Sexually dimorphic innate immunological responses of pre-pubertal Brahman cattle following an intravenous lipopolysaccharide challenge.

This study was designed to characterize potential sexually dimorphic immunological responses following a lipopolysaccharide (LPS) challenge in beef cattle. Six female (heifers) and five male (bulls) Brahman calves (average age=253 ± 19.9 and 288 ± 47.9 days; average body weight=194 ± 11 kg and 247 ± 19 kg for heifers and bulls, respectively) were challenged with LPS (0.25 µg LPS/kg body weight). Following administration of LPS, all cattle displayed increased sickness behavior beginning at 0.5h, with heifers on average displaying less sickness behavior than bulls. A febrile response was observed in all animals following LPS administration, with a maximum response observed from 4 to 5.5h. The average rectal temperature response was greater in heifers than bulls. In all cattle there were elevated serum concentrations of cortisol from 0.5 to 8h, TNF-α from 1 to 2.5h, IL-6 from 2 to 8h, and IFN-γ from 2.5 to 7h after LPS challenge. Additionally, serum concentrations of TNF-α were greater in heifers than bulls from 1.5 to 2h after the LPS challenge. Concentrations of IFN-γ were also greater on average in bulls than heifers. Leukopenia occurred from 1 to 8h, with a decreased neutrophil to lymphocyte ratio for the first 5h among all calves. These data demonstrate the existence of a sexually dimorphic acute-phase response in pre-pubertal Brahman calves. Specifically, heifers may have a more robust acute response to LPS challenge, even though bulls display more signs of sickness.

Sexually dimorphic stress and pro-inflammatory cytokine responses to an intravenous corticotropin-releasing hormone challenge of Brahman cattle following transportation.

This study was designed to characterize potential sexually dimorphic stress and immunological responses following a corticotropin-releasing hormone (CRH) challenge in beef cattle. Six female (heifers) and six male (bulls) Brahman calves (264 ± 12 d of age) were administered CRH intravenously (0.5 µg of CRH/kg body mass) after which serum concentrations of cortisol increased from 0.5 h to 4 h. From 1 h to 4 h after CRH administration, serum cortisol concentrations were greater in heifers than in bulls. In all cattle, increased serum concentrations of TNF-α, IL-6 and IFN-γ were observed from 2.5 h to 3 h after CRH, with greater concentrations of IFN-γ and IL-6 in heifers than bulls. Heifer total leukocyte counts decreased 1 h after CRH administration, while bull leukocyte counts and percent neutrophils decreased 2 h after CRH administration. Heifers had greater rectal temperatures than bulls, yet rectal temperatures did not change following administration of CRH. There was no effect of CRH administration on heart rate. However, bulls tended to have increased heart rate 2 h after CRH administration than before CRH. Heifer heart rate was greater than bulls throughout the study. These data demonstrate that acute CRH administration can elicit a pro-inflammatory response, and cattle exhibit a sexually dimorphic pro-inflammatory cytokine and cortisol response to acute CRH administration.

Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4.

The tumor suppressor protein p53 is a transcription factor that induces G(1) arrest of the cell cycle and/or apoptosis. The murine double-minute protein MDM2 and its homologue MDM4 (also known as MDMX) are critical regulators of p53. Altered transcripts of the human homologue of mdm2, MDM2, have been identified in human tumors, such as invasive carcinoma of the breast, lung carcinoma, and liposarcoma. MDM2 alternate forms act to negatively regulate the normal MDM2 gene product, thus activating p53. Although many reports have documented a plethora of tumor types characterized by MDM2 alternative transcripts, few have investigated the signals that might initiate alternative splicing. We have identified a novel role of these alternative MDM2 transcripts in the normal surveillance mechanism of the cell and in DNA damage response. We report that alternate forms of MDM2 are detected after UV irradiation. Furthermore, we show that mouse cells treated with UV are also characterized by alternative transcripts of mdm2, suggesting that this is an important and evolutionarily conserved mechanism for regulating the expression of MDM2/mdm2. An additional p53 regulator and mdm2 family member, MDM4, is likewise alternatively spliced following UV irradiation. By activating alternative splicing of both MDM2 and MDM4, yet another layer of p53 regulation is initiated by the cells in response to damage. A stepwise model for malignant conversion by which alternate forms of MDM2 and MDM4 place selective pressure on the cells to acquire additional alterations in the p53 pathway is herein proposed.

Gender and adolescent alcohol use disorders on BOLD (blood oxygen level dependent) response to spatial working memory.

AIMS: To determine how alcohol use differentially affects brain functioning in male and female adolescents. METHODS: Adolescents with alcohol use disorders (AUDs; 7 female, 11 male) and control adolescents without AUDs (9 female, 12 male), aged 14-17 years, performed spatial working memory and vigilance tasks during functional magnetic resonance imaging. RESULTS: Gender, AUD and their interaction were significantly associated with brain activation patterns to the tasks. There were interactions in the superior frontal, superior temporal, cingulate and fusiform regions, in which female and male adolescents with AUDs showed a different brain response from each other and control subjects. Overall, female adolescents with AUDs showed a greater departure from normal activation patterns than male adolescents with AUD. CONCLUSIONS: Adolescent alcohol involvement may affect male and female brains differently, and adolescent females may be somewhat more vulnerable to adverse alcohol effects. With continued drinking, these adolescents may be at an increased risk for behavioural deficits.

Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome.

Individuals with Li-Fraumeni syndrome carry inherited mutations in the p53 tumor suppressor gene and are predisposed to tumor development. To examine the mechanistic nature of these p53 missense mutations, we generated mice harboring a G-to-A substitution at nucleotide 515 of p53 (p53+/515A) corresponding to the p53R175H hot spot mutation in human cancers. Although p53+/515A mice display a similar tumor spectrum and survival curve as p53+/- mice, tumors from p53+/515A mice metastasized with high frequency. Correspondingly, the embryonic fibroblasts from the p53515A/515A mutant mice displayed enhanced cell proliferation, DNA synthesis, and transformation potential. The disruption of p63 and p73 in p53-/- cells increased transformation capacity and reinitiated DNA synthesis to levels observed in p53515A/515A cells. Additionally, p63 and p73 were functionally inactivated in p53515A cells. These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes.

An FMRI study of response inhibition in youths with a family history of alcoholism.

Disinhibition among alcoholics may precede or result from alcohol use disorders (AUDs). It remains unclear how disinhibition might contribute to AUD risk among youths with a family history of alcoholism (FHP). We used functional magnetic resonance imaging (fMRI) to explore inhibition-related neural risk factors for AUD. Participants were 12- to 14-year-old nondrinkers, including 12 FHP youths and 14 youths with no family history of alcoholism (FHN). Youths performed a go/no-go task during fMRI acquisition. At a conservative threshold, FHN youths showed less inhibitory response than FHP youths in the left middle frontal gyrus, despite similar task performance between groups. Using a more liberal threshold, FHP youths also demonstrated less response in additional frontal regions. These preliminary findings suggest that FHP youths show less inhibitory frontal response than FHN youths. Altered neural activation among FHP youths may underlie subsequent disinhibition and could be related to the AUD risk.