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Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC- 1β, also known as Ppargc1a and Ppargclb, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1a and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction., Multiple biological processes driven by diverse molecular factors conspire progressively to diminish organ function with advancing age. Molecular and cellular analyses of age-related conditions such as muscle atrophy, diabetes and [...]

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. Bcl2L12 (for Bcl2-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBM's classical features. Whereas Bcl2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing Bcl2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of Bcl2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The Bcl2L12 transcriptome revealed a striking induction of the small heat shock protein [alpha]-basic-crystallin ([alpha]B-crystallin/HspB5), a link reinforced by robust [alpha]B-oystallin expression in Bcl2L12-expressing orthotopic glioma and strong coexpression of [alpha]B-crystallin and Bcl2L12 proteins in human primary GBMs. On the functional level, enforced [alpha]B-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knockdown of [alpha]B-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous [alpha]B-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, [alpha]B-crystallin selectively binds procaspase-3 and its cleavage intermediates in vitro and in vivo. Thus, [alpha]B-crystallin is a Bcl2L12-induced oncoprotain that enables Bcl2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties. heat shock protein | apoptosis/necrosis balance | glial cells

Widespread basalts and rhyolites were erupted in Madagascar during the Late Cretaceous. These are considered to be related to the Marion hot spot and the breakup of Madagascar and Greater India. Seventeen argon-40/argon-39 age determinations reveal that volcanic rocks and dikes from the 1500-kilometer-long rifted eastern margin of Madagascar were emplaced rapidly (mean age = 87.6 ± 0.6 million years ago) and that the entire duration of Cretaceous volcanism on the island was no more than 6 million years. The evidence suggests that the thick lava pile at Volcan de I'Androy in the south of the island marks the focal point of the Marion hot spot at ~88 million years ago and that this mantle plume was instrumental in causing continental breakup., Many of Earth's flood basalt provinces occur at the rifted margins of continents and can be linked to the initiation of oceanic hot spot tracks [1, 2]. Flood basalt provinces [...]

Computer-aided design (CAD) is a valuable tool for construction engineering to improve technical support of construction operations. The benefits obtained from CAD applications in the field include increased timeliness and accuracy of field drawings, improved communication of technical information tailored to the specific needs of the user, and increased field productivity. These benefits result from using CAD to automate existing processes and to provide new information for construction. Examples of using CAD to automate existing processes include planning survey layout, planning construction sequence and methods, analyzing concrete placements, designing formwork for concrete, and coordinating subcontractors. The new processes and products include analyzing design requirements, planning site development, analyzing requirements for construction equipment, and planning concrete construction operations. Taking full advantage of the potential benefits of CAD requires experimentation to determine the applications that best fit the needs of the firm, projects, and training. The new construction-engineering capabilities from effective use of CAD highlight the need to integrate technical information supplied and used by design firms and construction contractors.

Several of the world's flood basalt provinces display two distinct times of major eruptions separated by between 20 million and 90 million years. These double flood basalts may occur because a starting mantle plume head can separate from its trailing conduit upon passing the interface between the upper mantle and the lower mantle. This detached plume head eventually triggers the first flood basalt event. The remaining conduit forms a new plume head, which causes the second eruptive event. The second plume head is predicted to arrive at the lithosphere at least 10 million years after the first plume head, in general agreement with observations regarding double flood basalts., One hundred and twenty million years ago, much of the Ontong java Plateau was formed in a cataclysmic event involving the ejection of tens of millions of cubic kilometers of [...]

Geochemical anomalies in the mid-ocean ridge basalts (MORB), which are compositionally alike, indicate the presence of a near-ridge hotspot. The plume-jet model postulates that the plume rises to the ridge as a single jet and disperses along it. Several geophysical data support this model. Moreover, the helium isotope composition of MORB is determined by physical processes occuring within the mantle as the plume-derived material migrates to the melting zone below the ridge axis.