Biology subjects

Cohen, K.

Publications and source records attributed to Cohen, K..

7 recordsLinked to original sources

bioRxiv2026

Genome-wide association study in Heterogeneous Stock rats identifies genetic loci associated with aversion-based learning and cocaine aversion

Addiction is a complex and heritable trait which progresses through several developmental stages, each of which is presumably influenced by multiple partially overlapping genetic factors. Cocaine initially produces rewarding effects, followed by aversive effects including anxiety, craving, anhedonia, and withdrawal. These aversive effects have been suggested to contribute to the etiology of cocaine use disorders (CUD), as repeated exposure is thought to desensitize the rewarding effects and sensitize the aversive effects through a process involving both aberrant reward-based learning and aberrant avoidance-based learning. We examined the genetic basis of aversion learning using both food-based and cocaine-based behavioral assays in outbred Heterogenous Stock (HS) rats. A total of 1,074 HS rats (35.3% male) underwent runway operant cocaine-seeking, food-based progressive ratio and punishment testing, and locomotion testing. These phenotypes were significantly heritable (with h2 estimates as high as 0.307) and identified significant (p < 0.05) genetic loci related to avoidance-based learning including from the punishment task on Chromosomes 2, 3, 5, and 6, and the cocaine-operant runway latency task on Chromosome X. 172 positional candidate genes were identified from significant and suggestive loci, including Cdh10, Cdh12, Cdh18 which have previously been associated with smoking initiation from human GWAS, Adcy3, Cfap206, and Drc1 which are associated with primary neuronal cilia, as well as SNPs associated with novelty-related and social interaction phenotypes in independent samples of HS rats. Our results suggest that these aversion learning phenotypes are themselves complex heritable traits influenced by multiple genetic loci, which may pleiotropically affect other aspects of addiction biology.

genetics↗

bioRxiv2024

Something to sink your teeth into: the mechanics of tooth indentation in frugivorous fishes

Frugivorous vertebrates engage in a mutualism with fruiting plants: the former receive a nutrient subsidy and the latter benefit by having their seeds distributed far from parent plants. Vertebrate frugivores like primates and bats have particular morphologies, like wide jaws and blunt teeth, which are thought to aid in dismantling fruit and obtaining trapped sugars. However, variation among frugivores and fruits has made the identification of common frugivore phenotypes difficult. We measured the performance of frugivorous fish dentitions whether this performance was comparable to fruit-eating bats and primates. We also explored how fruit characteristics affect puncture performance, and how indentation of fruit differs mechanically from harder foods like nuts. Finally, we used photoelasticity and videography to visualize how serrasalmid dentitions propagate stresses in simple gel models. We expected that frugivore dentitions would exhibit low force and then high work when engaging fruit tissues. Aligning with our expectation, the most frugivorous serrasalmid we tested, Colossoma, had dental performance that matched the low force, high work model. Indentation behavior differed between food types, both between fruits and nuts, and among different fruits. We also documented considerable differences in the indentation performances of different serrasalmid dentitions, among frugivores, omnivores, and carnivores. We propose that some differences in the morphology of frugivore dentitions make them better for granivory (eating seeds) than the softer fruit tissues. Fishes exhibit convergent mechanical and morphological strategies with other vertebrates for obtaining nutrition from fruits and seeds.

evolutionary biology↗

bioRxiv2022

Hematopoiesis and cell growth are differentially regulated by TAL1 isoforms

T-cell acute lymphoblastic leukemia (T-ALL) protein 1 (TAL1) is a central transcription factor in hematopoiesis. The timing and level of TAL1 expression orchestrate the differentiation to specialized blood cells and its overexpression is a common cause of T-ALL. Here we studied the two protein isoforms of TAL1, short and long, that are generated by the use of alternative promoters as well as by alternative splicing. We analyzed the expression of each isoform by deleting an enhancer or insulator, or by opening chromatin at the enhancer location. Our results show that each enhancer promotes expression from a specific TAL1 promoter. Expression from a specific promoter gives rise to a unique 5 UTR with differential regulation of translation. Moreover, our study suggests that the enhancers regulate TAL1 exon 3 alternative splicing by inducing changes in the chromatin at the splice site, which we demonstrate is mediated by KMT2B. Furthermore, our results indicate that TAL1-short binds more strongly to TAL1 E-protein partners and functions as a stronger transcription factor than TAL1-long. Specifically TAL1-short has a unique transcription signature promoting apoptosis. Finally, when we expressed both isoforms in mice bone-marrow, we found that while overexpression of both isoforms prevents lymphoid differentiation, expression of TAL-short alone leads to hematopoietic stem cell exhaustion. Furthermore, we found that TAL1-short promoted erythropoiesis and reduced cell survival in the CML cell line K562. While TAL1 and its partners are considered promising therapeutic targets in the treatment of T-ALL, our results show that TAL1-short could act as a tumor suppressor and suggest that altering TAL1 isoforms ratio could be a preferred therapeutic approach.

molecular biology↗

bioRxiv2022

The City Nature Challenge - A global citizen science phenomenon contributing to biodiversity knowledge and informing local government practices

The bioblitz phenomenon has recently branched into cities, presenting exciting opportunities for local governments to channel participants efforts toward local issues. The City Nature Challenge (CNC) is one such initiative that has been quickly uptaken by hundreds of municipalities worldwide. Despite high participation, we still lack a framework for evaluating how the CNC contributes to local biodiversity knowledge and to inform local government practices. Here, we develop such a tool and present a case study that illustrates its applicability. We demonstrate that the collected records contributed to a better understanding of contemporary, local biodiversity patterns and provided a more realistic representation of understudied groups such as insects and fungi. Importantly, we show that the CNC presented local governments with a cost-effective tool to make informed, evidence-based management and policy decisions, improve education and engagement programs, foster cross-council collaborations, and support a stronger sense of environmental stewardship within the local community.

scientific communication and education↗

bioRxiv2021

Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects

SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterized 198 antibodies isolated from four COVID19+ subjects and identified 14 SARS-CoV-2 neutralizing antibodies. One targeted the NTD, one recognized an epitope in S2 and twelve bound the RBD. Three anti-RBD neutralizing antibodies cross-neutralized SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs to the ACE2 receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency rather than the antibody epitope specificity regulates the in vivo protective potential of anti-SARS-CoV-2 antibodies. The anti-S2 antibody also neutralized SARS-CoV-1 and all four cross-neutralizing antibodies neutralized the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.

immunology↗

bioRxiv2021

VEGFA's distal enhancer regulates its alternative splicing in CML

Enhancer demethylation in leukemia and lymphoma was shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in vascularization and cancer progression. Since transcription and splicing are coupled in space and time, we hypothesized that the VEGFA enhancer can also regulate the genes alternative splicing to contribute to the pathology of CML. Our results show that mutating the VEGFA +157 enhancer promotes exclusion of exons 6b and 7 and activating the enhancer by tethering a chromatin activator has the opposite effect. In line with these results, CML patients display high enhancer activity and inclusion of VEGFA exons 6b and 7. To search for a key protein connecting transcription with alternative splicing, we analyzed 161 chromatin immunoprecipitation (ChIP)-seq experiments for DNA binding proteins and found that PML and CCNT2 bind VEGFAs promoter and enhancer. CCNT2 is a positive regulator of RNA polymerase II (RNAPII) transcription elongation and indeed its silencing promotes exclusion of exons 6b and 7. Slowing down RNAPII elongation promotes exclusion of exons 6b and 7. Thus our results suggest that VEGFAs +157 enhancer regulates its alternative splicing by increasing RNAPII elongation rate via CCNT2. Our work demonstrates the importance of the interplay between transcription and alternative splicing.

cancer biology↗

bioRxiv2016

Genome-wide association study in Collaborative Cross mice revealed a skeletal role for Rhbdf2

Osteoporosis, the most common bone disease, is characterized by a low bone mass and increased risk of fractures. Importantly, individuals with the same bone mineral density (BMD), as measured on two dimensional (2D) radiographs, have different risks for fracture, suggesting that microstructural architecture is an important determinant of skeletal strength. Here we took advantage of the rich phenotypic and genetic diversity of the Collaborative Cross (CC) mice. Using microcomputed tomography, we examined key structural parameters in the femoral cortical and trabecular compartments of male and female mice from 34 CC lines. These traits included the trabecular bone volume fraction, number, thickness, connectivity, and spacing, as well as structural morphometric index. In the mid-diaphyseal cortex, we recorded cortical thickness and volumetric BMD.\n\nThe broad-sense heritability of these traits ranged between 50 to 60%. We conducted a genome-wide association study to unravel 5 quantitative trait loci (QTL) significantly associated with 6 of the traits. We refined each locus by combining information obtained from the known ancestry of the mice and RNA-Seq data from publicly available sources, to shortlist potential candidate genes. We found strong evidence for new candidate genes, including Rhbdf2, which association to trabecular bone volume fraction and number was strongly suggested by our analyses. We then examined knockout mice, and validated the causal action of Rhbdf2 on bone mass accrual and microarchitecture.\n\nOur approach revealed new genome-wide QTLs and a series of genes that have never been associated with bone microarchitecture. This study demonstrates for the first time the skeletal role of Rhbdf2 on the physiological remodeling of both the cortical and trabecular bone. This newly assigned function for Rhbdf2 can prove useful in deciphering the predisposing factors of osteoporosis and propose new investigative avenues toward targeted therapeutic solutions.\n\nAuthor summaryIn this study, we used the novel mouse reference population, the Collaborative Cross (CC), to identify new causal genes in the regulation of bone microarchitecture, a critical determinant of bone strength. This approach provides a clear advantage in terms of resolution and dimensionality of the morphometric features (versus humans) and rich allelic diversity (versus classical mouse populations), over current practices of bone-related genome-wide association studies.\n\nOur genome-wide study revealed 5 loci significantly associated with microstructural traits in the cortical and trabecular bone. We found strong evidence for new candidate genes, in particular, Rhbdf2. We then validated the specific role of Rhbdf2 on bone mass accrual and microarchitecture using knockout mice. Importantly, this study is the first demonstration of a physiological role for Rhbdf2.

genetics↗