Faculty Bibliography

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite beta-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of beta-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of beta-hydroxybutyrate. Electrophysiological measurements indicate that beta-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

INTRODUCTION: Devices for male circumcision (MC) are becoming available in 14 priority countries where MC is being implemented for HIV prevention. Understanding potential impact on demand for services is one important programmatic consideration because countries determine whether to scale up devices within MC programs. METHODS: A population-based survey measuring willingness to undergo MC, assuming availability of surgical MC and 3 devices, was conducted among 1250 uncircumcised men, ages 10-49 years in Zambia and 1000 uncircumcised men, ages 13-49 years in Zimbabwe. Simulated Test Market methodology was used to estimate incremental MC demand and the extent to which devices might be preferred over surgery, assuming availability of: surgical MC in both countries; the devices PrePex, ShangRing, and Unicirc in Zambia; and PrePex in Zimbabwe. RESULTS: Modeled estimates indicate PrePex has the potential to provide an overall increase in MC demand ranging from an estimated 13%-50%, depending on country and WHO prequalification ages, replacing 11%-41% of surgical procedures. In Zambia, ShangRing could provide 8% overall increase, replacing 45% of surgical procedures, and Unicirc could provide 30% overall increase, replacing 85% of surgical procedures. CONCLUSIONS: In both countries, devices have potential to increase overall demand for MC, assuming wide scale awareness and availability of circumcision by the devices. With consideration for age and country, PrePex may provide the greatest potential increase in demand, followed by Unicirc (measured in Zambia only) and ShangRing (also Zambia only). These results inform one program dimension for decision making on potential device introduction strategies; however, they must be considered within the broader programmatic context.

The bioavailability of members of the transforming growth factor beta (TGF-beta) family is controlled by a number of mechanisms. Bona fide TGF-beta is sequestered into the matrix in a latent state and must be activated before it can bind to its receptors. Here, we review the molecules and mechanisms that regulate the bioavailability of TGF-beta and compare these mechanisms with those used to regulate other TGF-beta family members. We also assess the physiological significance of various latent TGF-beta activators, as well as other extracellular modulators of TGF-beta family signaling, by examining the available in vivo data from knockout mouse models and other biological systems.

AIMS: Myocardial ischemia remains the prime cause of morbidity and mortality in the United States. Ischemic preconditioning (IPC) is a powerful form of endogenous protection against myocardial infarction. We studied alterations in KATPchannels surface density as a potential mechanism of IPC's protection. METHODS AND RESULTS: Using cardiac-specific knockout of Kir6.2 subunits, we demonstrate an essential role for sarcolemmal KATPchannels in the infarct-limiting effect of IPC in the mouse heart. With biochemical membrane fractionation, we demonstrated that sarcolemmal KATPchannel subunits are distributed both to the sarcolemma and intracellular endosomal compartments. Global ischemia causes a loss of sarcolemmal KATPchannel subunit distribution and internalization to endosomal compartments. Ischemia-induced internalization of KATPchannels was prevented by CaMKII inhibition. KATPchannel subcellular redistribution was also observed with immunohistochemistry. Ischemic preconditioning prior to the index ischemia reduces not only the infarct size, but also prevents KATPchannel internalization. Furthermore, not only did adenosine mimic IPC by preventing infarct size, but it also prevented ischemia-induced KATPchannel internalization via a PKC-mediated pathway. We show that preventing endocytosis with dynasore reduces both KATPchannel internalization and strongly mitigates infarct development. CONCLUSIONS: Our data demonstrate that plasticity of KATPchannel surface expression must be considered as a potentially important mechanism of the protective effects of IPC and adenosine.

Mammalian cells have evolved specialized mechanisms to sense and repair double-strand breaks (DSBs) to maintain genomic stability. However, in certain cases, the activity of these pathways can lead to aberrant DNA repair, genomic instability and tumorigenesis. One such case is DNA repair at the natural ends of linear chromosomes, known as telomeres, which can lead to chromosome-end fusions. Here, we review data obtained over the past decade and discuss the mechanisms that protect mammalian chromosome ends from the DNA damage response. We also discuss how telomere research has helped to uncover key steps in DSB repair. Last, we summarize how dysfunctional telomeres and the ensuing genomic instability drive the progression of cancer.

BACKGROUND: Recent studies have implicated specific assembly subtypes of beta-amyloid (Abeta) peptide, specifically soluble oligomers (soAbeta) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Abeta assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Abeta assemblies including soAbeta. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Abeta antibodies to the clinical bioactivity of IVIg has been lacking. METHODS: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Abeta conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAbeta levels using standard anti-soAbeta antibodies. RESULTS: We provide evidence that NU4-type soAbeta (NU4-soAbeta) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Abeta plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAbeta and A11-soAbeta but not OC-type fibrillar Abeta oligomers. CONCLUSIONS: We propose that targeting of specific soAbeta assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Abeta antibody drugs.

PURPOSE: Prior studies report that weekend admission to an intensive care unit is associated with increased mortality, potentially attributed to the organizational structure of the unit. This study aims to determine whether treatment of hypotension, a risk factor for mortality, differs according to level of staffing. METHODS: Using the Multiparameter Intelligent Monitoring in Intensive Care database, we conducted a retrospective study of patients admitted to an intensive care unit at Beth Israel Deaconess Medical Center who experienced one or more episodes of hypotension. Episodes were categorized according to the staffing level, defined as high during weekday daytime (7 am-7 pm) and low during weekends or nighttime (7 pm-7 am). RESULTS: Patients with a hypotensive event on a weekend were less likely to be treated compared with those that occurred during the weekday daytime (P = .02). No association between weekday daytime vs weekday nighttime staffing levels and treatment of hypotension was found (risk ratio, 1.02; 95% confidence interval, 0.98-1.07). CONCLUSION: Patients with a hypotensive event on a weekend were less likely to be treated than patients with an event during high-staffing periods. No association between weekday nighttime staffing and hypotension treatment was observed. We conclude that treatment of a hypotensive episode relies on more than solely staffing levels.

Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of alpha-smooth muscle actin-expressing stromal cells. Integrin alpha10beta1 can serve as a receptor for the HU177 epitope in alpha-smooth muscle actin-expressing stromal cells and subsequently regulates Erk-dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized alpha10beta1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors.