Nayeli Gutiérrez

Effective MAPK-targeted therapies require greater pathway inhibition in tumors than in normal tissues. Although pan-RAF inhibitors have demonstrated activity in RAS-mutant cancers, combinations with MEK inhibitors require dose reductions because of toxicity, limiting clinical benefit. Here, we show that this toxicity results from MEK inhibitor-mediated feedback relief, which promotes RAF activation and enhances pan-RAF inhibitor binding in normal cells. We identify a distinct mechanism of RAF inhibition by RAF/MEK glues: by stabilizing RAF-MEK complexes, these compounds trap RAF in the cytosol, preventing membrane recruitment required for RAF activation. This spatial modulation mechanism preserves tumor-selective MAPK inhibition and enables full-dose combination therapy with pan-RAF inhibitors. This therapeutic strategy produced robust tumor regressions in multiple RAS-mutant tumor models, including models refractory to current RAS/MAPK-targeting therapies. Our findings underscore drug-induced proximity as a strategy to achieve tumor selectivity and support the clinical development of RAF/MEK glue plus pan-RAF inhibitor combinations for RAS-mutant tumors.

Four new taxa of the tribe Apomecynini are described from Mexico: Apomystirio gen. nov. and Apomystirio hispidum sp. nov. from the state of Chiapas; Adetaptera ignota sp. nov. from the state of Chiapas; and Adetus lunaris sp. nov. from the state of Jalisco.

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.

Tetraopes longhorn beetles are known for their resistance to milkweed plant toxins and their coevolutionary dynamics with milkweed plants (Asclepias). This association is considered a textbook example of coevolution, in which each species of Tetraopes is specialized to feed on one or a few species of Asclepias. A major challenge to investigating coevolutionary hypotheses and conducting molecular ecology studies lies in the limited understanding of the evolutionary history and biogeographical patterns of Tetraopes. By integrating genomic, morphological, paleontological, and geographical data, we present a robust phylogeny of Tetraopes and their relatives, using three inference methods with varying subsets of data, encompassing 2–12 thousand UCE loci. We elucidate the diversification patterns of Tetraopes species across major biogeographical regions and their colonization of the American continent. Our findings suggest that the genus originated in Central America approximately 21 million years ago during the Miocene and diversified from the Mid-Miocene to the Pleistocene. These events coincided with intense geological activity in Central America. Additionally, independent colonization events in North America occurred from the Late Miocene to the early Pleistocene, potentially contributing to the early diversification of the group. Our data suggest that a common ancestor of Tetraopini migrated into North America, likely facilitated by North Atlantic land bridges, while closely related tribes diverged in Asia and Europe during the Paleocene. Establishing a robust and densely sampled phylogeny of Tetraopes beetles provides a foundation for investigating micro- and macroevolutionary phenomena, including clinal variation, coevolution, and detoxification mechanisms in this ecologically important group.

Two new species of Acanthocinini (Lamiinae) from Mexico are described: Hyperplatys mexicanus sp. nov. from the state of Morelos; and Urgleptes martini sp. nov. from the states of Jalisco and Morelos.

After describing Phrynidius jonesi Gutiérrez, Toledo & Noguera, 2020 (Coleoptera, Cerambycidae, Lamiinae), the authors had the opportunity to study a conspecific individual of this species and recognize that the holotype had been erroneously determined as a male when in fact it was a female. Here, we rectify this error and provide morphological information for the identification of both sexes. Additionally, we record Phrynidius armatus Linsley, 1933 from Chiapas, Mexico. Finally, we document P. cristinae Gutiérrez et al. 2020 feeding on a fungus, which represents the first record for any species of the genus Phrynidius with this adult feeding habit.

Two new species of cerambycid beetles are described and illustrated: Morrisia skillmani from Guatemala and Adetaptera jejetama from Mexico. Additionally, a map illustrating the geographic distribution of the species of Morrisia Santos-Silva et al., 2019, and a key to the species of the genus are provided.

Taxonomic placement of the enigmatic monotypic Mexican longhorned beetle genus Vesperoctenus Bates is examined through inclusion in and reanalysis of the dataset of Haddad et al. (2018, Systematic Entomology 43: 68–89). We describe and discuss the phylogenetic significance of the internal structures of a recently collected V. flohri female from the Sierra de la Laguna mountain range in Mexico, the same specimen from which phylogenomic data was generated. Our phylogenomic analyses (469 genes) recovered Vesperoctenus with maximal statistical support within the cerambyciform family Vesperidae, sister to Vesperus Dejean (Vesperinae). Vesperus + Vesperoctenus were recovered sister to Philinae, and collectively form a clade sister to Anoplodermatinae. Thus, we place V. flohri within Vesperidae: Vesperinae: Vesperoctenini based on analyses of large-scale phylogenomic data. Finally, we propose that the conservation status of V. flohri merits assessment.

A lo largo de este documento se resalta el legado académico y humano de Martín Leonel Zurita-García (1979-2020). Se describe su trayectoria académica sobre todo en su fase universitaria, en la que se dedicó al campo de la Entomología, particularmente de la Sistemática, Biogeografía y Ecología de los coleópteros elatéridos, así como a la Entomología Forense. Publicó 17 artículos científicos y cuatro capítulos de libros; participó en cinco congresos nacionales y dos congresos internacionales. Martín Zurita es autor de siete taxones de Coleoptera. Como docente, impartió las asignaturas de Sistemática, Biogeografía y Entomología Forense, en la Facultad de Ciencias y la Facultad de Medicina de la UNAM, así como en la Universidad Simón Bolívar. Fungió como director o codirector de nueve tesis de Licenciatura en Biología que versan sobre Sistemática, Faunística y Entomología Forense. Asimismo, participó como jurado en cuatro exámenes de grado (tres de Maestría y uno de Doctorado). La segunda parte del documento es testimonial, incluye las sentidas palabras expresadas por hermanos, maestro, amigos, alumnos y colegas en quienes Martín Zurita dejó una profunda huella.