The Role of NLRP3 Inflammasome Activation and Oxidative Stress in Varicocele-Mediated Male Hypofertility

Varicocele (VC) is the most common abnormality identified in men evaluated for hypofertility. Increased levels of reactive oxygen species (ROS) and reduced antioxidants concentrations are key contributors in varicocele-mediated hypofertility. Moreover, inflammation and alterations in testicular immunity negatively impact male fertility. In particular, NLRP3 inflammasome activation was hypothesized to lead to seminal inflammation, in which the levels of specific cytokines, such as IL-1β and IL-18, are overexpressed. In this review, we described the role played by oxidative stress (OS), inflammation, and NLRP3 inflammasome activation in VC disease. The consequences of ROS overproduction in testis, including inflammation, lipid peroxidation, mitochondrial dysfunction, chromatin damage, and sperm DNA fragmentation, leading to abnormal testicular function and failed spermatogenesis, were highlighted. Finally, we described some therapeutic antioxidant strategies, with recognized beneficial effects in counteracting OS and inflammation in testes, as possible therapeutic drugs against varicocele-mediated hypofertility.     

Supporting Scientific Collaboration: Methods, Tools and Concepts

This paper discusses the interrelationship between e-Science and CSCW in terms of key substantive, methodological and conceptual innovations made in both fields. In so doing, we hope to draw out the existing relationship between CSCW and e-Science research, and to map out some key future challenges where the two areas of research may become more closely aligned. In considering what may be required to draw the two more closely together, the paper focuses primarily on investigations that have been undertaken in two dedicated initiatives into e-Science, along with the key issues emerging from these studies.     

Spatial consistency of dense features within interest regions for efficient landmark recognition

Recently, feature grouping has been proposed as a method for improving retrieval results for logos and web images. This relies on the idea that a group of features matching over a local region in an image is more discriminative than a single feature match. In this paper, we evolve this concept further and apply it to the more challenging task of landmark recognition. We propose a novel combination of dense sampling of SIFT features with interest regions which represent the more salient parts of the image in greater detail. In place of conventional dense sampling used in category recognition that computes features on a regular grid at a number of fixed scales, we allow the sampling density and scale to vary based on the scale of the interest region. We develop new techniques for exploring stronger geometric constraints inside the feature groups and computing the match score. The spatial information is stored efficiently in an inverted index structure. The proposed approach considers part-based matching of interest regions instead of matching entire images using a histogram under bag-of-words. This helps reducing the influence of background clutter and works better under occlusion. Experiments reveal that directing more attention to the salient regions of the image and applying proposed geometric constraints helps in vastly improving recognition rates for reasonable vocabulary sizes.     

Auditory-phonetic projection and lexical structure in the recognition of sine-wave words.

Speech remains intelligible despite the elimination of canonical acoustic correlates of phonemes from the spectrum. A portion of this perceptual flexibility can be attributed to modulation sensitivity in the auditory-to-phonetic projection, although signal-independent properties of lexical neighborhoods also affect intelligibility in utterances composed of words. Three tests were conducted to estimate the effects of exposure to natural and sine-wave samples of speech in this kind of perceptual versatility. First, sine-wave versions of the easy and hard word sets were created, modeled on the speech samples of a single talker. The performance difference in recognition of easy and hard words was used to index the perceptual reliance on signal-independent properties of lexical contrasts. Second, several kinds of exposure produced familiarity with an aspect of sine-wave speech: (a) sine-wave sentences modeled on the same talker; (b) sine-wave sentences modeled on a different talker, to create familiarity with a sine-wave carrier; and (c) natural sentences spoken by the same talker, to create familiarity with the idiolect expressed in the sine-wave words. Recognition performance with both easy and hard sine-wave words improved after exposure only to sine-wave sentences modeled on the same talker. Third, a control test showed that signal-independent uncertainty is a plausible cause of differences in recognition of easy and hard sine-wave words. The conditions of beneficial exposure reveal the specificity of attention underlying versatility in speech perception. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Macroporous calcium phosphate ceramic implants for sustained drug delivery

Limited blood circulation to the skeletal tissue is a major cause of reduced therapeutic effects seen with drugs administered by conventional systemic ways. To resolve this issue and obtain a sufficiently high local concentration to induce therapeutic effects, several implanted drug delivery systems have been developed for hard tissues using biomaterials.We have designed a drug delivery device based on hydroxylapatite (HA) and tested it in vitro using metronidazol and chloramphenicol as model compounds. Porous HA ceramics were prepared with two different shapes (cylindrical and spherical). Known amounts of drugs were introduced inside a drilled hole and sealed with wax. The ceramics were then suspended in stirred distilled water in closed polypropylene vials. Drug release was observed during several weeks.A mathematical model used to describe drug release from HA was elaborated based on the expressions of Fick's laws. The experimental kinetic results could be related to ceramic constitution and to drug localization.     

Candida albicans homologue of GGP1/GAS1 gene is functional in Saccharomyces cerevisiae and contains the determinants for glycosylphosphatidylinositol attachment

The GGP1/GAS1/CWH52 gene of Saccharomyces cerevisiae encodes a major exocellular 115 kDa glycoprotein (gp115) anchored to the plasma membrane through a glycosylphosphatidylinositol (GPI). The function of gp115 is still unknown but the analysis of null mutants suggests a possible role in the control of morphogenesis. PHR1 gene isolated from Candida alibicans is homologous to the GGP1 gene. In this report we have analysed the ability of PHR1 to complement a ggp1Δ mutation in S. cerevisiae. The expression of PHR1 controlled by its natural promoter or by the GGP1 promoter has been studied. In both cases we have observed a complete complementation of the mutant phenotype. Moreover, immunological analysis has revealed that PHR1 in budding yeast gives rise to a 75–80 kDa protein anchored to the membrane through a GPI, indicating that the signal for GPI attachment present in the C. albicans gene product is functional in S. cerevisiae.     

Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.     

Macrophage-Mediated Melanoma Reduction after HP-NAP Treatment in a Zebrafish Xenograft Model

The Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is endowed with immunomodulatory properties that make it a potential candidate for anticancer therapeutic applications. By activating cytotoxic Th1 responses, HP-NAP inhibits the growth of bladder cancer and enhances the anti-tumor activity of oncolytic viruses in the treatment of metastatic breast cancer and neuroendocrine tumors. The possibility that HP-NAP exerts its anti-tumor effect also by modulating the activity of innate immune cells has not yet been explored. Taking advantage of the zebrafish model, we examined the therapeutic efficacy of HP-NAP against metastatic human melanoma, limiting the observational window to 9 days post-fertilization, well before the maturation of the adaptive immunity. Human melanoma cells were xenotransplanted into zebrafish embryos and tracked in the presence or absence of HP-NAP. The behavior and phenotype of macrophages and the impact of their drug-induced depletion were analyzed exploiting macrophage-expressed transgenes. HP-NAP administration efficiently inhibited tumor growth and metastasis and this was accompanied by strong recruitment of macrophages with a pro-inflammatory profile at the tumor site. The depletion of macrophages almost completely abrogated the ability of HP-NAP to counteract tumor growth. Our findings highlight the pivotal role of activated macrophages in counteracting melanoma growth and support the notion that HP-NAP might become a new biological therapeutic agent for the treatment of metastatic melanomas.     

The effect of cocoa fermentation and weak organic acids on growth and ochratoxin A production by Aspergillus species

The acidic characteristics of cocoa beans have influence on flavor development in chocolate. Cocoa cotyledons are not naturally acidic, the acidity comes from organic acids produced by the fermentative microorganisms which grow during the processing of cocoa. Different concentrations of these metabolites can be produced according to the fermentation practices adopted in the farms, which could affect the growth and ochratoxin A production by fungi. This work presents two independent experiments carried out to investigate the effect of some fermentation practices on ochratoxin A production by Aspergillus carbonarius in cocoa, and the effect of weak organic acids such as acetic, lactic and citric at different pH values on growth and ochratoxin A production by A. carbonarius and Aspergillus niger in culture media. A statistical difference (ρ<0.05) in the ochratoxin A level in the cured cocoa beans was observed in some fermentation practices adopted. The laboratorial studies demonstrate the influence of organic acids on fungal growth and ochratoxin A production, with differences according to the media pH and the organic acid present. Acetic acid was the most inhibitory acid against A. carbonarius and A. niger. From the point of view of food safety, considering the amount of ochratoxin A produced, fermentation practices should be conducted towards the enhancement of acetic acid, although lactic and citric acids also have an important role in lowering the pH to improve the toxicity of acetic acid.