New insights into androgen-dependent Wolffian duct development

In mammals, male and female fetal reproductive tracts are initially indistinguishable with Wolffian ducts (WD) and Mullerian ducts (MD) present in both sexes. Androgens play a vital role in masculinisation of the fetus, including WD rescue and development in males; however, the mechanisms that underlie this process are unknown. The aims of the current study therefore were to investigate the timing and mechanisms involved in androgen mediated WD development. The present study exposed pregnant rats to the androgen receptor antagonist, flutamide (50 or 100 mgkg⁻¹), Di(n-butyl) phthalate (DBP; 500 mgkg⁻¹) which reduces testicular testosterone production, and/or exogenous testosterone during specific time windows in fetal life in order to establish the key time windows for androgenregulated WD development and the possible mechanisms involved.These studies confirmed the vital role for androgens in WD development and highlighted their critical involvement in establishing the early patterning of WD development between el5.5-17.5, prior to any sign of morphological differentiation. At this stage, androgens receptors (AR) are only expressed in the stroma, not in the epithelium, thus androgens must regulate WD differentiation via stroma-epithelial interactions. Contrastingly, high levels of androgens were not required during morphological differentiation of the WD between el 9.5- 21.5 (when coiling occurs). Impaired androgen action during the correct window of development disrupted WD development as evidenced by reduced coiling of the future epididymis. This was likely due to a demonstrated reduction in cell proliferation in both stromal and epithelial compartments, impaired stromal differentiation, reduced epithelial cell height and ultimately epithelial degradation. These stromal abnormalities were noted prior to observing any obvious abnormalities in the epithelium, further highlighting regulation of the epithelium by the stroma. The mechanisms involved in this impaired WD development include interruption to the basement membrane and extracellular matrix, as evidenced by altered expression of some intermediate filaments. These were similar to the mechanisms noted in the regressing female WD but impaired androgen action did not induce apoptosis in the male WD, which was observed in the regressing WD in females. Maternal exposure to testosterone during gestation was able to rescue the female WD and even induce some degree of morphological differentiation, although this was to a lesser degree than that noted in the normal male

Toward a Public Enforcement Model for Directors\u27 Duty of Oversight

This Article proposes a public enforcement model for the fiduciary duties of corporate directors. Under the dominant model of corporate governance, the principal function of the board of directors is to oversee the conduct of senior corporate officials. When directors fail to provide proper oversight, the consequences can be severe for shareholders, creditors, employees, and society at large. Despite general agreement on the importance of director oversight, courts have yet to develop a coherent doctrine governing director liability for the breach of oversight duties. In Delaware, the dominant state for U.S. corporate law, the courts tout the importance of board oversight in dicta, yet emphasize in holdings that directors cannot be personally liable for oversight failures, absent evidence that they intentionally violated their duties

Androgen action via testicular arteriole smooth muscle cells is important for leydig cell function, vasomotion and testicular fluid dynamics

Regulation of blood flow through the testicular microvasculature by vasomotion is thought to be important for normal testis function as it regulates interstitial fluid (IF) dynamics which is an important intra-testicular transport medium. Androgens control vasomotion, but how they exert these effects remains unclear. One possibility is by signalling via androgen receptors (AR) expressed in testicular arteriole smooth muscle cells. To investigate this and determine the overall importance of this mechanism in testis function, we generated a blood vessel smooth muscle cell-specific AR knockout mouse (SMARKO). Gross reproductive development was normal in SMARKO mice but testis weight was reduced in adulthood compared to control littermates; this reduction was not due to any changes in germ cell volume or to deficits in testosterone, LH or FSH concentrations and did not cause infertility. However, seminiferous tubule lumen volume was reduced in adult SMARKO males while interstitial volume was increased, perhaps indicating altered fluid dynamics; this was associated with compensated Leydig cell failure. Vasomotion was impaired in adult SMARKO males, though overall testis blood flow was normal and there was an increase in the overall blood vessel volume per testis in adult SMARKOs. In conclusion, these results indicate that ablating arteriole smooth muscle AR does not grossly alter spermatogenesis or affect male fertility but does subtly impair Leydig cell function and testicular fluid exchange, possibly by locally regulating microvascular blood flow within the testis

Effect of androgen treatment during foetal and/or neonatal life on ovarian function in prepubertal and adult rats

We investigated the effects of different windows of testosterone propionate (TP) treatment during foetal and neonatal life in female rats to determine whether and when excess androgen exposure would cause disruption of adult reproductive function. Animals were killed prepubertally at d25 and as adults at d90. Plasma samples were taken for hormone analysis and ovaries serial sectioned for morphometric analyses. In prepubertal animals, only foetal+postnatal and late postnatal TP resulted in increased body weights, and an increase in transitory, but reduced antral follicle numbers without affecting total follicle populations. Treatment with TP during both foetal+postnatal life resulted in the development of streak ovaries with activated follicles containing oocytes that only progressed to a small antral (smA) stage and inactive uteri. TP exposure during foetal or late postnatal life had no effect upon adult reproductive function or the total follicle population, although there was a reduction in the primordial follicle pool. In contrast, TP treatment during full postnatal life (d1-25) resulted in anovulation in adults (d90). These animals were heavier, had a greater ovarian stromal compartment, no differences in follicle thecal cell area, but reduced numbers of anti-Mullerian hormone-positive smA follicles when compared with controls. Significantly reduced uterine weights lead reduced follicle oestradiol production. These results support the concept that androgen programming of adult female reproductive function occurs only during specific time windows in foetal and neonatal life with implications for the development of polycystic ovary syndrome in women

Novel Metabolic Attributes of Cyanothece, a Group of Unicellular Nitrogen Fixing Cyanobacteria.

The genus Cyanothece comprises unicellular cyanobacteria that are morphologically diverse and ecologically versatile. Studies over the last decade have established members of this genus to be important components of the marine ecosystem, contributing significantly to the nitrogen and carbon cycle. System-level studies of Cyanothece sp. ATCC 51142, a prototypic member of this group, revealed many interesting metabolic attributes. To identify the metabolic traits that define this class of cyanobacteria, five additional Cyanothece strains were sequenced to completion. The presence of a large, contiguous nitrogenase gene cluster and the ability to carry out aerobic nitrogen fixation distinguishCyanothece as a genus of unicellular, aerobic nitrogen-fixing cyanobacteria.Cyanothece cells can create an anoxic intracellular environment at night, allowing oxygen-sensitive processes to take place in these oxygenic organisms. Large carbohydrate reserves accumulate in the cells during the day, ensuring sufficient energy for the processes that require the anoxic phase of the cells. Our study indicates that this genus maintains a plastic genome, incorporating new metabolic capabilities while simultaneously retaining archaic metabolic traits, a unique combination which provides the flexibility to adapt to various ecological and environmental conditions. Rearrangement of the nitrogenase cluster inCyanothece sp. strain 7425 and the concomitant loss of its aerobic nitrogen-fixing ability suggest that a similar mechanism might have been at play in cyanobacterial strains that eventually lost their nitrogen-fixing ability. IMPORTANCE The unicellular cyanobacterial genus Cyanothece has significant roles in the nitrogen cycle in aquatic and terrestrial environments. Cyanothece sp. ATCC 51142 was extensively studied over the last decade and has emerged as an important model photosynthetic microbe for bioenergy production. To expand our understanding of the distinctive metabolic capabilities of this cyanobacterial group, we analyzed the genome sequences of five additional Cyanothece strains from different geographical habitats, exhibiting diverse morphological and physiological attributes. These strains exhibit high rates of N2 fixation and H2production under aerobic conditions. They can generate copious amounts of carbohydrates that are stored in large starch-like granules and facilitate energy-intensive processes during the dark, anoxic phase of the cells. The genomes of some Cyanothece strains are quite unique in that there are linear elements in addition to a large circular chromosome. Our study provides novel insights into the metabolism of this class of unicellular nitrogen-fixing cyanobacteria

Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity

Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate. While grossly normal at birth, we observed an unexpected phenotype of spinal protrusion in Nkx3.1:Cre;Erk5fl/fl (Erk5fl/fl) mice by ~6–8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5fl/fl mice had a severely deformed curved thoracic spine, with an associated loss of trabecular bone volume. Although sex-specific differences were observed, histomorphometry measurements revealed that both bone resorption and bone formation parameters were increased in male Erk5fl/fl mice compared to wild type (WT) littermates. Osteopenia occurs where the rate of bone resorption exceeds that of bone formation, so we investigated the role of the osteoclast compartment. We found that treatment of RANKL-stimulated primary bone marrow-derived macrophage (BMDM) cultures with small molecule ERK5 pathway inhibitors increased osteoclast numbers. Furthermore, osteoclast numbers and expression of osteoclast marker genes were increased in parallel with reduced Erk5 expression in cultures generated from Erk5fl/fl mice compared to WT mice. Collectively, these results reveal a novel role for Erk5 during bone maturation and homeostasis in vivo

The influence of location, ownership, and the presence of a coactor on the processing of objects.

Humans operate in complex environments where social interactions require individuals to constantly attend to people and objects around them. Despite the complexity of these interactions from a visuomotor perspective, humans can engage and thrive in social settings. The purpose of the current study was to examine the simultaneous influence of multiple social cues (i.e., ownership and the presence of a coactor) on the processing of objects. Participants performed an object-based compatibility task in the presence and absence of a coacting confederate. Participants indicated whether pictures of mugs (that were either self-owned or unowned) were upright or inverted. The pictures appeared at one of 2 locations (a near or far location relative to the participant) on a computer screen laid flat on (parallel to) the tabletop. When present, the coactor stood on the opposite side of the screen/table. Analysis of response times (RTs) indicated that the processing of objects was influenced by the object’s ownership status, the presence of the coactor, and where the object was located on the screen. Specifically, RTs for pictures of self-owned mugs were shorter than unowned mugs, but only when the pictures were located at the near location. Further, the presence of a confederate resulted in shorter RTs for pictures located at the near but not the far location. These findings suggest that when objects were placed at the far location, the additional social cues of ownership and social context did not influence visuomotor processing of the objects

Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR).

Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR), inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk

New Insights into the Role of Androgens in Wolffian Duct Stabilization in Male and Female Rodents

Androgen-mediated wolffian duct (WD) development is programmed between embryonic d 15.5 (e15.5) and 17.5 in male rats, and WD differentiation has been shown to be more susceptible to reduced androgen action than is its initial stabilization. We investigated regulation of these events by comparing fetal WD development at e15.5–postnatal d0 in male and female androgen receptor knockout mice, and in rats treated from e14.5 with flutamide (100 mg/kg/d) plus di-n(butyl) phthalate (500 mg/kg/d) to block both androgen action and production, testosterone propionate (20 mg/kg/d) to masculinize females, or vehicle control. In normal females, WD regression occurred by e15.5 in mice and e18.5 in rats, associated with a lack of epithelial cell proliferation and increased apoptosis, disintegration of the basement membrane, and reduced epithelial cell height. Exposure to testosterone masculinized female rats including stabilization and partial differentiation of WDs. Genetic or chemical ablation of androgen action in males prevented masculinization and induced WD regression via similar processes to those in normal females, except this occurred 2–3 d later than in females. These findings provide the first evidence that androgens may not be the only factor involved in determining WD fate. Other factors may promote survival of the WD in males or actively promote WD regression in females, suggesting sexually dimorphic differences in the preprogrammed setup of the WD

Differential prefrontal and subcortical circuitry engagement during encoding of semantically related words in patients with late‐life depression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109350/1/gps4165.pd