Shedding the load of hypertension: the proteolytic processing of angiotensin-converting enzyme

A number of membrane proteins are enzymatically cleaved or 'shed' from the cell surface, resulting in the modulation of biological events and opening novel pharmaceutical approaches to diverse diseases by targeting shedding. Our focus has been on understanding the shedding of angiotensin-converting enzyme (ACE), an enzyme that plays a pivotal role in blood pressure regulation. The identification of novel hereditary ACE mutations that result in increased ACE shedding has advanced our understanding of the role of ACE shedding in health and disease. Extensive biochemical and molecular analysis has helped to elucidate the mechanism of ACE shedding. These findings point to the potential therapeutic role of targeting shedding in regulating tissue ACE levels in cardiovascular disease.     

The Male Bisexuality Debate Revisited: Some Bisexual Men Have Bisexual Arousal Patterns

Self-identified bisexual men report high sexual arousal to both male and female stimuli, but no study to date has compellingly demonstrated that such men have a bisexual pattern of genital arousal. We examined sexual arousal patterns among bisexual men recruited using stringent criteria designed to exclude those who were less likely to have sexual interest in both sexes. Furthermore, we included a bisexual stimulus depicting a man engaged in sex simultaneously with another man and a woman. On average, the bisexual men showed a bisexual arousal pattern, with respect to both self-reported and genital arousal. Additionally, the bisexual men were more aroused by the bisexual stimulus compared with the homosexual and heterosexual men. Some bisexual-identified men have bisexual genital arousal patterns, although it remains unclear how common they are.     

In vivo and in vitro expression of connexin 43 in human teeth

Gap junctions are composed of transmembrane proteins belonging to the connexin family. These proteins permit the exchange of mall regulatory molecules directly between cells for the control of growth, development and differentiation. Although the presence of gap junctions in teeth has been already evidenced, the involved connexins have not yet been identified in human species. Here, we examined the distribution of connexin 43 (Cx43) in embryonic and permanent intact and carious human teeth. During tooth development, Cx43 localized both in epithelial and mesenchymal dental cells, correlated with cytodifferentiation gradients. In adult intact teeth, Cx43 was distributed in odontoblast processes. While Cx43 expression was downregulated in mature intact teeth, Cx43 appeared to be upregulated in odontoblasts facing carious lesions. In cultured pulp cells, Cx43 expression was related to the formation of mineralized nodules. These results indicate that Cx43 expression is developmentally regulated in human dental tissues, and suggest that Cx43 may participate in the processes of dentin formation and pathology.     

Pathways for abiotic organic synthesis at submarine hydrothermal fields

Arguments for an abiotic origin of low-molecular weight organic compounds in deep-sea hot springs are compelling owing to implications for the sustenance of deep biosphere microbial communities and their potential role in the origin of life. Theory predicts that warm H₂-rich fluids, like those emanating from serpentinizing hydrothermal systems, create a favorable thermodynamic drive for the abiotic generation of organic compounds from inorganic precursors. Here, we constrain two distinct reaction pathways for abiotic organic synthesis in the natural environment at the Von Damm hydrothermal field and delineate spatially where inorganic carbon is converted into bioavailable reduced carbon. We reveal that carbon transformation reactions in a single system can progress over hours, days, and up to thousands of years. Previous studies have suggested that CH₄ and higher hydrocarbons in ultramafic hydrothermal systems were dependent on H₂ generation during active serpentinization. Rather, our results indicate that CH₄ found in vent fluids is formed in H₂-rich fluid inclusions, and higher n-alkanes may likely be derived from the same source. This finding implies that, in contrast with current paradigms, these compounds may form independently of actively circulating serpentinizing fluids in ultramafic-influenced systems. Conversely, widespread production of formate by ΣCO₂ reduction at Von Damm occurs rapidly during shallow subsurface mixing of the same fluids, which may support anaerobic methanogenesis. Our finding of abiogenic formate in deep-sea hot springs has significant implications for microbial life strategies in the present-day deep biosphere as well as early life on Earth and beyond.Seawater-derived hydrothermal fluids venting at oceanic spreading centers are a net source for dissolved carbon to the deep sea, with vent fluid carbon contents directly tied to the sustenance of the subseafloor biosphere (1). Highly reducing fluids rich in dissolved H₂, such as those discharging from serpentinizing hydrothermal systems, are of particular interest because of the potential for abiotic reduction of dissolved inorganic carbon (ΣCO2=CO2+HCO3−+CO32−) to organic compounds (2–6) and their potential role as precursor compounds for prebiotic chemistry associated with the origin of life (7). Although there is increasing evidence that supports an abiotic origin for CH₄ and other low-molecular weight organic compounds in ultramafic-hosted hydrothermal systems (8–10), the physical conditions, reaction pathways, and timescales that control abiotic organic synthesis at oceanic spreading centers remain elusive. Working models for the formation of abiotic CH₄ and other hydrocarbons observed in vent fluids involve reduction of ΣCO₂ and/or CO through Fischer–Tropsch-type processes during active circulation of seawater-derived hydrothermal fluids that are highly enriched in dissolved H₂ because of serpentinization of host rocks; however, this mechanism has not been conclusively shown in natural systems. Others have suggested that leaching of CH₄ and low-molecular weight hydrocarbons from magmatic fluid inclusions hosted in plutonic rocks may contribute at some level to the inventory of organic compounds observed in axial hot-spring fluids (1, 11, 12). The relative influence of these processes has important implications for the total flux and real-time concentrations of aqueous organic compounds delivered to the oceans by ridge-crest hydrothermal activity. Here, we use multiple lines of evidence to preclude abiotic reduction of ΣCO₂ to CH₄ during active fluid circulation but show that it is reduced to the metastable intermediate species formate instead.     

Adenovirus‐based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor α transgenic mice

Objective

Rheumatoid arthritis is a prototype of a destructive inflammatory disease. Inflammation triggered by the overexpression of tumor necrosis factor α (TNFα) is a driving force of this disorder and mediates tissue destruction. Since matrix metalloproteinases (MMPs) are among the molecules activated by TNFα, we hypothesized that overexpression of their natural inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP‐1), in TNFα transgenic mice could inhibit the development of destructive arthritis.

Methods

Systemic treatment was carried out by replication‐defective adenoviral vectors for TIMP‐1, β‐galactosidase, or phosphate buffered saline (PBS), which were applied once at the onset of arthritis. Clinical, serologic, radiologic, and histologic outcomes were assessed 18 days after the treatment.

Results

The AdTIMP‐1 group showed significantly reduced paw swelling and increased grip strength compared with the 2 control groups, whereas total body weight, TNFα, and interleukin‐6 levels were similar in all 3 groups. Radiographic assessment revealed a significant reduction of joint destruction in the AdTIMP‐1 group; this was confirmed by histologic analyses showing reduced formation of pannus and erosions in the AdTIMP‐1 group compared with the AdLacZ and PBS control groups. The formation of arthritis‐specific autoantibodies to heterogeneous nuclear RNP A2 was not observed in the AdTIMP‐1 group but was present in the 2 control groups.

Conclusion

These results indicate a central role of MMPs in TNFα‐mediated tissue damage in vivo and a promising therapeutic role for TIMP‐1.