Dietary restriction (DR) is a dietary regimen that extends lifespan in many organisms. One mechanism contributing to the conserved effect of DR on longevity is the cellular recycling process autophagy, which is induced in response to nutrient scarcity and increases sequestration of cytosolic material into double-membrane autophagosomes for degradation in the lysosome. Although autophagy plays a direct role in DR-mediated lifespan extension in the nematode Caenorhabditis elegans, the contribution of autophagy in individual tissues remains unclear. In this study, we show a critical role for autophagy in the intestine, a major metabolic tissue, to ensure lifespan extension of dietary-restricted eat-2 mutants. The intestine of eat-2 mutants has an enlarged lysosomal compartment and flux assays indicate increased turnover of autophagosomes, consistent with an induction of autophagy in this tissue. This increase in intestinal autophagy may underlie the improved intestinal integrity we observe in eat-2 mutants, since whole-body and intestinal-specific inhibition of autophagy in eat-2 mutants greatly impairs the intestinal barrier function. Interestingly, intestinal-specific inhibition of autophagy in eat-2 mutants leads to a decrease in motility with age, alluding to a potential cell non-autonomous role for autophagy in the intestine. Collectively, these results highlight important functions for autophagy in the intestine of dietary-restricted C. elegans.

Objective:To define the natural history of X-linked myotubular myopathy (MTM).Methods:We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33).Results:We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non–muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays.Conclusions:MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention.

We present a detailed study of the six-dimensional phase space of the electron beam produced by the Cornell Energy Recovery Linac Photoinjector, a high-brightness, high repetition rate (1.3 GHz) DC photoemission source designed to drive a hard x-ray energy recovery linac (ERL). A complete simulation model of the injector has been constructed, verified by measurement, and optimized. Both the horizontal and vertical 2D transverse phase spaces, as well as the time-resolved (sliced) horizontal phase space, were simulated and directly measured at the end of the injector for 19 and 77 pC bunches at roughly 8 MeV. These bunch charges were chosen because they correspond to 25 and 100 mA average current if operating at the full 1.3 GHz repetition rate. The resulting 90% normalized transverse emittances for 19 ð77Þ pC=bunch were 0:23 AE 0:02 ð0:51 AE 0:04Þ m in the horizontal plane, and 0:14 AE 0:01 ð0:29 AE 0:02Þ m in the vertical plane, respectively. These emittances were measured with a corresponding bunch length of 2:1 AE 0:1 ð3:0 AE 0:2Þ ps, respectively. In each case the rms momentum spread was determined to be on the order of 10 À3 . Excellent overall agreement between measurement and simulation has been demonstrated. Using the emittances and bunch length measured at 19 pC=bunch, we estimate the electron beam quality in a 1.3 GHz, 5 GeV hard x-ray ERL to be at least a factor of 20 times better than that of existing storage rings when the rms energy spread of each device is considered. These results represent a milestone for the field of high-brightness, highcurrent photoinjectors.

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