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High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

Divination —the consultation of an oracle in order to determine a course for future action— has long been considered a practice characteristic of “primitive mentality.” We describe research with the babalawo of Santería, who are expert in the divinatory system of Ifá. Our first goal is to offer an example of what Vygotsky called “concrete psychology”: the study of particular systems of psychological functions in the concrete circumstances of specific professional complexes. Our second goal is to explore the character of divination as psychological and social process, given the somewhat negative views of divination expressed by many social scientists, including Lévy-Bruhl and Vygotsky himself. Analysis of a recorded consultation identified features characteristic of institutional discourse. We argue that the institutional facts of divination may constitute an unfamiliar ontology, but the epistemology —the appeal to logic and to empirical evidence— is a familiar one.

La adivinación -consulta de un oráculo con el fin de determinar acciones futuras- se ha considerado una práctica característica de la "mentalidad primitiva". A continuación se presenta una investigación con los babalawos de la santería: los expertos en el sistema de adivinación de Ifá. El primer objetivo fue dar un ejemplo de lo que Vygotsky llamó "psicología concreta": el estudio de sistemas de funciones psicológicas particulares dentro de las circunstancias concretas de complejos profesionales específicos. El segundo objetivo fue explorar la adivinación como proceso psicológico y social, examinando las nociones, un tanto negativas, que han expresado algunos científicos sociales sobre este concepto, incluyendo a Lévy-Bruhl y al mismo Vygotsky. Algunos rasgos característicos del discurso institucional se identificaron a través del análisis de registros de audio de consultas al oráculo por parte de los autores. En este trabajo se argumentó que los aspectos institucionales de la adivinación pueden constituir una ontología poco común, pero una epistemología familiar.

Targeted protein degradation is an important mechanism carried out by the cellular machinery, one that is gaining momentum as an exploitable strategy for the development of drug-like compounds. Molecules which are able to induce proximity between elusive therapeutic targets of interest and E3 ligases which subsequently leads to proteasomal degradation of the target are beginning to decrease the percentage of the human proteome described as undruggable. Therefore, having the ability to screen for, and understand the mechanism of, such molecules is becoming an increasingly attractive scientific focus. We have established a number of cascade experiments including cell-based assays and orthogonal triage steps to provide annotation to the selectivity and mechanism of action for compounds identified as putative degraders from a primary high throughput screen against a high value oncology target. We will describe our current position, using PROTACs as proof-of-concept, on the analysis of these novel outputs and highlight challenges encountered.