Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape

Phosphorylation Regulates SIRT1 Function

BACKGROUND: SIR2 is an NAD(+)-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported. METHODOLOGY/PRINCIPAL FINDINGS: We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD(+)-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13]. CONCLUSIONS/SIGNIFICANCE: Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]-[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify phosphorylation by cell cycle dependent kinases as a major mechanism controlling the level and function of this sirtuin and complement recent reports of factors that inhibit [17], [18] and activate [19] SIRT1 by protein-protein interactions

Barriers to Predicting the Mechanisms and Risk Factors of Non-Contact Anterior Cruciate Ligament Injury

High incidences of non-contact anterior cruciate ligament (ACL) injury, frequent requirements for ACL reconstruction, and limited understanding of ACL mechanics have engendered considerable interest in quantifying the ACL loading mechanisms. Although some progress has been made to better understand non-contact ACL injuries, information on how and why non-contact ACL injuries occur is still largely unavailable. In other words, research is yet to yield consensus on injury mechanisms and risk factors. Biomechanics, video analysis, and related study approaches have elucidated to some extent how ACL injuries occur. However, these approaches are limited because they provide estimates, rather than precise measurements of knee - and more specifically ACL - kinematics at the time of injury. These study approaches are also limited in their inability to simultaneously capture many of the contributing factors to injury

The radial forearm snake flap: An underutilized technique for fasciocutaneous and osteocutaneous forearm flaps with primary closure

Background: The radial forearm free flap (RFFF) is associated with troublesome donor site morbidity related to split thickness skin grafting (STSG). The radial forearm snake flap with primary closure of the donor site may reduce donor site complications. Methods: Single institution, retrospective cohort study comparing rates of delayed donor site wound healing and tendon exposure in 52 patients undergoing radial forearm snake flap and 95 patients undergoing conventional RFFF with STSG closure of the donor site. Results: Tendon exposure occurred in zero (0%) patients undergoing snake flap and four (4.2%) patients undergoing conventional RFFF (0/52 vs. 4/95; p = 0.297). Delayed wound healing occurred in zero (0%) patients undergoing snake flap and 19 (20.0%) patients undergoing conventional RFFF (0/52 vs. 19/95; p \u3c 0.001). Conclusions: The radial forearm snake flap provides an alternative to conventional RFFF harvest, which enables primary donor site closure with reduced rates of delayed donor site healing

Foraminiferal Patterns in Deglacial Sediment in the Western Ross Sea, Antarctica: Life Near Grounding Lines

Improved multibeam swath bathymetry allows targeted coring of glacial landforms aiming at improving our understanding of sedimentary facies that developed in glacimarine settings during the post-Last Glacial Maximum (LGM) deglaciation. Coupled with radiocarbon dates, we explore foraminiferal records from 18 sediment cores from the western Ross Sea largely from sites near paleo–grounding lines. We investigate post-LGM foraminiferal assemblages from glacimarine environments, including those proximal and more distal to paleo–grounding lines, including environments influenced by subglacial meltwater outflow and further removed from direct glacial influence and subject to different oceanographic conditions. Agglutinated benthic foraminiferal assemblages dominate open marine facies deposited under the presence of High Salinity Shelf Water and significant primary production, while calcareous foraminiferal assemblages characterize grounding line-proximal settings, some of which were potentially influenced by Modified Circumpolar Deep Water. Rapid deposition of meltwater plume deposits inhibited and, in some cases, significantly altered foraminifera abundance and diversity. Broadly in the Ross Sea, it appears that the high bathymetric gradient of grounding zone wedges is a key factor promoting rich benthic foraminiferal communities in habitats proximal to grounding lines. Therefore, we demonstrate that paleo–grounding line settings may archive high quality in situ foraminiferal data, which is imperative for paleoenvironmental and geochemical studies on glaciated continental margins worldwide

Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue <b>7</b> with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp³ to sp² at C-7 is well tolerated. Analogue <b>7</b> was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge <b>7</b> represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid <i>R</i>-α-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, <b>7</b> could serve as a new lead compound for developing selective largazole analogues

Quantitative palaeobathymetric reconstructions based on foraminiferal proxies: a case study from the Neogene of south‐west Spain

International audienceQuantitative palaeobathymetric reconstructions based on foraminiferal proxies have been used in a wide variety of geological studies on tectonic, climatic and environmental changes in sedimentary basins. However, palaeo-water-depth estimates are frequently biased due to taphonomic processes (dissolution, transport) as well as local conditions (primary productivity, oxygen content, and organic matter fluxes). This study evaluated the level of reliability of three commonly used transfer equations based on planktic and benthic foraminiferal proxies that produce different palaeobathymetric results, using Neogene sediments from the Guadalquivir Basin, south-west Spain. The most trustworthy method involves removing abundant infaunal benthic foraminifera before applying the palaeo-water-depth equation based on benthic foraminiferal water-depth ranges and presence/absence of species. This new approach provides sound palaeobathymetric results that improve estimations of long and short-term relative sea-level changes with negligible influence of taphonomic as well as ecological factors. When using one equation based on planktic/benthic ratios (P/B ratios), removing all infaunal benthic foraminiferal species improves the accuracy of P/B ratios, which yields more accurate palaeodepth reconstructions despite the low level of trustworthiness of this equation for both long and short-term relative sea-level variations

Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue <b>7</b> with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp³ to sp² at C-7 is well tolerated. Analogue <b>7</b> was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge <b>7</b> represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid <i>R</i>-α-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, <b>7</b> could serve as a new lead compound for developing selective largazole analogues