Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The number of DEG identified in the bovine PFC (16,384) is similar to that identified in mice (15,423) and silver foxes (14,000), the latter also in the PFC.

“The number of DEG identified in the bovine PFC (16,384) is similar to that identified in mice (15,423) [47] and silver foxes (14,000) [40], the latter also in the PFC.”

• cites [47] Han X, Wu X, Chung WY, Li T, Nekrutenko A, Altman NS, et al. Transcriptome of embryonic and neonatal mouse cortex by high-throughput RNA sequencing. Proc Natl Acad Sci. 2009;106(31):12741–6 https://doi.org/10.1073/pnas.0902417106. sourceNot checked yet

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• cites [40] Kukekova AV, Johnson JL, Xiang X, Feng S, Liu S, Rando HM, et al. Red fox genome assembly identifies genomic regions associated with tame and aggressive behaviours. Nat Ecol Evol. 2018;2(9):1479–91 https://doi.org/10.1038/s41559-018-0611-6. sourceNot checked yet

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May combine two claims.

Within the up-regulated enriched pathways in the aggressive cohort, biological functions related to cellular, muscular and SNC development and function, heart formation and development, and immune responses were found.

“Within the up-regulated enriched pathways in the aggressive cohort, we found biological functions related with processes such as cellular, muscular and SNC development and function, heart formation and development, and immune responses (Supplementary Table 5).”

May combine two claims.

The up- and down-regulated DEG with ≥1 WR values compared with the compendium gene-list yielded 50 genes, 24 up and 26 down-regulated in the aggressive group of Lidia individuals.

“This comparison yielded 50 genes, 24 up and 26 down-regulated in the aggressive group of Lidia individuals (Table 2).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The mean proportion of mapped reads with the STAR software was 91.8%, similar among different samples (from 88.07 to 94.91%).

“The mean proportion of mapped reads with the STAR software was 91.8%, similar among different samples (from 88.07 to 94.91%) (Supplementary Table 1).”

May combine two claims.

Differential expression analysis revealed a total of 16,384 DEG between the aggressive and non-aggressive groups; of these, 1196 were statistically significant, producing 10,640 isoforms.

“revealing a total of 16,384 DEG between the aggressive and non-aggressive groups; of these genes, 1196 were statistically significant, producing 10,640 isoforms (8.86 transcripts per gene) (Table 1, Fig. 1a).”

May combine two claims.

The integrin and Alzheimer disease-presenilin signaling pathways are among the top enriched up-regulated pathways in the aggressive Lidia group.

“Among the top enriched up-regulated pathways in the aggressive Lidia group, the integrin and Alzheimer disease-presenilin signaling pathways are well-known gene routes in the development of abnormal aggressive behaviors [48] (Table 3).”

May combine two claims.

IPA analysis found that the most relevant results were under physiological system development and function and disease and disorders categories; top terms related to Nervous system development and function (p 4.10E-08, 6 DEGs), Neurological disease (p 6.33E-06, 5 DEGs), and Psychological disorders (p 6.33E-06, 3 DEGs).

“Within these categories, the top of the list gathered terms related with Nervous system development and function (highest p-value range of 4.10E-08 and 6 DEGs), and Neurological disease (highest p-value range of 6.33E-06 and 5 DEGs), and Psychological disorders (highest p-value range of 6.33E-06 and 3 DEGs) in their respective categories.”

Probably not a substantial claim: may not pass S3 (load-bearing).

RNA-sequencing of the sixteen PFC samples generated an average of 78.3 million paired-end reads per sample.

“The RNA-sequencing of the sixteen PFC samples generated an average of 78.3 million paired-end reads per sample.”

May combine two claims.

Within down-regulated DEGs in the aggressive cohort, GO biological processes included 260 genes as uniquely mapped IDs implicated in 243 processes (FDR ≤ 0.05), with highest significant values being dendritic cell cytokine production, trans-synaptic signaling by endocannabinoid, trans-synaptic signaling by lipid, negative regulation of renin secretion into blood stream, and melanocyte adhesion, 84

“Within the down-regulated DEGs in the aggressive cohort, the GO biological processes included 260 genes as uniquely mapped IDs implicated in 243 processes (FDR ≤ 0.05), the highest significant values being dendritic cell cytokine production, trans-synaptic signaling by endocannabinoid, trans-synaptic signaling by lipid, negative regulation of renin secretion into blood stream and melanocyte”

May combine two claims.

Of the statistically significant DEG, 918 were up-regulated and 278 were down-regulated in the aggressive group.

“A total of 918 up-regulated and 278 down-regulated differentially expressed genes (DEG) were identified”

• Also stated in: § Sequencing and read assembly · plain

  “Gene expression differences of the up-regulated DEG (log2FC ≥ 0.1) were greater in number, involving 918 genes, than those down-regulated; 278 DEG (log2FC ≤ 0.1)”

May combine two claims.

Under more permissive analyses, where weighted ranking was not taken into account, all intersections between cattle DEGs and aggression-associated genes were significant, whether considering genome population size 22,000 or 18,700, and whether considering all or only brain expression studies.

“It should be noted that under more permissive analyses, where weighted ranking was not taken into account, all intersections between cattle DEGs and aggression-associated genes were significant, whether considering a genome population size of 22,000 or 18,700 genes, and whether considering all or only brain expression studies.”

May combine two claims.

Functional network analyses predicted that 16 of these molecules are associated with behavioral function, among them aggressive behavior (p-value 2.99E-05).

“Furthermore, the functional network analyses predicted that 16 of these molecules are associated with behavioral function, among them aggressive behavior (p-value 2.99E-05) (Table 5).”

May combine two claims.

When taking only genes weight-ranked 1 or above identified in previous expression studies, 96 genes remained from CSCA; 13 were also present among Lidia DEGs, significantly unlikely by chance even under restrictive analysis (p=0.006).

“When we took only genes weight-ranked 1 or above that had been identified in previous expression studies (i.e. identified in at least two expression studies, or in one such study, as well as at least one GWAS, selective sweep, knock-out study, OMIM, or OMIA) 96 genes remained from our CSCA. Of these 13 were also present among the Lidia DEGs, a number significantly unlikely to have occurred by ch”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the network shown in Fig. 2, two Mitogen Activated Protein Kinases (MAPK) and two Extracellular Signal Regulated Kinases (ERK) occupy a position within the network.

“In the network shown in Fig. 2, two Mitogen Activated Protein Kinases (MAPK) and two Extracellular Signal Regulated Kinases (ERK) (outlined in grey color) occupy a position within the network.”

May combine two claims.

The top enriched categories - regulation of amino acid import across plasma membrane (GO:0010958) and regulation of amino acid transmembrane transport (GO:1903789) - are each comprised of multiple genes that regulate the import of and uptake of glutamate.

“The top enriched categories — regulation of amino acid import across plasma membrane (GO:0010958) and regulation of amino acid transmembrane transport (GO:1903789) — are each comprised of multiple genes that regulate the import of and uptake of glutamate (Supplementary Table 5).”

May combine two claims.

Five upstream regulators were predicted to be major transcriptional regulators of a set of three DEGs; two up-regulated (COL13A1 and IGF2) and the down-regulated BDNF gene.

“Finally, five upstream regulators were predicted to be major transcriptional regulators of a set of three DEGs; two up-regulated (COL13A1and IGF2) and the down-regulated BDNF gene (Fig. 3).”

May combine two claims.

The Lidia and Wagyu breeds differ significantly in their agonistic responses; Lidia is known as one of the most aggressive bovine breeds, whereas Wagyu bovines are docile animals selected and bred to ease handling.

“The two breeds differ significantly in their agonistic responses, the Lidia being known as one of the most aggressive bovine breeds, whereas Wagyu bovines are docile animals, selected and bred by farmers with the aim of easing their handling [26].”

• cites [26] Takanishi N, Oishi K, Kumagai H, Uemura M, Hirooka H. Factors influencing the priority of access to food and their effects on the carcass traits for Japanese black (Wagyu) cattle. Animal. 2015;9(12):2017–23 https://doi.org/10.1017/S1751731115001214. sourceNot checked yet

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The expression of aggressive behavior depends on the interaction between environmental and genetic factors, with a genetic additive component of around 50% in humans.

“Research has shown that the expression of aggressive behavior depends on the interaction between environmental and genetic factors, with a genetic additive component ranging around 50% in humans [4].”

• cites [4] Tuvblad C, Baker LA. Human aggression across the lifespan: genetic propensities and environmental moderators. Adv Genet. 2011;75:171–214 https://doi.org/10.1016/B978-0-12-380858-5.00007-1. sourceNot checked yet

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Classified as probably not a substantial claim.

Molecular correlates of animal aggressive behaviors resemble varying biological mechanisms in human pathological aggression.

“A large number of preclinical studies using different animal species as models has been encouraged on the reasoning that molecular correlates of animal aggressive behaviors resemble varying biological mechanisms in human pathological aggression [5].”

• cites [5] Blanchard DC, Blanchard RJ. What can animal aggression research tell us about human aggression? Horm Behav. 2003;44(3):171–7 https://doi.org/10.1016/S0018-506X(03)00133-8. sourceNot checked yet

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PFC lesions result in impulsive and antisocial behaviors in humans.

“The PFC role in aggression has been studied in different species, e.g. PFC lesions result in impulsive and antisocial behaviors in humans [23] and offensive aggression in rodents [17].”

• cites [23] Brower MC, Price BH. Neuropsychiatry of frontal lobe dysfunction in violent and criminal behaviour: a critical review. J Neurol Neurosurg Psychiatry. 2001;71(6):720–6 https://doi.org/10.1136/jnnp.71.6.720. sourceNot checked yet

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Similar results are reported in RNA-seq profiles of different dog breeds.

“Similar results are reported in RNA-seq profiles of different dog breeds [25].”

• cites [25] Våge J, Bønsdorff TB, Arnet E, Tverdal A, Lingaas F. Differential gene expression in brain tissues of aggressive and non-aggressive dogs. BMC Vet Res. 2010;6(1):3. sourceNot checked yet

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Modern humans have markedly reduced intraspecific reactive aggression when compared to extant primates.

“In conjunction with findings that our species has markedly reduced intraspecific reactive aggression when compared to extant primates, this has helped to spur research into the hypothesis that, relative to archaic hominins, modern humans have undergone positive selection for a reduction in reactive aggression towards each other [13].”

• cites [13] Wrangham RW. Hypotheses for the evolution of reduced reactive aggression in the context of human self-domestication. Front Psychol. 2019;10:1914. sourceNot checked yet

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PFC lesions result in offensive aggression in rodents.

“The PFC role in aggression has been studied in different species, e.g. PFC lesions result in impulsive and antisocial behaviors in humans [23] and offensive aggression in rodents [17].”

• cites [17] Craig IW, Halton KE. Genetics of human aggressive behaviour. Hum Genet. 2009;126(1):101–13 https://doi.org/10.1007/s00439-009-0695-9. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

GRIK3 has been targeted in modern human evolution and in multiple domestication events, including in dogs, sheep, yaks, and across multiple cattle breeds.

“This gene has been targeted in modern human evolution and in multiple domestication events, including in dogs, sheep, yaks, and across multiple cattle breeds [16, 19, 20].”

• cites [16] Eusebi PG, Cortés O, Dunner S, Cañón J. Detection of selection signatures for agonistic behavior in cattle. J Anim Breed Genet. 2018;135(3):170–7 https://doi.org/10.1111/jbg.12325. sourceNot checked yet

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• cites [19] Mariadassou M, Ramayo-Caldas Y, Charles M, Féménia M, Renand G, Rocha D. Detection of selection signatures in Limousin cattle using whole-genome resequencing. Anim Genet. 2020;51(5):815–9 https://doi.org/10.1111/age.12982. sourceNot checked yet

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• cites [20] Qanbari S, Pausch H, Jansen S, Somel M, Strom TM, Fries, et al. Classic Selective Sweeps Revealed by Massive Sequencing in Cattle. PLoS Genet. 2014;10(2). sourceNot checked yet

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A catalogue of gene-specific sequence variants was detected as differentially expressed between a strain of silver fox selected for aggressive behaviors and its tame counterpart.

“Moreover, a catalogue of gene-specific sequence variants was detected as differentially expressed between a strain of silver fox selected for aggressive behaviors when compared to its tame counterpart [24].”

• cites [24] Kukekova AV, Johnson JL, Teiling C, Li L, Oskina IN, Kharlamova AV, et al. Sequence comparison of prefrontal cortical brain transcriptome from a tame and an aggressive silver fox (Vulpes vulpes). BMC Genomics. 2011;12(1):482 https://doi.org/10.1186/1471-2164-12-482. sourceNot checked yet

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May combine two claims.

Lidia bovines belong to a primitive population selected for centuries to develop agonistic-aggressive responses, with moderate to high heritability estimates for the Lidia breed (0.20-0.36).

“Lidia bovines belong to a primitive population, selected for centuries to develop agonistic-aggressive responses by means of a series of traits that are registered by breeders on a categorical scale, which classifies aggression and fighting capacity, reporting moderate to high heritability estimates for the Lidia (0.20–0.36) [14, 15].”

• cites [14] Silva B, Gonzalo A, Cañón J. Genetic parameters of aggressiveness, ferocity and mobility in the fighting bull breed. Anim Res. 2006;55(1):65–70 https://doi.org/10.1051/animres:2005046. sourceNot checked yet

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• cites [15] Menéndez-Buxadera A, Cortés O, Cañon J. Genetic (co) variance and plasticity of behavioural traits in Lidia bovine breed. Ital J Anim Sci. 2017;16(2):208–16 https://doi.org/10.1080/1828051X.2017.1279035. sourceNot checked yet

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The Russian farm-fox experiment has shown that broad phenotypical changes can emerge from selection for reduced reactive aggression towards humans, a trait ubiquitous across domesticated species.

“The Russian farm-fox experiment has shown that such broad phenotypical changes can emerge from selection for reduced reactive aggression towards humans, a trait ubiquitous across domesticated species [12].”

• cites [12] Trut L, Oskina I, Kharlamova A. Animal evolution during domestication: the domesticated fox as a model. Biol Essays. 2009;31(3):349–60.Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

MAOA is an important locus widely associated with pathological forms of aggression, manifesting in humans in psychiatric conditions such as manic and bipolar disorders and schizophrenia.

“This includes a polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, an important locus widely associated with pathological forms of aggression which, in humans, manifests in a broad spectrum of psychiatric conditions, such as manic and bipolar disorders and schizophrenia, among others [17, 18].”

• cites [17] Craig IW, Halton KE. Genetics of human aggressive behaviour. Hum Genet. 2009;126(1):101–13 https://doi.org/10.1007/s00439-009-0695-9. sourceNot checked yet

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• cites [18] Eusebi PG, Sevane N, Cortés O, Contreras E, Cañon J, Dunner S. Aggressive behavior in cattle is associated with a polymorphism in the MAOA gene promoter. Anim Genet. 2019;51:14–21. sourceNot checked yet

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May combine two claims.

The Lidia breed has been selected exclusively for aggressive behavior related traits, and the tamed Wagyu breed has been selected for meat quality traits and docile behaviors to facilitate handling.

“The study is designed on the basis of the differences in aggressiveness reached through intensive human selection over the last centuries; whereas the Lidia breed has been selected exclusively for aggressive behavior related traits, the tamed Wagyu breed has been selected for meat quality traits and docile behaviors in order to facilitate handling [26].”

• cites [26] Takanishi N, Oishi K, Kumagai H, Uemura M, Hirooka H. Factors influencing the priority of access to food and their effects on the carcass traits for Japanese black (Wagyu) cattle. Animal. 2015;9(12):2017–23 https://doi.org/10.1017/S1751731115001214. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The eight Lidia individuals displayed similar scores on the four aggressiveness traits.

“The eight individuals displayed similar scores (Supplementary Table 2).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

DRD2 has been widely studied in schizophrenia, for which SNPs located in the gene promoter affect its transcriptional activity.

“The D2 dopamine receptor (DRD2) was identified as one of the top ranked genes and has been widely studied in schizophrenia, for which SNPs located in the gene promoter affect its transcriptional activity [58].”

• cites [58] d'Souza UM, Kel A, Sluyter F. From transcriptional regulation to aggressive behavior. Behav Genet. 2003;33(5):549–62 https://doi.org/10.1023/A:1025778817885. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

No agonistic encounters were registered among the Wagyu bovines nor against the personnel at the slaughterhouse.

“as expected from their natural docile behavior, no agonistic encounters were registered among them nor against the personnel at the slaughterhouse.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Kukekova et al. [24] compared PFC expression between aggressive and docile strains of silver fox and observed enrichment of pathways related to cellular movement, growth and proliferation, hematological system development and antigen presentation.

“Similar results were obtained by Kukekova et al. [24]; they compared the PFC expression between aggressive and docile strains of silver fox and also observed an enrichment of pathways related to cellular movement, growth and proliferation, hematological system development and antigen presentation.”

• cites [24] Kukekova AV, Johnson JL, Teiling C, Li L, Oskina IN, Kharlamova AV, et al. Sequence comparison of prefrontal cortical brain transcriptome from a tame and an aggressive silver fox (Vulpes vulpes). BMC Genomics. 2011;12(1):482 https://doi.org/10.1186/1471-2164-12-482. sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

The transcriptional correlates of aggression result, at least in part, from controlled artificial selection.

“These transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

All of the 24 up-regulated genes associated with aggressiveness and shared with previous studies are essential for neurodevelopment.

“All of the 24 up-regulated genes associated with aggressiveness and shared with previous studies, are essential for neurodevelopment.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Genealogical and behavioral scores of Lidia traits recorded between 1984 and 2010 and analyzed by Menéndez-Buxadera et al. using multi-trait reaction norm models revealed heritability values ranging between 0.230 and 0.308, with aggressiveness attaining the highest heritability score.

“The genealogical and behavioral scores of these traits have been recorded between 1984 and 2010 and analyzed by Menéndez-Buxadera et al. [15], using multi-trait reaction norm models, which revealed heritability values ranging between 0.230 and 0.308, with aggressiveness attaining the highest heritability score.”

• cites [15] Menéndez-Buxadera A, Cortés O, Cañon J. Genetic (co) variance and plasticity of behavioural traits in Lidia bovine breed. Ital J Anim Sci. 2017;16(2):208–16 https://doi.org/10.1080/1828051X.2017.1279035. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Aberrant presenilin expression plays an important role in Alzheimer's disease, with behaviors such as agitation and aggression frequently occurring in patients.

“It has been shown that aberrant presenilin expression also plays an important role in Alzheimer’s disease, with behaviors such as agitation and aggression frequently occurring in patients [22, 50].”

• cites [22] Siever LJ. Neurobiology of aggression and violence. Am J of Psych. 2008;165(4):429–42 https://doi.org/10.1176/appi.ajp.2008.07111774. sourceNot checked yet

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• cites [50] Ballard CG, Gauthier S, Cummings JL, Brodaty H, Grossberg GT, Robert P, et al. Management of agitation and aggression associated with Alzheimer disease. Nat Rev Neurol. 2009;5(5):245–55 https://doi.org/10.1038/nrneurol.2009.39. sourceNot checked yet

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In the nervous system, integrins are essential molecules for neuroplasticity.

“In the nervous system, integrins are essential molecules for neuroplasticity, i.e. the ability to adapt to internal and external stimuli by reorganizing its structure, function and connections [49].”

• cites [49] Cramer SC, Sur M, Dobkin BH, O'brien C, Sanger TD, Trojanowski JQ, et al. Harnessing neuroplasticity for clinical applications. Brain. 2011;134(6):1591–609 https://doi.org/10.1093/brain/awr039. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Fisher's exact test and FDR for multiple testing corrections were used for GO annotation and pathway enrichment scores.

“We used Fisher’s exact test for annotation and the FDR for multiple testing corrections, both for the up and down regulated DEG with P-values ≤0.05, to infer their pathway enrichment scores.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All these genes, RNAs and proteins appear to be involved in a heterogeneous array of biological functions related to behavior development and cell-to-cell signaling interactions.

“All these genes, RNAs and proteins appear to be involved in a heterogeneous array of biological functions related to behavior development and cell-to-cell signaling interactions.”

Classified as probably not a substantial claim.

A Benjamini-Hochberg False Discovery Rate was set as the threshold for statistically significant values of the Differentially Expressed Genes.

“A Benjamini-Hochberg False Discovery Rate (FDR), which defines the significance of the Cuffdiff output, was set as threshold for statistically significant values of the Differentially Expressed Genes (DEG).”

May combine two claims.

Testosterone is implicated in the modulation of PFC activity; when increased, it may affect fear-processing circuitry, which has been associated with reactive and abnormal aggressive responses.

“Testosterone is a sex hormone that has been implicated in the modulation of PFC activity; when increased, it may affect fear-processing circuitry, which has been associated with reactive and abnormal aggressive responses [52, 53].”

• cites [52] Radke S, Volman I, Mehta P, van Son V, Enter D, Sanfey A, et al. Testosterone biases the amygdala toward social threat approach. Sci Adv. 2015;1(5):e1400074. sourceNot checked yet

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• cites [53] Bakker-Huvenaars MJ, Greven CU, Herpers P, Wiegers E, Jansen A, Van Der Steen R, et al. Saliva oxytocin, cortisol, and testosterone levels in adolescent boys with autism spectrum disorder, oppositional defiant disorder/conduct disorder and typically developing individuals. Eur Neuropsychopharmacol. 2018;30:87–101. sourceNot checked yet

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Increased expression of integrins contributes to imbalanced synaptic function in specific pathological conditions, such as Alzheimer disease and schizophrenia, both often accompanied by episodic aggression and violence.

“Increased expression of integrins contributes to imbalanced synaptic function in specific pathological conditions, such as Alzheimer disease and schizophrenia, both often accompanied by episodic aggression and violence [48].”

• cites [48] Wu X, Reddy DS. Integrins as receptor targets for neurological disorders. Pharmacol Ther. 2012;134(1):68–81 https://doi.org/10.1016/j.pharmthera.2011.12.008. sourceNot checked yet

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Yang et al. [54] observed a strong association of genes belonging to the blood coagulation pathway with human psychiatric disorders, such as major depression and suicidal behavior.

“For example, Yang et al. [54] observed a strong association of genes belonging to the blood coagulation pathway with human psychiatric disorders, such as major depression and suicidal behavior.”

• cites [54] Yang Y, Chen J, Liu C, Fang L, Liu Z, Guo J, et al. The extrinsic coagulation pathway: a biomarker for suicidal behavior in major depressive disorder. Sci Rep. 2016;6(1):32882 https://doi.org/10.1038/srep32882. sourceNot checked yet

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Zhang-James et al. [36] reported a modest gene overlap between different categories of genetic evidence (human GWAS, genes with known causal evidence and rodent transcriptome genes).

“Similarly, Zhang-James et al. [36] reported a modest gene overlap between different categories of genetic evidence (human GWAS, genes with known causal evidence and rodent transcriptome genes).”

• cites [36] Zhang-James Y, Fernàndez-Castillo N, Hess JL, Malki K, Glatt SJ, Cormand B, et al. An integrated analysis of genes and functional pathways for aggression in human and rodent models. Mol Psych. 2019;24(11):1655–67. sourceNot checked yet

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The quote only partly states this claim.

Down-regulation of heterotrimeric G-protein pathways and GAD2 promotes the development of aggressive responses selected for in Lidia cattle.

“promoting the development of the aggressive responses selected for in Lidia cattle.”

• AssumptionRests on an assumption: The GAD2 gene is a repressor of agonistic reactions associated with PFC activity.
• AssumptionRests on an assumption: Heterotrimeric G-protein pathways are associated with low reactivity mental states.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Heterotrimeric G-protein pathways are the main signaling pathways downstream of receptor activation and have been functionally associated with major depression and bipolar disorders.

“These routes are the main signaling pathways downstream of receptor activation and have been functionally associated with major depression and bipolar disorders [56].”

• cites [56] González-Maeso J, Meana JJ. Heterotrimeric g proteins: insights into the neurobiology of mood disorders. Curr Neuropharmacol. 2006;4(2):127–38 https://doi.org/10.2174/157015906776359586. sourceNot checked yet

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A mutation in LAMA2 is associated with denervation atrophy of the muscle.

“The highest weight-ranked gene was the Laminin Subunit Alpha 2 (LAMA2), which encodes an extracellular matrix protein, and a mutation on which is associated with denervation atrophy of the muscle [57].”

• cites [57] Hall TE, Bryson-Richardson RJ, Berger S, Jacoby AS, Cole NJ, Hollway G, et al. The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin alpha2-deficient congenital muscular dystrophy. Proc Natl Acad Sci. 2007;104(17):7092–7 https://doi.org/10.1073/pnas.0700942104. sourceNot checked yet

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Zhang-James et al. [36] identified ERK/MAPK signaling as mechanisms underlying aggression.

“Similar results were obtained by Zhang-James et al. [36], who also identified ERK/MAPK signaling as mechanisms underlying aggression.”

• cites [36] Zhang-James Y, Fernàndez-Castillo N, Hess JL, Malki K, Glatt SJ, Cormand B, et al. An integrated analysis of genes and functional pathways for aggression in human and rodent models. Mol Psych. 2019;24(11):1655–67. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The PFC may not be representative of other brain regions also reported to play important roles in aggression, such as the amygdala, hippocampus or hypothalamus.

“Nonetheless, despite the PFC being a key region for the modulation of aggressive behavior, it may not be representative of other brain regions also reported to play important roles in aggression, such as the amygdala, hippocampus or hypothalamus.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

This pathway is highlighted as having been altered in multiple domestication events (including that of cattle), as well as in modern-human evolution.

“This pathway is also highlighted as having been altered in multiple domestication events (including that of cattle), as well as in modern-human evolution [10].”

• cites [10] Theofanopoulou C, Gastaldon S, O’Rourke T, Samuels BD, Messner A, Martins PT, et al. Self-domestication in Homo sapiens: Insights from comparative genomics. PLoS One. 2017;12:10. sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

This study constitutes an important first step towards the identification of genes that promote aggression in cattle, and provides a novel species as model organism for disentangling the variable mechanisms underlying aggressive behaviors in our own species.

“Nevertheless, this study constitutes an important first step towards the identification of genes that promote aggression in cattle, and provides a novel species as model organism for disentangling the variable mechanisms underlying aggressive behaviors in our own species.”

• AssumptionRests on an assumption: No prior study has described transcriptional mechanisms affecting aggressive behavior in cattle.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The MAPK/ERK cascade is a key regulator of cell growth and proliferation, and this signaling pathway activates the binding of different integrins at the cell surface to extracellular matrix proteins.

“The MAPK/ERK cascade is a key regulator of cell growth and proliferation, but most important, this signaling pathway activates the binding of different integrins at the cell surface to extracellular matrix proteins [60], linking its function with the up-regulated integrin pathway explained above.”

• cites [60] Yee KL, Weaver VM, Hammer DA. Integrin-mediated signalling through the MAP-kinase pathway. IET Syst Biol. 2008;2(1):8–15 https://doi.org/10.1049/iet-syb:20060058. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Malki et al. [36] observed that the MAPK signaling pathway was differentially expressed between aggressive and non-aggressive lines in mouse models.

“Malki et al. [36] performed a genome-wide transcriptome analysis of mouse models of aggression and also observed that the MAPK signaling pathway was differentially expressed between the aggressive and non-aggressive lines.”

• cites [36] Zhang-James Y, Fernàndez-Castillo N, Hess JL, Malki K, Glatt SJ, Cormand B, et al. An integrated analysis of genes and functional pathways for aggression in human and rodent models. Mol Psych. 2019;24(11):1655–67. sourceNot checked yet

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May combine two claims.

GAD2 is a GABA-synthesizing enzyme (converting glutamate to GABA), and low levels of GABA in the anterior cingulate cortex are associated with high levels of aggression.

“This gene, is a Gamma-aminobutyric acid (GABA)-synthesizing enzyme (converting glutamate to GABA), which has an inverse but linear relationship with measures of aggression: low levels of GABA in the anterior cingulate cortex are associated with high levels of aggression [59].”

• cites [59] Jager A, Amiri H, Bielczyk N, van Heukelum S, Heerschap A, Aschrafi A. Poelmans G, et al cortical control of aggression: GABA signalling in the anterior cingulate cortex. Eur Neuropsychopharmacol. 2017;30:5–16. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

One limitation of the current study is that we still need to consider some inherent biasing factors such as those associated to breed differences and external factors such as the conditions of the animal's slaughter.

“Furthermore, although our findings are consistent with gene expression studies of aggressive behaviors in other species, one limitation of the current study is that we still need to consider some inherent biasing factors such as those associated to breed differences and external factors such as the conditions of the animal’s slaughter.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Our findings open up the possibility that the Lidia share aspects of their neurotranscriptomic and behavioral profile with archaic humans, including elevated stress and aggressive reactivity.

“Given that the relevant archaic genomic regions are implicated in the regulation of gene expression, our findings open up the intriguing possibility that the Lidia share aspects of their neurotranscriptomic and behavioral profile with archaic humans, including elevated stress and aggressive reactivity.”

Probably not a substantial claim: may not pass S3 (load-bearing).

This has been proposed to alter the balance of glutamate-GABA interactions in stress-response circuits, including in prefrontal and limbic regions that regulate the hypothalamic-pituitary-adrenal (HPA) axis.

“This has been proposed to alter the balance of glutamate-GABA interactions in stress-response circuits, including in prefrontal and limbic regions that regulate the hypothalamic-pituitary-adrenal (HPA) axis [9].”

• cites [9] O’Rourke T, Boeckx C. Glutamate receptors in domestication and modern human evolution. Neurosci Biobehav Rev. 2020;108:341–57 https://doi.org/10.1016/j.neubiorev.2019.10.004. sourceNot checked yet

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May combine two claims.

Our observation that genes associated with archaic human regulatory changes show above-chance intersection with Lidia cattle DEGs mirrors findings that genetic changes in anatomically modern humans converge with those of domesticated species (including cattle).

“Our observation that genes associated with archaic human regulatory changes show above-chance intersection with Lidia cattle DEGs mirrors findings that genetic changes in anatomically modern humans converge with those of domesticated species (including cattle) [9, 10].”

• cites [9] O’Rourke T, Boeckx C. Glutamate receptors in domestication and modern human evolution. Neurosci Biobehav Rev. 2020;108:341–57 https://doi.org/10.1016/j.neubiorev.2019.10.004. sourceNot checked yet

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• cites [10] Theofanopoulou C, Gastaldon S, O’Rourke T, Samuels BD, Messner A, Martins PT, et al. Self-domestication in Homo sapiens: Insights from comparative genomics. PLoS One. 2017;12:10. sourceNot checked yet

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May combine two claims.

The modulator effect of these molecules appears to increase the up-regulation of biological processes such as hyperactive behavior and anxiety, which are often associated with aggressiveness, as well Alzheimer disease.

“The modulator effect of these molecules appears to increase the up-regulation of biological processes such as hyperactive behavior and anxiety, which are often associated with aggressiveness, as well Alzheimer disease, in concordance with the above findings.”