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Biology subjects

Bergeron, P.

Publications and source records attributed to Bergeron, P..

2 recordsLinked to original sources

Environmental effects on reproductive performance in preindustrial women

Early life environments can have long-lasting effects on adult reproductive performance, but disentangling the influence of early and adult life environments on fitness is challenging, especially for long-lived species. Using a detailed dataset spanning over two centuries, we studied how early and adult life environments impact reproductive performance in preindustrial women. We assessed the effect of environmental conditions associated with the parish of birth and the parish where the women had their offspring. We considered resource availability differences between rural, urban, northern, and southern parishes by comparing women who switched environments during their lifetime with those who did not. We found that urban-born women had an earlier age at first reproduction and lower offspring survival to adulthood than rural-born women, while South Quebec women had more offspring born than North Quebec women. Moreover, switching from urban to rural led to higher offspring survival, while the reverse had the opposite effect. In addition, moving from South to North resulted in fewer offspring born and surviving, whereas moving from North to South had the inverse effect. Finally, women who changed from rural to urban and from South to North had their first child at an older age compared to those who stayed in the same urbanity type. Our study underscores the complex and interactive effects of early and adult life environments on reproductive traits, highlighting the need to consider both when studying environmental effects on reproductive outcomes.

ecology↗

CryoEM reveals unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors

The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel pain target due to its striking human genetics. However, clinically available drugs (e.g. lidocaine, carbamazepine, etc.) are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9, and the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. Moreover, understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor series. To advance inhibitor design targeting the NaV1.7 channel, we established an iterative system to routinely obtain high-resolution ligand-bound NaV1.7 structures using cryogenic electron microscopy (cryo-EM). We report that GDC-0310 engages the NaV1.7 voltage-sensing domain 4 (VSD4) through an unexpected binding mode orthogonal to the arylsulfonamide class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, this study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. It also underscores an important role of the membrane bilayer in the discovery of selective NaV channel modulators.

bioengineering↗