Vaccine Hesitancy Under the Magnifying Glass: A Systematic Review of the Uses and Misuses of an Increasingly Popular Construct.

Resistance to vaccines has hindered attempts to contain and prevent outbreaks of infectious diseases for centuries. More recently, however, the term "vaccine hesitancy" has been used to describe not necessarily outright resistance but also a delay in acceptance or uncertainty regarding vaccines. Given concerns about hesitancy and its impact on vaccine uptake rates, researchers increasingly shifted the focus from resistance to vaccines toward vaccine hesitancy. Acknowledging the urgency to accurately assess the phenomenon, it is critical to understand the state of the literature, focusing on issues of conceptualization and operationalization. To carry out this systematic review, we collected and analyzed all published empirical articles from 2000 to 2021 that explicitly included quantitative self-report measures of vaccine hesitancy (k = 86). Using a mixed-method approach, the review demonstrates and quantifies crucial inconsistencies in the measurement of the construct, lack of clarity in regard to the determination of who should or should not be defined as hesitant, and overreliance on unrepresentative samples. Crucially, our analysis points to a potential systematic bias toward exaggerating the level of hesitancy in the population. Modeling a vaccine hesitancy co-citation network, the analysis also points to the existence of insular academic silos that make it harder to achieve a unified measurement tool. Theoretical and practical implications for academics, practitioners, and policymakers are discussed.

Composition and architecture of the Schizosaccharomyces pombe Rad18 (Smc5-6) complex.

The rad18 gene of Schizosaccharomyces pombe is an essential gene that is involved in several different DNA repair processes. Rad18 (Smc6) is a member of the structural maintenance of chromosomes (SMC) family and, together with its SMC partner Spr18 (Smc5), forms the core of a high-molecular-weight complex. We show here that both S. pombe and human Smc5 and -6 interact through their hinge domains and that four independent temperature-sensitive mutants of Rad18 (Smc6) are all mutated at the same glycine residue in the hinge region. This mutation abolishes the interactions between the hinge regions of Rad18 (Smc6) and Spr18 (Smc5), as does mutation of a conserved glycine in the hinge region of Spr18 (Smc5). We purified the Smc5-6 complex from S. pombe and identified four non-SMC components, Nse1, Nse2, Nse3, and Rad62. Nse3 is a novel protein which is related to the mammalian MAGE protein family, many members of which are specifically expressed in cancer tissue. In initial steps to understand the architecture of the complex, we identified two subcomplexes containing Rad18-Spr18-Nse2 and Nse1-Nse3-Rad62. The subcomplexes are probably bridged by a weaker interaction between Nse2 and Nse3.

Nse2, a component of the Smc5-6 complex, is a SUMO ligase required for the response to DNA damage.

The Schizosaccharomyces pombe SMC proteins Rad18 (Smc6) and Spr18 (Smc5) exist in a high-M(r) complex which also contains the non-SMC proteins Nse1, Nse2, Nse3, and Rad62. The Smc5-6 complex, which is essential for viability, is required for several aspects of DNA metabolism, including recombinational repair and maintenance of the DNA damage checkpoint. We have characterized Nse2 and show here that it is a SUMO ligase. Smc6 (Rad18) and Nse3, but not Smc5 (Spr18) or Nse1, are sumoylated in vitro in an Nse2-dependent manner, and Nse2 is itself autosumoylated, predominantly on the C-terminal part of the protein. Mutations of C195 and H197 in the Nse2 RING-finger-like motif abolish Nse2-dependent sumoylation. nse2.SA mutant cells, in which nse2.C195S-H197A is integrated as the sole copy of nse2, are viable, whereas the deletion of nse2 is lethal. Smc6 (Rad18) is sumoylated in vivo: the sumoylation level is increased upon exposure to DNA damage and is drastically reduced in the nse2.SA strain. Since nse2.SA cells are sensitive to DNA-damaging agents and to exposure to hydroxyurea, this implicates the Nse2-dependent sumoylation activity in DNA damage responses but not in the essential function of the Smc5-6 complex.