The permeation of dynorphin A 1–6 across the blood brain barrier and its effect on bovine brain microvessel endothelial cell monolayer permeability

Dynorphin A 1–17 (Dyn A 1–17) is an endogenous neuropeptide known to act at the kappa opioid receptor; it has been implicated in a number of neurological disorders, including neuropathic pain, stress, depression, and Alzheimer's and Parkinson's diseases. The investigation of Dyn A 1–17 metabolism at the blood–brain barrier (BBB) is important since the metabolites exhibit unique biological functions compared to the parent compound. In this work, Dyn A 1–6 is identified as a metabolite of Dyn A 1–17 in the presence of bovine brain microvessel endhothelial cells (BBMECs), using LC–MS/MS. The transport of Dyn A 1–6 at the BBB was examined using this in vitro cell culture model of the BBB. Furthermore, the permeation of the BBB by the low molecular weight permeability marker fluorescein was characterized in the presence and absences of Dyn A 1–6.     

Sexual orientation and bias in self-reported BMI

Our objective was to determine if sexual orientation groups differ in accuracy of BMI (kg/m(2)) calculated from self-reported height and weight and if weight status modifies possible differences. Using gender-stratified multiple linear regression to analyze Wave III of the National Longitudinal Study of Adolescent Health (n = 12,197), we examined the association of sexual orientation with BMI calculated from self-reported height and weight (self-reported BMI), controlling for BMI calculated from objectively measured height and weight (objectively measured BMI) as well as demographic, health, and behavioral variables. We tested for effect modification of the relationship between sexual orientation and self-reported BMI by objectively measured BMI. The population underestimated their BMI (females: β = 0.87, P < 0.001; males = 0.86, P < 0.001). Sexual orientation groups differed little in their accuracy of reporting; only gay males had significant underreporting (β = -0.37, P = 0.038) relative to their heterosexual peers. We found no evidence of effect modification of the relationship of sexual orientation and self-reported BMI by objectively measured BMI. With the exception of gay males, sexual orientation groups are consistent in their underreporting of BMI thus providing confidence in most comparisons of weight status based on self-report. Self-reporting of weight and height by gay males may exaggerate the differences in BMI between gay and heterosexual males.     

CD73-generated adenosine promotes osteoblast differentiation

CD731 is a GPI-anchored cell surface protein with ecto-5'-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73(-/-)) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild-type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A(2A) receptors (A(2A)AR) and A(2B) receptors (A(2B)AR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A(2B)AR antagonist but not with an A(2A) AR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A(2B)AR signaling.     

Draft Genome Sequences for Two Metal-Reducing Pelosinus fermentans Strains Isolated from a Cr(VI)-Contaminated Site and for Type Strain R7

Pelosinus fermentans 16S rRNA gene sequences have been reported from diverse geographical sites since the recent isolation of the type strain. We present the genome sequence of the P. fermentans type strain R7 (DSM 17108) and genome sequences for two new strains with different abilities to reduce iron, chromate, and uranium.     

APOBEC deaminases-mutases with defensive roles for immunity

In recent years, tremendous progress has been made in the elucidation of the biological roles and molecular mechanisms of the apolioprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) family of enzymes. The APOBEC family of cytidine deaminases has important functional roles within the adaptive and innate immune system. Activation induced cytidine deaminase (AID) plays a central role in the biochemical steps of somatic hypermutation and class switch recombination during antibody maturation, and the APOBEC 3 enzymes are able to inhibit the mobility of retroelements and the replication of retroviruses and DNA viruses, such as the human immunodeficiency virus type-1 and hepatitis B virus. Recent advances in structural and functional studies of the APOBEC enzymes provide new biochemical insights for how these enzymes carry out their biological roles. In this review, we provide an overview of these recent advances in the APOBEC field with a special emphasis on AID and APOBEC3G.     

Embryonic stem cells lacking the epigenetic regulator Cfp1 are hypersensitive to DNA-damaging agents and exhibit decreased Ape1/Ref-1 protein expression and endonuclease activity

Modulation of chromatin structure plays an important role in the recruitment and function of DNA repair proteins. CXXC finger protein 1 (Cfp1), encoded by the CXXC1 gene, is essential for mammalian development and is an important regulator of chromatin structure. Murine embryonic stem (ES) cells lacking Cfp1 (CXXC1^?/?) are viable but demonstrate a dramatic decrease in cytosine methylation, altered histone methylation, and an inability to differentiate. We find that ES cells lacking Cfp1 are hypersensitive to a variety of DNA-damaging agents. In addition, CXXC1^?/? ES cells accumulate more DNA damage and exhibit decreased protein expression and endonuclease activity of AP endonuclease (Ape1/Ref-1), an enzyme involved in DNA base excision repair. Expression in CXXC1^?/? ES cells of either the amino half of Cfp1 (amino acids 1–367) or the carboxyl half of Cfp1 (amino acids 361–656) restores normal Ape1/Ref-1 protein expression and rescues the hypersensitivity to DNA-damaging agents, demonstrating that Cfp1 contains redundant functional domains. Furthermore, retention of either the DNA-binding activity of Cfp1 or interaction with the Setd1A and Setd1B histone H3-Lys4 methyltransferase complexes is required to restore normal sensitivity of CXXC1^?/? ES cells to DNA-damaging agents. These results implicate Cfp1 as a regulator of DNA repair processes.     

Contributions of marginal offspring to reproductive success of Nazca booby (Sula granti) parents: tests of multiple hypotheses

While obligate siblicide is a phylogenetically widespread behavior, known from plants, insects, birds, and other taxa, with important implications for life history evolution, comprehensive evaluations of its costs and benefits to parents are rare. We used 12 years of breeding and band resight data to evaluate the importance of several potential benefits that marginal offspring (the usual victims of obligate siblicide) could provide to parent Nazca boobies (Sula granti), a seabird. We found no evidence for the resource-tracking hypothesis: 99.95% of two-chick broods were reduced to one chick before fledging, and the single exceptional brood probably lost one chick between fledging and independence. Behavioral observations indicated that siblicidal aggression caused most mortality of marginal chicks, and at least contributed to the remainder. We also found no evidence that marginal offspring provide a food resource for other family members. Marginal chicks benefit parents via adoption into other families, and possibly also in the context of progeny choice, but these benefits are minor compared to the insurance that marginal chicks provide against early failure of core (first-hatched) offspring. Further evaluation of the Insurance Egg Hypothesis showed that marginal and core offspring are functionally equivalent in the absence of sibling interactions, and that core offspring incur no detectable costs from behaving siblicidally. Nazca boobies are truly obligate brood reducers, with parents receiving principally insurance benefits from marginal offspring, but many birds and other taxa exhibiting persistent, unconditional sibling aggression do not exhibit universal brood reduction. Insurance is only one of several potential benefits that marginal offspring can confer on parents, and a multi-hypothesis approach to decompose the different types of benefits is required to understand the evolution of clutch size in other obligately siblicidal species.     

Hibernation confers resistance to intestinal ischemia-reperfusion injury

The damaging effects of intestinal ischemia-reperfusion (I/R) on the gut and remote organs can be attenuated by subjecting the intestine to a prior, less severe I/R insult, a process known as preconditioning. Because intestines of hibernating ground squirrels experience repeated cycles of hypoperfusion and reperfusion, we examined whether hibernation serves as a model for natural preconditioning against I/R-induced injury. We induced intestinal I/R in either the entire gut or in isolated intestinal loops using rats, summer ground squirrels, and hibernating squirrels during natural interbout arousals (IBA; body temperature 37-39 degrees C). In both models, I/R induced less mucosal damage in IBA squirrels than in summer squirrels or rats. Superior mesenteric artery I/R increased MPO activity in the gut mucosa and lung of rats and summer squirrels and the liver of rats but had no effect in IBA squirrels. I/R in isolated loops increased luminal albumin levels, suggesting increased gut permeability in rats and summer squirrels but not IBA squirrels. The results suggest that the hibernation phenotype is associated with natural protection against intestinal I/R injury.