The importance of having two X chromosomes

Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may explain some features of X chromosome aneuploidies such as in Turner and Klinefelter syndromes

The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance

BACKGROUND: Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. METHODS: In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. RESULTS: Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. CONCLUSIONS: We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions

Early Clinical Experiences for Second-Year Student Pharmacists at an Academic Medical Center

Objective. To examine student outcomes associated with the Student Medication and Reconciliation Team (SMART) program, which was designed to provide second-year student pharmacists at the University of North Carolina (UNC) Eshelman School of Pharmacy direct patient care experience at UNC Medical Center

Characterization of Synaptically Connected Nuclei in a Potential Sensorimotor Feedback Pathway in the Zebra Finch Song System

Birdsong is a learned behavior that is controlled by a group of identified nuclei, known collectively as the song system. The cortical nucleus HVC (used as a proper name) is a focal point of many investigations as it is necessary for song production, song learning, and receives selective auditory information. HVC receives input from several sources including the cortical area MMAN (medial magnocellular nucleus of the nidopallium). The MMAN to HVC connection is particularly interesting as it provides potential sensorimotor feedback to HVC. To begin to understand the role of this connection, we investigated the physiological relation between MMAN and HVC activity with simultaneous multiunit extracellular recordings from these two nuclei in urethane anesthetized zebra finches. As previously reported, we found similar timing in spontaneous bursts of activity in MMAN and HVC. Like HVC, MMAN responds to auditory playback of the bird's own song (BOS), but had little response to reversed BOS or conspecific song. Stimulation of MMAN resulted in evoked activity in HVC, indicating functional excitation from MMAN to HVC. However, inactivation of MMAN resulted in no consistent change in auditory responses in HVC. Taken together, these results indicate that MMAN provides functional excitatory input to HVC but does not provide significant auditory input to HVC in anesthetized animals. We hypothesize that MMAN may play a role in motor reinforcement or coordination, or may provide modulatory input to the song system about the internal state of the animal as it receives input from the hypothalamus

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

GABA inactivation of the area ventral to MMAN resulted in a reduction in auditory responses in HVC.

<p>A, Left, HVC response to ten iterations of BOS before, during, and after GABA application. Right, normalized response to BOS. B. Location of the GABA injection (*). Dye was located ventral to LPS and medial to Area X (outlined by dotted line). The midline is indicated by the line (arrow). Scale bar, 200 µm. M, medial; V, ventral.</p

Comparison of auditory responses and song selectivity in simultaneously recorded multiunit activity in MMAN and HVC.

<p>A. Comparison of the response strength in HVC and MMAN. HVC had a significantly larger RS to BOS than did MMAN (*; paired t-test, p<0.05). The response to REV and CON in HVC and MMAN were not significantly different (REV, p = 0.17; CON, p = 0.47). B. Z-score for auditory-evoked activity in HVC and MMAN. HVC had a significantly higher z-score to BOS than did MMAN (*; paired t-test, BOS, p<0.01). The response in HVC and MMAN to REV and CON were not significantly different (REV, p = 0.20; CON, p = 0.15). C. Comparison of z-scores from simultaneous recorded activity in HVC and mMAN. Black diagonal line is the unity line. D. Both HVC and MMAN were selective for BOS vs REV and BOS vs CON. Selectivity was defined as d′>0.5 (dashed horizontal line). E. HVC was more selective for BOS versus CON than simultaneously recorded MMAN, as many points lie above the unity line than expected at random (p<0.05). The points for BOS versus CON did not lie significantly above the unity line than expected at random (p>0.05). The grey bars demark non-significant d′ values for MMAN and HVC; i.e., −0.5>d′>0.5.</p

Inactivation of MMAN resulted in little change in HVC auditory responses.

<p>A. Example of auditory evoked activity in MMAN and HVC before (left) and with (right) GABA application to MMAN. Top trace, PSTH of HVC response to ten iterations of BOS playback. Bin size, 25 ms. Middle trace, single, raw example of multiunit activity in HVC. Bottom trace, sonogram of BOS. B. Location of GABA application in MMAN approximated by rhodamine labeling (arrows). LMAN is outlined to the right of the dye (dotted semicircle, *). Scale bar, 200 µm. The dashed vertical line denotes the midline. Dorsal is upward. C. Average response of HVC to BOS presentation before (pre), during (GABA) and after (post) BOS presentation. In two experiments (filled squares) GABA application to MMAN did not produce a significant change in HVC response. In one experiment (open squares) there was a significant decrease in the HVC response to BOS during GABA application compared to pre and post GABA application (ANOVA, p<0.5, Tukey post-hoc). In one bird (open stars) the response to BOS increased throughout the duration of the experiment (pre, GABA, and post were all significantly different than each other; p<0.5, ANOVA, Tukey post-hoc). D. Normalized responses of data shown in C.</p

Schematic of the feedback loop to HVC through MMAN.

<p>For clarity, anatomical connections are only shown for the right hemisphere. HVC projects to the robust nucleus of the archipallium (RA), which projects to the (DMP). DMP projects bilaterally to MMAN. RA also projects to premotor nuclei that control the syrinx and respiration (PAm and RAm). Abbrev: DMP, dorsomedial nucleus of the posterior thalamus; MMAN, medial magnocellular nucleus of the nidopallium; nXIIts, tracheosyringeal part of the hypoglossal nucleus; PAm, paraambigualis; RAm, retroambigualis.</p

Auditory-evoked action potential activity in MMAN and HVC.

<p>Simultaneous multiunit activity from ipsilateral MMAN and HVC in response to playback of the bird's own song (BOS), the BOS in reverse (REV), and conspecific (CON) song. For both HVC and MMAN, top row, raw data for a single playback of each song; middle row, raster plot of activity to thirty iterations of each song; bottom row, peri-stimulus time histogram (PSTH) of the cumulative response to each song playback. Bin size = 25 ms. The response strength (RS) for each response is given, * indicates a RS that was significantly greater than 0 (one-tailed t-test; p<0.05). For MMAN response to REV, p = 0.06; CON, p = 0.08.</p