Biology subjects

Fabbri, M.

Publications and source records attributed to Fabbri, M..

6 recordsLinked to original sources

bioRxiv2024

CAMKV Kinase Signaling Is a Novel Therapeutic Avenue with Prognostic Relevance in Neuroblastoma

Neuroblastoma (NB) can be a highly aggressive malignancy in children. However, the precise mechanisms driving NB tumorigenesis remain elusive. This study revealed the critical role of CREB phosphorylation in NB cell proliferation. By employing a CRISPR-Cas9 knockout screen targeting calcium/calmodulin-dependent protein kinase (CaMK) family members, we identified the CaM kinase-like vesicle-associated (CAMKV) protein as a kinase that mediates direct phosphorylation of CREB to promote NB cell proliferation. CAMKV was found to be a transcriptional target of MYCN/MYC in NB cells. CAMKV knockout and knockdown effectively suppressed NB cell proliferation and tumor growth both in vitro and in vivo. Bioinformatic analysis revealed that high CAMKV expression is significantly correlated with poor patient survival. High-risk NB frequently had high CAMKV protein levels by Immunohistochemical staining. Integrated transcriptomic and proteomic analyses of CAMKV knockdown cells unveiled downstream targets involved in CAMKV-regulated phosphorylation and signaling pathways, many of which are linked to neural development and cancer progression. We identified small molecule inhibitors targeting CAMKV and further demonstrated the efficacy of one inhibitor in suppressing NB tumor growth and prolonging the survival of mice bearing xenografted tumors. These findings reveal a critical role for CAMKV kinase signaling in NB growth and identified CAMKV kinase as a potential therapeutic target and prognostic marker for patients with NB.

cancer biology↗

bioRxiv2023

A Brain-Wide Map of Neural Activity during Complex Behaviour

A key challenge in neuroscience is understanding how neurons in hundreds of interconnected brain regions integrate sensory inputs with prior expectations to initiate movements and thereby make decisions. It is difficult to meet this challenge if different laboratories apply different analyses to different recordings in different regions during different behaviours. Here, we report a comprehensive set of recordings from 621733 neurons across 139 mice in 12 labs performing a decision-making task with sensory, motor, and cognitive components, obtained with 699 Neuropixels probe insertions covering 279 brain areas in the left forebrain and midbrain and the right hindbrain and cerebellum. We provide an initial appraisal of this brain-wide map, assessing how neural activity encoded key task variables. Representations of visual stimuli appeared transiently in classical visual areas after stimulus onset and then spread to ramp-like activity in a collection of mid- and hindbrain regions that also encoded choices. Neural responses correlated with motor action almost everywhere in the brain. Responses to reward delivery and consumption versus negative feedback were also widespread. This publicly available dataset represents an unprecedented resource for understanding how computations distributed across and within brain areas drive behaviour.

neuroscience↗

bioRxiv2023

Brain-wide representations of prior information in mouse decision-making

The neural representations of prior information about the state of the world are poorly understood. To investigate them, we examined brain-wide Neuropixels recordings and widefield calcium imaging collected by the International Brain Laboratory. Mice were trained to indicate the location of a visual grating stimulus, which appeared on the left or right with prior probability alternating between 0.2 and 0.8 in blocks of variable length. We found that mice estimate this prior probability and thereby improve their decision accuracy. Furthermore, we report that this subjective prior is encoded in at least 20% to 30% of brain regions which, remarkably, span all levels of processing, from early sensory areas (LGd, VISp) to motor regions (MOs, MOp, GRN) and high level cortical regions (ACAd, ORBvl). This widespread representation of the prior is consistent with a neural model of Bayesian inference involving loops between areas, as opposed to a model in which the prior is incorporated only in decision-making areas. This study offers the first brain-wide perspective on prior encoding at cellular resolution, underscoring the importance of using large scale recordings on a single standardized task.

neuroscience↗

bioRxiv2022

Sinking a giant: quantitative macroevolutionary comparative methods debunk qualitative assumptions

Myhrvold et al.1 suggest that our inference of subaqueous foraging among spinosaurids2 is undermined by selective bone sampling, inadequate statistical procedures, and use of inaccurate ecological categorizations. Myhrvold et al.1 ignore major details of our analyses and results, and instead choose to portray our inferences as if they were based on qualitative interpretations of our plots, without providing additional analyses to support their claims. In this manuscript, we thoroughly discuss all the concerns exposed by Myhrvold et al.1. Additional analyses based on our original datasets2 and novel data presented by Myhrvold et al.1 do not change our original interpretations: while the spinosaurid dinosaurs Spinosaurus and Baryonyx are recovered as subaqueous foragers, Suchomimus is inferred as a non-diving animal.

paleontology↗

bioRxiv2021

Ecological constraints on highly evolvable olfactory receptor genes and morphology

While evolvability of genes and traits may promote specialization during species diversification, how ecology subsequently restricts such variation remains unclear. Chemosensation requires animals to decipher a complex chemical background to locate fitness-related resources, and thus the underlying genomic architecture and morphology must cope with constant exposure to a changing odorant landscape; detecting adaptation amidst extensive chemosensory diversity is an open challenge. Phyllostomid bats, an ecologically diverse clade that evolved plant-visiting from an insectivorous ancestor, suggest the evolution of novel food detection mechanisms is a key innovation: phyllostomids behaviorally rely strongly on olfaction, while echolocation is supplemental. If this is true, exceptional variation in underlying olfactory genes and phenotypes may have preceded dietary diversification. We compared olfactory receptor (OR) genes sequenced from olfactory epithelium transcriptomes and olfactory epithelium surface area of bats with differing diets. Surprisingly, although OR evolution rates were quite variable and generally high, they are largely independent of diet. Olfactory epithelial surface area, however, is relatively larger in plant-visiting bats and there is an inverse relationship between OR evolution rates and surface area. Relatively larger surface areas suggest greater reliance on olfactory detection and stronger constraint on maintaining an already diverse OR repertoire. Instead of the typical case in which specialization and elaboration is coupled with rapid diversification of associated genes, here the relevant genes are already evolving so quickly that increased reliance on smell has led to stabilizing selection, presumably to maintain the ability to consistently discriminate among specific odorants -- a potential ecological constraint on sensory evolution. Significance StatementThe evolutionary relationship between genes and morphology is complex to decipher, and macroevolutionary trends are often measured independently; this is especially challenging to quantify in unstable genomic regions or hypervariable traits. Odorant cues are detected by proteins encoded by the largest and fasted-evolving gene family in the mammalian genome and expressed in epithelia distributed on elaborate bony structures in the nose, posing a challenge to quantification. Yet, the direct interaction of the olfactory system with environmental signals strongly suggest that selection shapes its immense diversity. In neotropical bats, where reliance on plant-visiting evolved from an insectivorous ancestor, we discovered clear dietary differences amongst species, but only after considering morphological and molecular data simultaneously, emphasizing the power of a coupled analysis.

evolutionary biology↗

bioRxiv2020

Hidden limbs in the limbless skink Brachymeles lukbani: developmental observations

Reduced limbs and limblessness have evolved independently in many lizard clades. Skinks exhibit a wide range of limb-reduced morphologies, but only some species have been used to study the embryology of limb reduction (i.g., digit reduction in Chalcides and limb reduction in Scelotes). The genus Brachymeles, a Southeast Asian clade of skinks, includes species with a range of limb morphologies, from pentadactyl to functionally as well as structurally limbless species. Adults of the small, snake-like species Brachymeles lukbani show no sign of external limbs in the adult except for small depressions where they might be expected to occur. Embryos of B. lukbani in early stages of development, on the other hand, show a truncated but well-developed limb with a stylopod and a zeugopod, but no signs of an autopod. As development proceeds, the limbs small size persists even while the embryo elongates. These observations are made based on external morphology. We used florescent whole-mount immunofluorescence to visualize the morphology of skeletal elements and muscles within the embryonic limb of B. lukabni. Early stages have a humerus and separated ulna and radius cartilages; associated with these structures are dorsal and ventral muscle masses as those found in the embryos of other limbed species. While the limb remains small, the pectoral girdle grows in proportion to the rest of the body, with well-developed skeletal elements and their associated muscles. In later stages of development, the small limb is still present under the skin but there are few indications of its presence, save for the morphology of the scale covering it. The adult morphology consists of a well-developed pectoral girdle, small humerus, extremely reduced ulna and radius, and well-developed limb musculature connected to the pectoral girdle. These muscles form in association with a developing limb during embryonic stages, a hint that "limbless" lizards that possesses these muscles may have or have had at least transient developing limbs, as we find in B. lukbani. Overall, the observed pattern of ontogenetic reduction, leading to an externally limbless adult in which a limb rudiment is hidden and covered under the trunk skin, is a situation called cryptomelia. The results of this work add to our growing understanding of clade-specific patterns of limb reduction and the convergent evolution of limbless phenotypes through different developmental processes.

evolutionary biology↗