Reichert, M. | Search bioRxiv

bioRxiv2020

Sex-specific speed-accuracy tradeoffs shape neural processing of acoustic signals

Speed-accuracy tradeoffs - being fast at the risk of being wrong - are fundamental to many decisions and natural selection is expected to resolve these tradeoffs according to the costs and benefits of behavior. We here test the prediction that females and males should integrate information from courtship signals differently because they experience different payoffs along the speed-accuracy continuum. We fitted a neural model of decision making (a drift-diffusion model of integration to threshold) to behavioral data from the grasshopper Chorthippus biguttulus to determine the parameters of temporal integration of acoustic directional information used by male grasshoppers to locate receptive females. The model revealed that males had a low threshold for initiating a turning response, yet a large integration time constant enabled them to continue to gather information when cues were weak. This contrasts with parameters estimated for females of the same species when evaluating potential mates, in which response thresholds were much higher and behavior was strongly influenced by unattractive stimuli. Our results reveal differences in neural integration consistent with the sex-specific costs of mate search: Males often face competition and need to be fast, while females often pay high error costs and need to be deliberate.

neuroscience↗

bioRxiv2020

Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Purpose The myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target, therefore identifying druggable synthetic lethal interactions in MYC-active PDAC may lead to novel precise therapies.Methods Cluster analysis using direct MYC target genes was used to identify PDAC with active MYC. We profiled the transcriptome of established human cell lines, murine primary PDAC cell lines and also accessed public available repositories for transcriptomic profiling. Networks active in MYC hyperactive subtypes were analyzed by gene set enrichment analysis. An unbiased pharmacological drug screen with FDA-approved anti-cancer drugs was conducted to define MYC-associated vulnerabilities, which were validated by analysis of drug response repositories and genetic gain- and loss-of-function experiments.Results In an unbiased pharmacological drug screen with FDA-approved anti-cancer drugs we detected that the proteasome inhibitor bortezomib triggers a MYC-associated vulnerability. By integrating publicly available data sets we found the unfolded protein response as a signature connected to MYC. Furthermore, the increased sensitivity of MYC hyperactive PDACs to bortezomib was validated in genetically modified PDAC cells.Conclusions In sum, we provide evidence that perturbing the ubiquitin proteasome system might be an option to target MYC hyperactive PDAC cells and our data provide the rationale to further develop precise targeting of the ubiquitin-proteasome system as a subtype-specific therapeutic approach.Competing Interest StatementThe authors have declared no competing interest.Abbrevations4-OHT4-hydoxytamoxifenATF4activating transcription factor 4BETbromodomain and extra terminal motifCNVcopy number variationCTD2cancer target discovery and development networkdepmapdependency mapDoRothEAdiscriminant regulon expression analysisGSEAgene set enrichment analysisICGCinternational cancer gene consortiumMYCmyelocytomatosis oncogenePDACpancreatic ductal adenocarcinomaPERKproteinkinase RNA-activated-like ER kinaseSUMOsmall-ubiquitin-like modifierTCGAthe cancer genome atlasUPRunfolded protein responseUPSubiquitin proteasome systemView Full Text

cancer biology↗