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Dynamin 1‐like protein (DNM1L) mediates fission of mitochondria and peroxisomes, and dysfunction of DNM1L has been implicated in several neurological disorders. To study the molecular basis of mitochondrial remodelling, we determined the crystal structure of DNM1L that is comprised of a G domain, a bundle signalling element and a stalk. DNM1L assembled via a central stalk interface, and mutations in this interface disrupted dimerization and interfered with membrane binding and mitochondrial targeting. Two sequence stretches at the tip of the stalk were shown to be required for ordered assembly of DNM1L on membranes and its function in mitochondrial fission. In the crystals, DNM1L dimers further assembled via a second, previously undescribed, stalk interface to form a linear filament. Mutations in this interface interfered with liposome tubulation and mitochondrial remodelling. Based on these results and electron microscopy reconstructions, we propose an oligomerization mode for DNM1L which differs from that of dynamin and might be adapted to the remodelling of mitochondria. The crystal structure of DNM1L, a mediator of mitochondrial and peroxisomal fusion, suggests an assembly mode differing from dynamin and being uniquely adapted to accommodate mitochondria.

Roquin proteins mediate mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs via their Roquin domain. Here we present the crystal structure of a Roquin domain, revealing a mostly helical protein fold bearing a winged helix-turn-helix motif. By combining structural, biochemical and mutation analyses, we gain insight into the mode of RNA binding. We show that the winged helix-turn-helix motif is involved in the binding of constitutive decay elements-containing stem-loop mRNAs. Moreover, we provide biochemical evidence that Roquin proteins are additionally able to bind to duplex RNA and have the potential to be functional in different oligomeric states. Roquin proteins mediate the degradation of mRNAs through the recognition of stem-loop structures present within their 3′ UTR. Here Schuetz et al . present the crystal structure of a Roquin domain and, through complementary biochemical analyses, provide insight into Roquin's mode of RNA binding through a winged helix-turn-helix motif.

Balanced fusion and fission are key for the proper function and physiology of mitochondria 1 , 2 . Remodelling of the mitochondrial inner membrane is mediated by the dynamin-like protein mitochondrial genome maintenance 1 (Mgm1) in fungi or the related protein optic atrophy 1 (OPA1) in animals 3 – 5 . Mgm1 is required for the preservation of mitochondrial DNA in yeast 6 , whereas mutations in the OPA1 gene in humans are a common cause of autosomal dominant optic atrophy—a genetic disorder that affects the optic nerve 7 , 8 . Mgm1 and OPA1 are present in mitochondria as a membrane-integral long form and a short form that is soluble in the intermembrane space. Yeast strains that express temperature-sensitive mutants of Mgm1 9 , 10 or mammalian cells that lack OPA1 display fragmented mitochondria 11 , 12 , which suggests that Mgm1 and OPA1 have an important role in inner-membrane fusion. Consistently, only the mitochondrial outer membrane—not the inner membrane—fuses in the absence of functional Mgm1 13 . Mgm1 and OPA1 have also been shown to maintain proper cristae architecture 10 , 14 ; for example, OPA1 prevents the release of pro-apoptotic factors by tightening crista junctions 15 . Finally, the short form of OPA1 localizes to mitochondrial constriction sites, where it presumably promotes mitochondrial fission 16 . How Mgm1 and OPA1 perform their diverse functions in membrane fusion, scission and cristae organization is at present unknown. Here we present crystal and electron cryo-tomography structures of Mgm1 from Chaetomium thermophilum . Mgm1 consists of a GTPase (G) domain, a bundle signalling element domain, a stalk, and a paddle domain that contains a membrane-binding site. Biochemical and cell-based experiments demonstrate that the Mgm1 stalk mediates the assembly of bent tetramers into helical filaments. Electron cryo-tomography studies of Mgm1-decorated lipid tubes and fluorescence microscopy experiments on reconstituted membrane tubes indicate how the tetramers assemble on positively or negatively curved membranes. Our findings convey how Mgm1 and OPA1 filaments dynamically remodel the mitochondrial inner membrane. Crystal and electron cryo-tomography structures of Mgm1 from Chaetomium thermophilum reveal that Mgm1 forms bent tetramers, which further assemble into helical filaments on both positively and negatively curved membranes.

Early or convenience voting—understood in this context to be relaxed administrative rules and procedures by which citizens can cast a ballot at a time and place other than the precinct on Election Day—is a popular candidate for election reformers. Typically, reformers argue that maximization of turnout is a primary goal, and reducing barriers between voters and the polls is an important method for achieving higher turnout. Arguments in favor of voting by mail, early in-person voting, and relaxed absentee requirements share this characteristic. While there are good theoretical reasons, drawn primarily from the rational choice tradition, to believe that early voting reforms should increase turnout, the empirical literature has found decidedly mixed results. While one prominent study suggests that voting by mail is associated with a 10% increase in turnout, other studies find smaller—but still statistically significant—increases in turnout associated with other convenience voting methods.This work is supported by the Carnegie Corporation of New York, the AEI/Brookings Election Reform Project, and the Charles McKinley Fund of Reed College. Thanks to Caroline Tolbert and Daniel Smith for sharing data with us, and to David Magleby for comments on an earlier version of this paper. All responsibility for interpretations lay with the authors.

Early or convenience voting—understood in this context to be relaxed administrative rules and procedures through which citizens can cast a ballot at a time and place other than the precinct on election day—is a popular watchword among election reformers. Early voting is attractive because of claims that increased convenience reduces the costs of voting, resulting in higher turnout and higher-quality voter decisions. For this reason, states have experimented extensively with early voting laws. Yet the empirical literature finds mixed results, with some studies suggesting a turnout increase as large as 10 percent, while others find that voting convenience

Purpose Exercise is efficacious for people living after a cancer diagnosis. However, implementation of exercise interventions in real-world settings is challenging. Implementation outcomes are defined as ‘the effects of deliberate and purposive actions to implement new treatments, practices, and services’. Measuring implementation outcomes is a practical way of evaluating implementation success. This systematic review explores the implementation outcomes of exercise interventions evaluated under real-world conditions for cancer care. Methods Using PRISMA guidelines, an electronic database search of Medline, PsycInfo, CINAHL, Web of Science, SportsDiscus, Scopus and Cochrane Central Registry of Controlled Trials was conducted for studies published between January 2000 and February 2020. The Moving through Cancer registry was hand searched. The Implementation Outcomes Framework guided data extraction. Inclusion criteria were adult populations with a cancer diagnosis. Efficacy studies were excluded. Results Thirty-seven articles that described 31 unique programs met the inclusion criteria. Implementation outcomes commonly evaluated were feasibility (unique programs n  = 17, 54.8%) and adoption (unique programs n  = 14, 45.2%). Interventions were typically delivered in the community (unique programs n = 17, 58.6%), in groups (unique programs n  = 14, 48.3%) and supervised by a qualified health professional (unique programs n  = 14, 48.3%). Implementation outcomes infrequently evaluated were penetration (unique programs n = 1, 3.2%) and sustainability (unique programs n = 1, 3.2%). Conclusions Exercise studies need to measure and evaluate implementation outcomes under real-world conditions. Robust measurement and reporting of implementation outcomes can help to identify what strategies are essential for successful implementation of exercise interventions. Implications for cancer survivors Understanding how exercise interventions can be successful implemented is important so that people living after a cancer diagnosis can derive the benefits of exercise.

The Manual Ability Classification System (MACS) has been developed to classify how children with cerebral palsy (CP) use their hands when handling objects in daily activities. The classification is designed to reflect the child's typical manual performance, not the child's maximal capacity. It classifies the collaborative use of both hands together. Validation was based on the experience within an expert group, a review of the literature, and thorough analysis of children across a spectrum of function. Discussions continued until consensus was reached, first about the constructs, then about the content of the five levels. Parents and therapists were interviewed about the content and the description of levels. Reliability was tested between pairs of therapists for 168 children (70 females, 98 males; with hemiplegia [n=52], diplegia [n=70], tetraplegia [n=19], ataxia [n=6], dyskinesia [n=19], and unspecified CP [n=2]) between 4 and 18 years and between 25 parents and their children's therapists. The results demonstrated that MACS has good validity and reliability. The intraclass correlation coefficient between therapists was 0.97 (95% confidence interval 0.96–0.98), and between parents and therapist was 0.96 (0.89–0.98), indicating excellent agreement.

Exercise is an efficacious therapy for many chronic diseases. Integrating efficacious evidence-based interventions (EBIs), such as exercise, into daily healthcare practice is a slow and complex pursuit. Implementation science seeks to understand and address this phenomenon by conducting studies about the methods used to promote the routine uptake of EBIs. The purpose of this article is to explore implementation science and a common conceptual framework in the discipline, the Consolidated Framework for Implementation Research (CFIR), as it applies to exercise EBI. We conclude by offering recommendations for future research that leverage implementation science priorities to highlight the potential of this research field for advancing the implementation of exercise EBI.

As newly synthesized glycoproteins move through the secretory pathway, the asparagine-linked glycan (N-glycan) undergoes extensive modifications involving the sequential removal and addition of sugar residues. These modifications are critical for the proper assembly, quality control and transport of glycoproteins during biosynthesis. The importance of N-glycosylation is illustrated by a growing list of diseases that result from defects in the biosynthesis and processing of N-linked glycans. The major rhodopsin in Drosophila melanogaster photoreceptors, Rh1, is highly unique among glycoproteins, as the N-glycan appears to be completely removed during Rh1 biosynthesis and maturation. However, much of the deglycosylation pathway for Rh1 remains unknown. To elucidate the key steps in Rh1 deglycosylation in vivo, we characterized mutant alleles of four Drosophila glycosyl hydrolases, namely α-mannosidase-II (α-Man-II), α-mannosidase-IIb (α-Man-IIb), a β-N-acetylglucosaminidase called fused lobes (Fdl), and hexosaminidase 1 (Hexo1). We have demonstrated that these four enzymes play essential and unique roles in a highly coordinated pathway for oligosaccharide trimming during Rh1 biosynthesis. Our results reveal that α-Man-II and α-Man-IIb are not isozymes like their mammalian counterparts, but rather function at distinct stages in Rh1 maturation. Also of significance, our results indicate that Hexo1 has a biosynthetic role in N-glycan processing during Rh1 maturation. This is unexpected given that in humans, the hexosaminidases are typically lysosomal enzymes involved in N-glycan catabolism with no known roles in protein biosynthesis. Here, we present a genetic dissection of glycoprotein processing in Drosophila and unveil key steps in N-glycan trimming during Rh1 biosynthesis. Taken together, our results provide fundamental advances towards understanding the complex and highly regulated pathway of N-glycosylation in vivo and reveal novel insights into the functions of glycosyl hydrolases in the secretory pathway.