Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line

Resistance to cadmium (Cd)-induced testicular necrosis is an autosomal recessive trait defined as the Cdm locus. Using positional cloning, we previously identified the Slc39a8 (encoding an apical-surface ZIP8 transporter protein) as the gene most likely responsible for the phenotype. In situ hybridization revealed that endothelial cells of the testis vasculature express high ZIP8 levels in two sensitive inbred mouse strains and negligible amounts in two resistant strains. In the present study, we isolated a 168.7-kb bacterial artificial chromosome (BAC), carrying only the Slc39a8 gene, from a Cd-sensitive 129/SvJ BAC library and generated BAC-transgenic mice. The BTZIP8-3 line, having three copies of the 129/SvJ Slc39a8 gene inserted into the Cd-resistant C57BL/6J genome (having its normal two copies of the Slc39a8 gene), showed tissue-specific ZIP8 mRNA expression similar to wild-type mice, mainly in lung, testis, and kidney. The 2.5-fold greater expression paralleled the fact that the BTZIP8-3 line has five copies, whereas wild-type mice have two copies, of the Slc39a8 gene. The ZIP8 mRNA and protein localized especially to endothelial cells of the testis vasculature in BTZIP8-3 mice. Cd treatment reversed Cd resistance (seen in nontransgenic littermates) to Cd sensitivity in BTZIP8-3 mice; reversal of the testicular necrosis phenotype confirms that Slc39a8 is unequivocally the Cdm locus. ZIP8 also localized specifically to the apical surface of proximal tubule cells in the BTZIP8-3 kidney. Cd treatment caused acute renal failure and signs of proximal tubular damage in the BTZIP8-3 but not nontransgenic littermates. BTZIP8-3 mice should be a useful model for studying Cd-induced disease in kidney. kidney; testis; ZIP8; bacterial artificial chromosome     

Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase?

Selective Androgen Receptor Modulators (SARMs) are a novel class of AR ligands that possess tissue-selective pharmacological activities. SARMs of various chemical structures have been discovered and characterized, and lead compounds with much improved specificity for AR, in vivo pharmacokinetic profiles, and higher degree of tissue selectivity have entered clinical development, and are expected to dramatically expand the clinical applications of androgens. With the rapid progress in SARM discovery and increasing demand for mechanism-based drug design, more and more research efforts have been devoted to the mechanisms of action of the observed tissue selectivity of SARMs. There is increasing enthusiasm in adapting the molecular mechanisms of action from SERM research to the SARM field; however, is the SARM story really so complicated? The tissue-specific expression of 5alpha-reductase might provide a simple explanation for this puzzle.     

Potential drivers of samango monkey (Cercopithecus albogularis) population subdivision in a highly fragmented mountain landscape in northern South Africa

Primates - Forests affected by fragmentation are at risk of losing their primate populations over the long term. The impact of fragmentation on primate populations has been studied in several...     

Low-level lead exposure increases systolic arterial pressure and endothelium-derived vasodilator factors in rat aortas

Chronic lead exposure induces hypertension and alters endothelial function. However, treatment with low lead concentrations was not yet explored. We analyzed the effects of 7 day exposure to low lead concentrations on endothelium-dependent responses. Wistar rats were treated with lead (1st dose 4 μg/100 g, subsequent dose 0.05 μg/100 g, i.m. to cover daily loss) or vehicle; blood levels attained at the end of treatment were 9.98 μg/dL. Lead treatment had the following effects: increase in systolic blood pressure (SBP); reduction of contractile response to phenylephrine (1 nM-100 μM) of aortic rings; unaffected relaxation induced by acetylcholine (0.1 nM-300 μM) or sodium nitroprusside (0.01 nM-0.3 μM). Endothelium removal, N(G)-nitro-L-arginine methyl ester (100 μM) and tetraethylammonium (2 mM) increased the response to phenylephrine in treated rats more than in untreated rats. Aminoguanidine (50 μM) increased but losartan (10 μM) and enalapril (10 μM) reduced the response to phenylephrine in treated rats. Lead treatment also increased aortic Na(+)/K(+)-ATPase functional activity, plasma angiotensin-converting enzyme (ACE) activity, protein expression of the Na(+)/K(+)-ATPase alpha-1 subunit, phosphorylated endothelial nitric oxide synthase (p-eNOS), and inducible nitric oxide synthase (iNOS). Our results suggest that on initial stages of lead exposure, increased SBP is caused by the increase in plasma ACE activity. This effect is accompanied by increased p-eNOS, iNOS protein expression and Na(+)/K(+)-ATPase functional activity. These factors might be a compensatory mechanism to the increase in SBP.     

An in vivo polymicrobial biofilm wound infection model to study interspecies interactions

Chronic wound infections are typically polymicrobial; however, most in vivo studies have focused on monospecies infections. This project was designed to develop an in vivo, polymicrobial, biofilm-related, infected wound model in order to study multispecies biofilm dynamics and in relation to wound chronicity. Multispecies biofilms consisting of both Gram negative and Gram positive strains, as well as aerobes and anaerobes, were grown in vitro and then transplanted onto the wounds of mice. These in vitro-to-in vivo multi-species biofilm transplants generated polymicrobial wound infections, which remained heterogeneous with four bacterial species throughout the experiment. We observed that wounded mice given multispecies biofilm infections displayed a wound healing impairment over mice infected with a single-species of bacteria. In addition, the bacteria in the polymicrobial wound infections displayed increased antimicrobial tolerance in comparison to those in single species infections. These data suggest that synergistic interactions between different bacterial species in wounds may contribute to healing delays and/or antibiotic tolerance.     

Increased infarct wall thickness by a bio-inert material is insufficient to prevent negative left ventricular remodeling after myocardial infarction

Background

Several injectable materials have been shown to preserve or improve cardiac function as well as prevent or slow left ventricular (LV) remodeling post-myocardial infarction (MI). However, it is unclear as to whether it is the structural support or the bioactivity of these polymers that lead to beneficial effects. Herein, we examine how passive structural enhancement of the LV wall by an increase in wall thickness affects cardiac function post-MI using a bio-inert, non-degradable synthetic polymer in an effort to better understand the mechanisms by which injectable materials affect LV remodeling.

Methods and Results

Poly(ethylene glycol) (PEG) gels of storage modulus G′ = 0.5±0.1 kPa were injected and polymerized in situ one week after total occlusion of the left coronary artery in female Sprague Dawley rats. The animals were imaged using magnetic resonance imaging (MRI) at 7±1 day(s) post-MI as a baseline and again post-injection 49±4 days after MI. Infarct wall thickness was statistically increased in PEG gel injected vs. control animals (p<0.01). However, animals in the polymer and control groups showed decreases in cardiac function in terms of end diastolic volume, end systolic volume and ejection fraction compared to baseline (p<0.01). The cellular response to injection was also similar in both groups.

Conclusion

The results of this study demonstrate that passive structural reinforcement alone was insufficient to prevent post-MI remodeling, suggesting that bioactivity and/or cell infiltration due to degradation of injectable materials are likely playing a key role in the preservation of cardiac function, thus providing a deeper understanding of the influencing properties of biomaterials necessary to prevent post-MI negative remodeling.     

The effect of cleft lip on adults' responses to faces: cross-species findings

Cleft lip and palate is the most common of the congenital conditions affecting the face and cranial bones and is associated with a raised risk of difficulties in infant-caregiver interaction; the reasons for such difficulties are not fully understood. Here, we report two experiments designed to explore how adults respond to infant faces with and without cleft lip, using behavioural measures of attractiveness appraisal ('liking') and willingness to work to view or remove the images ('wanting'). We found that infants with cleft lip were rated as less attractive and were viewed for shorter durations than healthy infants, an effect that was particularly apparent where the cleft lip was severe. Women rated the infant faces as more attractive than men did, but there were no differences in men and women's viewing times of these faces. In a second experiment, we found that the presence of a cleft lip in domestic animals affected adults' 'liking' and 'wanting' responses in a comparable way to that seen for human infants. Adults' responses were also remarkably similar for images of infants and animals with cleft lip, although no gender difference in attractiveness ratings or viewing times emerged for animals. We suggest that the presence of a cleft lip can substantially change the way in which adults respond to human and animal faces. Furthermore, women may respond in different ways to men when asked to appraise infant attractiveness, despite the fact that men and women 'want' to view images of infants for similar durations.     

Preventing annoyance from odors in spaceflight: a method for evaluating the sensory impact of rodent housing.

For the scientific community, the ability to fly mice under weightless conditions in space offers several advantages over the use of rats. These advantages include the option of testing a range of transgenic animals, the ability to increase the number of animals that can be flown, and reduced demands on shuttle resources (food, water, animal mass) and crew time (for water refill). Mice have been flown in animal enclosure module (AEM) hardware only once [Space Shuttle Transport System (STS)-90] and were dissected early in the mission, whereas rats have been flown in the AEM on >20 missions. This has been due, in part, to concerns that strong and annoying odors from mouse urine (vs. rat urine) will interfere with crew performance in the shuttle middeck. To screen and approve mice for flight, a method was developed to evaluate the odor containment performance of AEMs housing female C57BL/6J mice compared with AEMs housing Sprague-Dawley rats across a 21-day test period. Based on the results of this test, consensus was reached that mice could fly in the AEM hardware for up to 17 days (including prelaunch and contingency) and that the AEM hardware would likely contain odors beyond this duration. Human sensory and electronic nose analysis of the AEMs postflight demonstrated their success in containing odors from mice for the mission duration of STS-108 (13 days). Although this paper focuses specifically on odor evaluations for the space shuttle, the concern is applicable to any confined, closed-system environment for human habitation.