The effect of spinal cord injury on sexual function.

Spinal cord injury (SCI) causes severe neurological impairment with widespread motor, autonomic and sensory deficits, leading to a substantial quality of life impairment. The number of individuals with SCI increases by approximately 12,500 annually, and over 80% of individuals with SCI are males. SCI individuals rate sexual function as a top priority quality of life issue, and men with SCI likely suffer from sexual dysfunction, such as erectile and ejaculatory dysfunction, as well as infertility. Regardless of the high status of importance of sexual function, limited numbers of experimental studies in SCI animal models have focused on sexual function after SCI. Interestingly, human clinical research participants with SCI undergoing daily locomotor treadmill training have reported changes in sexual function. To advance targeted recovery of sexual function after SCI, a better understanding of the post-injury neural circuitry is necessary. The objective of this project was to determine the effect of activity-based training (ABT) on sexual function in a rat model of SCI and examine the effects of a contusion SCI on sexual function using improved quantifiable measures. Two well-established measures of sexual function were used to determine the effects of ABT on sexual function after SCI: the penile dorsiflexion reflex (PDFR) and bulbospongiosus electromyography. The second and third studies focused on determining the effect of a clinically relevant contusion injury of varying severities using kinematic analysis of the PDFR and real-time intracavernosal pressure recordings from the penis of rats undergoing mating behavior testing. ABT was shown to positively affect sexual function after SCI, where task-specific stepping and/or hindlimb loading impacts the local spinal cord circuitry responsible for sexual function. ABT may strengthen the residual fibers crossing the lesion epicenter, providing better coordination of supraspinal influences on the spinal cord sexual circuitry. Sexual function after SCI was determined to be correlated with the percent of white matter spared (a measure of injury severity), further supporting the disruption of spinobulbospinal coordination as the cause of sexual dysfunction after SCI. Kinematic analysis of the penile dorsiflexion reflex and telemetric recording of intracavernosal pressure may provide improved quantifiable measures for examining sexual function after SCI

Sex differences and effects of prenatal exposure to excess testosterone on ventral tegmental area dopamine neurons in adult sheep

Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesised to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep, with higher numbers of tyrosine hydroxylase (TH)‐immunoreactive (‐ir) cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30–90 or 60–90 resulted in increased numbers of VTA TH‐ir cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T‐treated ewes, which was primarily accounted for by greater numbers of TH‐ir cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T‐treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels within dopamine cells. Sex differences were also noted in numbers of TH‐ir cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH‐ir cells in the substantia nigra, suggesting that this sex difference is organised independently of prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T.We report a sex difference in ventral tegmental area (VTA) dopamine cells in the adult sheep with higher numbers of tyrosine hydroxylase (TH)‐immunoreactive cells in males than females. Moreover, prenatal exposure to excess T during gestational days 30–90 or 60–90 caused increased numbers of VTA TH‐immunoreactive cells in adult ewes compared to control females. Sex differences were also demonstrated in the substantia nigra, but prenatal T had no effect on TH in this area. Results indicate that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels in the VTA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111123/1/ejn12871.pd

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Nanotechnology-based approach for safer enrichment of semen with best spermatozoa

Abstract Background Advances in nanotechnology have permitted molecular-based targeting of cells through safe and biocompatible magnetic nanoparticles (MNP). Their use to detect and remove damaged spermatozoa from semen doses could be of great interest. Here, MNP were synthesized and tested for their ability to target apoptotic (annexin V) and acrosome-reacted (lectin) boar spermatozoa, for high-throughout retrieval in a magnetic field (nanoselection). The potential impacts of nanoselection on sperm functions and performance of offspring sired by sperm subjected to nanoselection were determined. Fresh harvested and extended boar semen was mixed with various amounts (0, 87.5, and 175 μg) of MNP-conjugates (Annexin V-MNP or Lectin-MNP) and incubated (10 to 15 min) for 37 °C in Exp. 1. In Exp. 2, extended semen was mixed with optimal concentrations of MNP-conjugates and incubated (0, 30, 90, or 120 min). In Exp. 3, the synergistic effects of both MNP-conjugates (87.5 μg – 30 min) on spermatozoa was evaluated, followed by sperm fertility assessments through pregnancy of inseminated gilts and performance of neonatal offspring. Sperm motion, viability, and morphology characteristics were evaluated in all experiments. Results Transmission electron microscopy, atomic force microscopy, and hyperspectral imaging techniques were used to confirm attachment of MNP-conjugates to damaged spermatozoa. The motility of nanoselected spermatozoa was improved (P  0.05). Conclusions The findings revealed the benefit of magnetic nanoselection for high-throughput targeting of damaged sperm, for removal and rapid and effortless enrichment of semen doses with highly motile, viable, and fertile spermatozoa. Therefore, magnetic nanoselection for removal of abnormal spermatozoa from semen is a promising tool for improving fertility of males, particularly during periods, such as heat stress during the summer months