DNA Damage Induced Cell Fates during Aging

Aging is a progressive loss of normal physiology, ultimately resulting in age-related pathology. One of the main drivers of aging is an accumulation of irreparable damage to the genome. This damage results in both an increase in cells undergoing apoptosis and an accumulation of senescent cells. These cell fates prevent oncogenesis at the expense of tissue homeostasis loss. A disproportional amount of apoptotic cells would severely damage tissue structure, while senescent cells have an altered secretion phenotype that reduces tissue function. We aimed to unravel the mechanisms and functions of age-related DNA damage responses to ultimately identify potential strategies that prolong healthspan during aging. We discovered that FOXO4 is progressively upregulated after senescence induction and is found in damage foci in senescent cells. Here, FOXO4 inhibits apoptosis through interacting with p53. We have developed a FOXO4-DRI peptide that blocks this interaction and thereby potently and selectively kills senescent cells, improving tissue homeostasis in fast aging XpdTTD/TTD and naturally aged mice. Furthermore, we have shown that this peptide can target cancer cells that exhibit senescence features, indicating that FOXO4-DRI has the potential to target the tumor micro-environment as well as the tumor itself. Besides senescence, we highlighted a micro-RNA signature that is upregulated during aging and inhibits DNA damage-dependent apoptosis in vitro. Furthermore, we showed that this signature is transferred to neighboring cells via extracellular vesicles. The miRNA targets and in vivo role were unknown and therefore we studied miR-30, a representative miRNA. MiR-30 inhibition proved to constitutively upregulate p53 expression, increasing apoptosis after UV-damage. This has potential detrimental effects during aging, since mouse models where p53 levels are increased show accelerated aging. Increasing cell preservation miRNAs may prevent apoptosis induction in cell types that are prone to cell death during aging. Overall this the

Thermal design issues and performance of microcalorimeter arrays at sub-Kelvin temperatures

We have produced 5/spl times/5 pixel arrays of microcalorimeters using bulk micromachining. Analysis of our data provides the thermal conductivity parameters of Si/sub x/N/sub y/ 1 /spl mu/m thick membranes at 100 mK. Moreover we find that the thermal transport at 100 mK in Si beams, with dimensions 1.25 mm /spl times/ 0.35mm /spl times/ 35/spl mu/m (length /spl times/ height /spl times/ width) is dominated by ballistic phonons with a mean free path of 110 /spl mu/m. These thermal parameters can be used for modelling future 32 /spl times/ 32 pixel arrays. In addition we operated three pixels in a 5 /spl times/ 5 array of microcalorimeters and find that the pixel to pixel reproducibility is very good. When used as an X-ray microcalorimeter individual pixels have a thermal decay time of 200 /spl mu/s is and their energy resolution is between 6 and 7 eV for 5.89 keV X-ray photons

Low radiographic muscle density is associated with lower overall and disease-free survival in early-stage colorectal cancer patients

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A Theory for Complex Systems Social Change: An Application of a General ‘Criticality’ Model

Within the developed nations deterioration in the basis of society, as dramatically demonstrated by the Lehman collapse, has reached extreme levels, and currently the formation of pro-change agents is approaching a decisive stage. Here, we will construct a complex systems \u27criticality\u27 model, apply it to social change, and examine its reliability and validity. The model derived a power law distribution of the output of social change. The validity of the model was verified by examining vote shares of parties in Japan. Based on the results of this examination, we propose a new quantitative strategy “information entropy enhancement” for social change

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field