Health benefits of late-onset metformin treatment every other week in mice

Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans

Analyzing diffuse scattering with supercomputers. Corrigendum

Errors in the paper by Michels-Clark, Lynch, Hoffmann, Hauser, Weber, Harrison &amp; Bürgi [J. Appl. Cryst. (2013), 46, 1616–1625] are corrected.</jats:p

Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice

<p>Very long chain fatty acids (VLCFA), either free or as components of glycerolipids and sphingolipids, are present in many organs. Elongation of very long chain fatty acids-4 (ELOVL4) belongs to a family of 6 members of putative fatty acid elongases that are involved in the formation of VLCFA. Mutations in ELOVL4 were found to be responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3) in human. We have previously disrupted the mouse <i>Elovl4</i> gene, and found that <i>Elovl4^+/-</i> mice were developmentally normal, suggesting that haploinsufficiency of ELOVL4 is not a cause for the juvenile retinal degeneration in STGD3 patients. However, <i>Elovl4^-/-</i> mice died within several hours of birth for unknown reason(s). To study functions of ELOVL4 further, we have explored the causes for the postnatal lethality in <i>Elovl4^-/-</i> mice. Our data indicated that the mutant mice exhibited reduced thickness of the dermis, delayed differentiation of keratinocytes, and abnormal structure of the stratum corneum. We showed that all <i>Elovl4^-/-</i> mice exhibited defective skin water permeability barrier function, leading to the early postnatal death. We further showed that the absence of ELOVL4 results in depletion in the epidermis of ceramides with &#969;-hydroxy very long chain fatty acids (&#8805;C28) and accumulation of ceramides with non &#969;-hydroxy fatty acids of C26, implicating C26 fatty acids as possible substrates of ELOVL4. These data demonstrate that ELOVL4 is required for VLCFA synthesis that is essential for water permeability barrier function of skin.</p

Expanding Lorentz and spectrum corrections to large volumes of reciprocal space for single-crystal time-of-flight neutron diffraction. Corrigendum

ISSN:0021-8898ISSN:1600-576

Expanding Lorentz and spectrum corrections to large volumes of reciprocal space for single-crystal time-of-flight neutron diffraction

Evidence is mounting that potentially exploitable properties of technologically and chemically interesting crystalline materials are often attributable to local structure effects, which can be observed as modulated diffuse scattering (mDS) next to Bragg diffraction (BD). BD forms a regular sparse grid of intense discrete points in reciprocal space. Traditionally, the intensity of each Bragg peak is extracted by integration of each individual reflection first, followed by application of the required corrections. In contrast, mDS is weak and covers expansive volumes of reciprocal space close to, or between, Bragg reflections. For a representative measurement of the diffuse scattering, multiple sample orientations are generally required, where many points in reciprocal space are measured multiple times and the resulting data are combined. The common post-integration data reduction method is not optimal with regard to counting statistics. A general and inclusive data processing method is needed. In this contribution, a comprehensive data analysis approach is introduced to correct and merge the full volume of scattering data in a single step, while correctly accounting for the statistical weight of the individual measurements. Development of this new approach required the exploration of a data treatment and correction protocol that includes the entire collected reciprocal space volume, using neutron time-of-flight or wavelength-resolved data collected at TOPAZ at the Spallation Neutron Source at Oak Ridge National Laboratory.ISSN:0021-8898ISSN:1600-576