARS index scores. Compared to men, women had lower MARS dimension 1 (‘medication adherence behavior’) and dimension 3 (‘negative side effects and attitudes toward psychotropic medication’) scores. First-generation antipsychotic use was also associated with lower MARS dimension 3 scores. Conclusion HSZ women reported lower adherence than men, mainly due to having more subjective negative side effects and worse attitudes toward psychotropic medication. Future longitudinal studies should confirm these findings and explore the applicability of specific pharmacological and non-pharmacological treatment strategies for HSZ women, including treatment dose adaptation and psychoeducation. Clinical trial number NCT01570712.

Abstract World population is projected to reach over nine billion by the year 2050, and ensuring food security while mitigating environmental impacts represents a major agricultural challenge. Thus, higher productivity must be reached through sustainable production by taking into account climate change, resources rarefaction like phosphorus and water, and losses of fertile lands. Enhancing crop diversity is increasingly recognized as a crucial lever for sustainable agro-ecological development. Growing legumes, a major biological nitrogen source, is also a powerful option to reduce synthetic nitrogen fertilizers use and associated fossil energy consumption. Organic farming, which does not allow the use of chemical, is also regarded as one prototype to enhance the sustainability of modern agriculture while decreasing environmental impacts. Here, we review the potential advantages of eco-functional intensification in organic farming by intercropping cereal and grain legume species sown and harvested together. Our review is based on a literature analysis reinforced with integration of an original dataset of 58 field experiments conducted since 2001 in contrasted pedo-climatic European conditions in order to generalize the findings and draw up common guidelines. The major points are that intercropping lead to: (i) higher and more stable grain yield than the mean sole crops (0.33 versus 0.27 kg m−2), (ii) higher cereal protein concentration than in sole crop (11.1 versus 9.8 %), (iii) higher and more stable gross margin than the mean sole crops (702 versus 577 € ha−1) and (iv) improved use of abiotic resources according to species complementarities for light interception and use of both soil mineral nitrogen and atmospheric N2. Intercropping is particularly suited for low-nitrogen availability systems but further mechanistic understanding is required to propose generic crop management procedures. Also, development of this practice must be achieved with the collaboration of value chain actors such as breeders to select cultivars suited to intercropping.

Calls for ecological principles in agriculture have gained momentum. Intercropping systems have long been designed by growing two, or more, annual crop species in the same field, aiming for a better resource use efficiency. However, assembly rules for their design are lacking. Notably, it is still unknown whether species performances are maximized during both the vegetative and reproductive phases given the sensitivity of reproductive allocation rules to resource limitation. Interestingly, ecological theory provides expectations regarding putative invariance of plant reproductive allometry (PRA) under non-limiting conditions for plant growth. Here we examined whether and how PRA changes in response to plant-plant interactions in intercropping systems, which can inform both ecological theory and the understanding of the functioning of intercropping systems. We analyzed a dataset of 28 field cereal-legume intercropping trials from various climatic and management conditions across Western Europe. PRA was quantified in both mixing and single-species situations. PRA was positively impacted in specific management conditions, leading to a greater increase in yield for a given increase in plant size. Variations in PRA were more beneficial for legumes grown in unfertilized mixture, which explains their use as a key component in actual intercrop systems. The response for cereals was similar but less pronounced in magnitude, and was greater under limiting resource conditions. Focusing on intercropping conditions, hierarchical competition (indicated by biomass difference between intercropped species) appears as a strong driver of the reproductive output of a given species. Plant reproductive allometry behaves in crop species in the same way as it does in wild species. However, contrary to theoretical expectations about an overall invariance of PRA, we highlighted taxon-specific and context-dependent effects of plant-plant interactions on PRA. This systematic deviation to PRA expectations could be leveraged to cultivate each species up to its reproductive optimum while accounting for the performance of the other, whether farmers' objective is to favor one species or to reach an equilibrium in seed production. Sowing density and cultivar choice could regulate the biomass of each component, with specific targets derived from allometric relationships, aiming for an optimal reproductive allocation in mixtures. Competing Interest Statement The authors have declared no competing interest. Footnotes * added supplementary files and link to data repository. * https://doi.org/10.5061/dryad.9ghx3ffhv

The programme to combat deforestation (PPCDAM) in the Brazilian Amazon , launched in 2004 and backed by commitments by the soya bean and beef sectors, has led to a considerable drop in the annual rate of deforestation. For territorial actors, it has been and continues to be a matter of conceiving, planning and implementing a rapid agrarian transition, based on a more efficient management of their various natural resources, of appropriating a limited physical space, and of creating the institutional capacities required to manage it sustainably. En Amazonie Brésilienne, depuis 2009, l’initiative « Município Verde » (Commune Verte) est née d’un engagement d’acteurs publics et privés dans certaines communes, afin de d’éliminer la déforestation, cadastrer les propriétés agricoles, promouvoir la restauration ou le reboisement des sols dégradés et l’intensification agricole via l’adoption de bonnes pratiques, et mettre en place un programme municipal de gestion environnementale. Le município de Paragominas, à l’origine de cette initiative, est parvenu en 2 ans à remplir les deux premiers objectifs, mais l’initiative se heurte à plusieurs obstacles pour garantir une gestion durable de ses ressources naturelles dans un contexte « zéro déforestation ». Nous analysons dans cette contribution les avancées et les limites actuelles auxquelles seule une démarche territoriale peut répondre.

Young's modulus, the ratio offeree per unit-cross-sectional-area to deformation, is a measure of elastic strength. It has been shown to be the primary determinant of crack initiation and propagation behavior in low-k films [2, 3], with lower modulus materials being weaker and more prone to mechanical failure. Higher Young's modulus materials have also been correlated with improved resistance to electromigration of copper [4].