Murine vaginal colonization model for investigating asymptomatic mucosal carriage of streptococcus pyogenes

While many virulence factors promoting Streptococcus pyogenes invasive disease have been described, specific streptococcal factors and host properties influencing asymptomatic mucosal carriage remain uncertain. To address the need for a refined model of prolonged S. pyogenes asymptomatic mucosal colonization, we have adapted a preestrogenized murine vaginal colonization model for S. pyogenes. In this model, derivatives of strains HSC5, SF370, JRS4, NZ131, and MEW123 established a reproducible, asymptomatic colonization of the vaginal mucosa over a period of typically 3 to 4 weeks' duration at a relatively high colonization efficiency. Prior treatment with estradiol prolonged streptococcal colonization and was associated with reduced inflammation in the colonized vaginal epithelium as well as a decreased leukocyte presence in vaginal fluid compared to the levels of inflammation and leukocyte presence in non-estradiol-treated control mice. The utility of our model for investigating S. pyogenes factors contributing to mucosal carriage was verified, as a mutant with a mutation in the transcriptional regulator catabolite control protein A (CcpA) demonstrated significant impairment in vaginal colonization. An assessment of in vivo transcriptional activity in the CcpA(−) strain for several known CcpA-regulated genes identified significantly elevated transcription of lactate oxidase (lctO) correlating with excessive generation of hydrogen peroxide to self-lethal levels. Deletion of lctO did not impair colonization, but deletion of lctO in a CcpA(−) strain prolonged carriage, exceeding even that of the wild-type strain. Thus, while LctO is not essential for vaginal colonization, its dysregulation is deleterious, highlighting the critical role of CcpA in promoting mucosal colonization. The vaginal colonization model should prove effective for future analyses of S. pyogenes mucosal colonization

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Journal of Microelectronic Research - May 2003

https://scholarworks.rit.edu/meec_archive/1012/thumbnail.jp

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Plasma Dynamics

Contains research objectives and summary of research on eighteen research projects split into seven sections and reports on four research projects.U.S. Atomic Energy Commission (Contract AT(l1-1)-3070)National Science Foundation (Grant GK-37979X1

Species-specific behavioral patterns correlate with differences in synaptic connections between homologous mechanosensory neurons

We characterized the behavioral responses of two leech species, Hirudo verbana and Erpobdella obscura, to mechanical skin stimulation and examined the interactions between the pressure mechanosensory neurons (P cells) that innervate the skin. To quantify behavioral responses, we stimulated both intact leeches and isolated body wall preparations from the two species. In response to mechanical stimulation, Hirudo showed local bending behavior, in which the body wall shortened only on the side of the stimulation. Erpobdella, in contrast, contracted both sides of the body in response to touch. To investigate the neuronal basis for this behavioral difference, we studied the interactions between P cells. Each midbody ganglion has four P cells; each cell innervates a different quadrant of the body wall. Consistent with local bending, activating any one P cell in Hirudo elicited polysynaptic inhibitory potentials in the other P cells. In contrast, the P cells in Erpobdella had excitatory polysynaptic connections, consistent with the segment-wide contraction observed in this species. In addition, activating individual P cells caused asymmetrical body wall contractions in Hirudo and symmetrical body wall contractions in Erpobdella. These results suggest that the different behavioral responses in Erpobdella and Hirudo are partly mediated by interactions among mechanosensory cells

Demonstration of the temporal matter-wave Talbot effect for trapped matter waves

We demonstrate the temporal Talbot effect for trapped matter waves using ultracold atoms in an optical lattice. We investigate the phase evolution of an array of essentially non-interacting matter waves and observe matter-wave collapse and revival in the form of a Talbot interference pattern. By using long expansion times, we image momentum space with sub-recoil resolution, allowing us to observe fractional Talbot fringes up to 10th order.Comment: 17 pages, 7 figure

Identification and Replication of Loci Involved in Camptothecin-Induced Cytotoxicity Using CEPH Pedigrees

To date, the Centre d'Etude Polymorphism Humain (CEPH) cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL) related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1±2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response

Pion, kaon, proton and anti-proton transverse momentum distributions from p+p and d+Au collisions at sNN=200\sqrt{s_{NN}} = 200 GeV

Identified mid-rapidity particle spectra of $\pi^{\pm}$, $K^{\pm}$, and $p(\bar{p})$ from 200 GeV p+p and d+Au collisions are reported. A time-of-flight detector based on multi-gap resistive plate chamber technology is used for particle identification. The particle-species dependence of the Cronin effect is observed to be significantly smaller than that at lower energies. The ratio of the nuclear modification factor ($R_{dAu}$) between protons $(p+\bar{p})$ and charged hadrons ($h$) in the transverse momentum range $1.2<{p_{T}}<3.0$ GeV/c is measured to be $1.19\pm0.05$(stat)$\pm0.03$(syst) in minimum-bias collisions and shows little centrality dependence. The yield ratio of $(p+\bar{p})/h$ in minimum-bias d+Au collisions is found to be a factor of 2 lower than that in Au+Au collisions, indicating that the Cronin effect alone is not enough to account for the relative baryon enhancement observed in heavy ion collisions at RHIC.Comment: 6 pages, 4 figures, 1 table. We extended the pion spectra from transverse momentum 1.8 GeV/c to 3. GeV/