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Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer’s disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo . Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action. Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.

Mutations in glucocerebrosidase (GBA1) cause Gaucher disease and also represent a common risk factor for Parkinson's disease and Dementia with Lewy bodies. Recently, new tool molecules were described which can increase turnover of an artificial substrate 4MUG when incubated with mutant N370S GBA1 from human spleen. Here we show that these compounds exert a similar effect on the wild-type enzyme in a cell-free system. In addition, these tool compounds robustly increase turnover of 4MUG by GBA1 derived from human cortex, despite substantially lower glycosylation of GBA1 in human brain, suggesting that the degree of glycosylation is not important for compound binding. Surprisingly, these tool compounds failed to robustly alter GBA1 turnover of 4MUG in the mouse brain homogenate. Our data raise the possibility that in vivo models with humanized glucocerebrosidase may be needed for efficacy assessments of such small molecules.

We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.

Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.

What is fraternity in politics? A virtue? A form of naïveté? The poor relation of the revolutionary triad: liberty, equality, fraternity? A metaphor destined to embody proletarian hopes of justice and the remote ideal of a universal Republic? In any case, not a human right but an idea “as embarrassing as it is indispensable,” as a philosopher put it in an article published in Le Monde in May 2002. Why embarrassing? Because although political action can create conditions favorable to the flourishing of fraternal sentiments, it cannot ensure that such sentiments will exist, nor can it verify, much less compel

En 1832, l’attentat à la pudeur sur enfant fait l’objet d’une législation spécifique sous la qualification d’attentat à la pudeur sans violence qui sanctionne toute relation sexuelle entre un adulte et un enfant de moins de 11 ans (13 à partir de 1863). La notion de consentement est donc rendue inopérante en droit, le législateur estimant qu’un enfant n’est pas en mesure de fournir un consentement digne de ce nom. Pourtant il y a loin de la loi à la pratique judiciaire qui ne cessera pas d’être hantée, tout au long des XIXe et XXe siècles par le questionnement sur le possible consentement donné par la victime à son agresseur et de véritables enquêtes sur la moralité de l’enfant. Ces interrogations vont prendre une sorte de densité scientifique à l’orée des années 1930, avec l’entrée en lice de la psychiatrie, occupant le champ du discours social et de la pratique judicaire et mettant à mal le principe de la légalité des peines. In 1832, indecent assault on a child was the subject of a specific legislation and was qualified as “indecent assault without violence” ; it sanctionned any sexual intercourse between an adult and a child under the age of 11 (13 from 1863 and later 15 from 1945 on). The notion of consent therefore became ineffective as the legislator estimated that a child could not produce a consent worthy of the name. However there was a wide gap between the law and its practice. That practice was haunted all through the 19 th and 20 th centuries by the recurrent question of the eventual consent of the victim to his/her attacker and also by genuine investigations into the child’s morals. These questions would later get a kind of scientific density in the early 1930’s together with the growing importance of psychiatry standing in the field of social speech and of law practice.

ABSTRACT IN FRENCH: En 1832, l'attentat à la pudeur sur enfant fait l'objet d'une législation spécifique sous la qualification d'attentat à la pudeur sans violence qui sanctionne toute relation sexuelle entre un adulte et un enfant de moins de 11 ans (13 à partir de 1863). La notion de consentement est donc rendue inopérante en droit, le législateur estimant qu'un enfant n'est pas en mesure de fournir un consentement digne de ce nom. Pourtant il y a loin de la loi à la pratique judiciaire qui ne cessera pas d'être hantée, tout au long des XIXe et XXe siècles par le questionnement sur le possible consentement donné par la victime à son agresseur et de véritables enquêtes sur la moralité de l'enfant. Ces interrogations vont prendre une sorte de densité scientifique à l'orée des années 1930, avec l'entrée en lice de la psychiatrie, occupant le champ du discours social et de la pratique judicaire et mettant à mal le principe de la légalité des peines. // ABSTRACT IN ENGLISH: In 1832, indecent assault on a child was the subject of a specific legislation and was qualified as `indecent assault without violence'; it sanctionned any sexual intercourse between an adult and a child under the age of 11 (13 from 1863 and later 15 from 1945 on). The notion of consent therefore became ineffective as the legislator estimated that a child could not produce a consent worthy of the name. However there was a wide gap between the law and its practice. That practice was haunted all through the 19th and 20th centuries by the recurrent question of the eventual consent of the victim to his/her attacker and also by genuine investigations into the child's morals. These questions would later get a kind of scientific density in the early 1930's together with the growing importance of psychiatry standing in the field of social speech and of law practice. Reprinted by permission of Société d'histoire moderne et contemporaine

L'inceste est le tabou par excellence, celui qui fonde la société. Le nommer, par le droit, n'est-ce pas lui retirer une partie de son poids symbolique ? À l'inverse, ne pas le punir en tant que tel, n'est-ce pas nier la souffrance spécifique qu'il engendre ? Si la souffrance des victimes est aujourd'hui reconnue, la nécessité d'inscrire l'inceste dans la loi demeure un sujet de débat.