A Comprehensive Study of the Effects by Sequence Truncation within Inverted Terminal Repeats (ITRs) on the Productivity, Genome Packaging, and Potency of AAV Vectors.

One of the primary challenges in working with adeno-associated virus (AAV) lies in the inherent instability of its inverted terminal repeats (ITRs), which play vital roles in AAV replication, encapsidation, and genome integration. ITRs contain a high GC content and palindromic structure, which occasionally results in truncations and mutations during plasmid amplification in bacterial cells. However, there is no thorough study on how these alterations in ITRs impact the ultimate AAV vector characteristics.

Management of patients with advanced epithelial ovarian cancer: a European survey.

Background: The aim of this study was to assess current European practices in the management of patients with advanced epithelial ovarian cancer in 2021.

Methods: A 58-question electronic survey was distributed anonymously to the members of six European learned societies. Initial diagnostic workup and staging, pathological data, surgical data, treatments and follow-up strategies were assessed.

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors.

Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.

Methylmalonic acidemia (MMA) is an inborn error of metabolism mostly caused by mutations in the mitochondrial methylmalonyl-CoA mutase gene (MMUT). MMA patients suffer from frequent episodes of metabolic decompensation, which can be life threatening. To mimic both the dietary restrictions and metabolic decompensation seen in MMA patients, we developed a novel protein-controlled diet regimen in a Mmut deficient mouse model of MMA and demonstrated the therapeutic benefit of mLB-001, a nuclease-free, promoterless recombinant AAV GeneRideTM vector designed to insert the mouse Mmut into the endogenous albumin locus via homologous recombination.

Results of a 2021 French National Survey on Management of Patients with Advanced Stage Epithelial Ovarian Cancer.

Background: The aim of this study was to assess current French practices in the management of patients with advanced epithelial ovarian cancer.

Method: a 58-question electronic survey was distributed anonymously to the members of the SFOG (French Society of Gynaecological Oncology), GINECO-ARCAGY (National Investigators Group for Ovarian and Breast Cancer Studies in France) and FRANCOGYN (French research group in oncological and gynaecological surgery). Initial diagnostic workup and staging, pathological data, surgical data, treatments and follow-up strategies were assessed.

Fruit and Vegetable Purchases in Farmer's Market Stands: Analysing Survey and Sales Data.

Farmers' market implementation holds promise for increasing access to healthy foods. Although rarely measured, purchase data constitute an intermediate outcome between food environment and actual consumption. In a study conducted with two seasonal Fruits and Vegetables (FV) stands in a disadvantaged area of Montréal (Canada), we analysed how accessibility, perception, and mobility-related factors were associated with FV purchase.

[Upper-extremity venous thrombosis: A retrospective study about 160 cases].

Aim: To describe the clinical features and etiologies of upper limb venous thrombosis (ULVT).

Methods: All patients with a clinically suspected ULVT, were included retrospectively from January to December 2016. Diagnosis of ULVT was based on doppler-ultrasonography.

Promoting access to fresh fruits and vegetables through a local market intervention at a subway station.

Objective: Alternative food sources (AFS) such as local markets in disadvantaged areas are promising strategies for preventing chronic disease and reducing health inequalities. The present study assessed how sociodemographic characteristics, physical access and fruit and vegetable (F&V) consumption are associated with market use in a newly opened F&V market next to a subway station in a disadvantaged neighbourhood.

Design: Two cross-sectional surveys were conducted among adults: (i) on-site, among shoppers who had just bought F&V and (ii) a telephone-based population survey among residents living within 1 km distance from the market.

Atomic structure of a rationally engineered gene delivery vector, AAV2.5.

AAV2.5 represents the first structure-guided in-silico designed Adeno-associated virus (AAV) gene delivery vector. This engineered vector combined the receptor attachment properties of AAV serotype 2 (AAV2) with the muscle tropic properties of AAV1, and exhibited an antibody escape phenotype because of a modified antigenic epitope.

Estimating the health benefits of planned public transit investments in Montreal.

Background: Since public transit infrastructure affects road traffic volumes and influences transportation mode choice, which in turn impacts health, it is important to estimate the alteration of the health burden linked with transit policies.

Objective: We quantified the variation in health benefits and burden between a business as usual (BAU) and a public transit (PT) scenarios in 2031 (with 8 and 19 new subway and train stations) for the greater Montreal region.

Method: Using mode choice and traffic assignment models, we predicted the transportation mode choice and traffic assignment on the road network.

[Oral anticoagulants adherence in elderly patients treated for atrial fibrillation in the era of direct oral anticoagulants].

Background: The aim of this study was to determine the level of adherence to oral anticoagulants in the population of elderly patients treated for a non-valvular atrial fibrillation (AF) in the era of direct oral anticoagulants.

Patients And Method: This transversal study used Morisky scale to assess adherence to oral anticoagulants. We also collected patients' reviews about the treatment and factors explaining a poor adherence.

Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.

TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no small-molecule inhibitors have been published for this challenging interface. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported.

Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.

The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods.

Cryo-electron Microscopy Reconstruction and Stability Studies of the Wild Type and the R432A Variant of Adeno-associated Virus Type 2 Reveal that Capsid Structural Stability Is a Major Factor in Genome Packaging.

Unlabelled: The adeno-associated viruses (AAV) are promising therapeutic gene delivery vectors and better understanding of their capsid assembly and genome packaging mechanism is needed for improved vector production. Empty AAV capsids assemble in the nucleus prior to genome packaging by virally encoded Rep proteins. To elucidate the capsid determinants of this process, structural differences between wild-type (wt) AAV2 and a packaging deficient variant, AAV2-R432A, were examined using cryo-electron microscopy and three-dimensional image reconstruction both at an ∼5.

Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B.

The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets.

Association of implementation of a public bicycle share program with intention and self-efficacy: The moderating role of socioeconomic status.

This natural experiment examines the effect of a public bicycle share program on cognitions and investigates the moderating influence of socioeconomic status on this effect. Two cross-sectional population-based surveys were conducted. Intention and self-efficacy to use the public bicycle share program were assessed by questionnaire.

Implementing a Public Bicycle Share Program: Impact on Perceptions and Support for Public Policies for Active Transportation.

Background: Favorable public opinion and support for policies are essential to favor the sustainability of environmental interventions. This study examined public perceptions and support for active living policies associated with implementing a public bicycle share program (PBSP).

Methods: Two cross-sectional population-based telephone surveys were conducted in 2009 and 2010 among 5011 adults in Montréal, Canada.

Adeno-associated virus structural biology as a tool in vector development.

Adeno-associated viruses (AAVs) have become important therapeutic gene delivery vectors in recent years. However, there are challenges, including intractable tissues/cell types and pre-existing immune responses, which need to be overcome for full realization of this system. This review addresses strategies aimed at improving AAV efficacy in the clinic through the creation of hybrid vectors that display altered or more targeted specific tissue tropisms, while also escaping recognition from host-derived neutralizing antibodies.

Grassroots projects aimed at the built environment: Association with neighbourhood deprivation, land-use mix and injury risk to road users.

Objectives: 1) To describe grassroots projects aimed at the built environment and associated with active transportation on the Island of Montreal; and 2) to examine associations between the number of projects and indicators of neighbourhood material and social deprivation and the built environment.

Method: We identified funding agencies and community groups conducting projects on built environments throughout the Island of Montreal. Through website consultation and a snowballing procedure, we inventoried projects that aimed at transforming built environments and that were carried out by community organizations between January 1, 2006, and November 1, 2010.

The impact of implementing a public bicycle share program on the likelihood of collisions and near misses in Montreal, Canada.

Objective: This study aimed to estimate the impact of implementing a public bicycle share program (PBSP) on the likelihood of self-reported collisions and near misses between cyclists and motor vehicles among cyclists living in Montreal.

Methods: A repeated cross sectional design was used. Surveys were conducted at the launch of the PBSP, at the end of the first and second seasons of implementation.

The potential modal shift and health benefits of implementing a public bicycle share program in Montreal, Canada.

Background: This study estimated the modal shift associated with the implementation of a public bicycle share program in Montreal, Canada.

Methods: A population-based sample of adults participated in two cross sectional telephone surveys. Self-reported travel behaviors were collected at the end of the first (fall 2009) and second (fall 2010) season of implementation.

Impact evaluation of a public bicycle share program on cycling: a case example of BIXI in Montreal, Quebec.

Objectives: We examined associations between residential exposure to BIXI (BIcycle-taXI)-a public bicycle share program implemented in Montreal, Quebec, in 2009, which increases accessibility to cycling by making available 5050 bicycles at 405 bicycle docking stations-and likelihood of cycling (BIXI and non-BIXI) in Montreal over the first 2 years of implementation.

Methods: Three population-based samples of adults participated in telephone surveys. Data collection occurred at the launch of the program (spring 2009), and at the end of the first (fall 2009) and second (fall 2010) seasons of implementation.

Internal consistency, concurrent validity, and discriminant validity of a measure of public support for policies for active living in transportation (PAL-T) in a population-based sample of adults.

Active living is a broad conceptualization of physical activity that incorporates domains of exercise; recreational, household, and occupational activities; and active transportation. Policy makers develop and implement a variety of transportation policies that can influence choices about how to travel from one location to another. In making such decisions, policy makers act in part in response to public opinion or support for proposed policies.

Stereoselective preparation of β,γ-methano-GABA derivatives.

The Kulinkovich-de Meijere reaction between an unsaturated Grignard reagent and a chiral amide takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans cyclopropylamines. These compounds are transformed in four steps into the corresponding N-protected β,γ-methano-GABA derivatives, which are obtained for the first time in enantiomerically pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.