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Quorum systems are a powerful mechanism for ensuring the consistency of replicated data. Production systems usually opt for majority quorums due to their simplicity and fault tolerance, but majority quorum systems provide poor throughput and scalability. Alternatively, researchers have invented a number of theoretically "optimal" quorum systems, but the underlying theory ignores many practical complexities such as machine heterogeneity and workload skew. In this paper, we conduct a pragmatic re-examination of quorum systems. We enrich the current theory on quorum systems with a number of practical refinements to find quorum systems that provide higher throughput, lower latency, and lower network load. We also develop a library Quoracle that precisely quantifies the available trade-offs between quorum systems to empower engineers to find optimal quorum systems, given a set of objectives for specific deployments and workloads. Our tool is available online at: https://github.com/mwhittaker/quoracle., To be published in PaPoC 2021 (https://papoc-workshop.github.io/2021/)

Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the β-sheet content in IAPP aggregates while rendering a new morphology of "stelliform" amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rodlike scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential for driving the specific interactions required to impel the accelerated IAPP aggregation. This study sheds new light on the structure-toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis.

Systematically reasoning about the fine-grained causes of events in a real-world distributed system is challenging. Causality, from the distributed systems literature, can be used to compute the causal history of an arbitrary event in a distributed system, but the event's causal history is an over-approximation of the true causes. Data provenance, from the database literature, precisely describes why a particular tuple appears in the output of a relational query, but data provenance is limited to the domain of static relational databases. In this paper, we present wat-provenance: a novel form of provenance that provides the benefits of causality and data provenance. Given an arbitrary state machine, wat-provenance describes why the state machine produces a particular output when given a particular input. This enables system developers to reason about the causes of events in real-world distributed systems. We observe that automatically extracting the wat-provenance of a state machine is often infeasible. Fortunately, many distributed systems components have simple interfaces from which a developer can directly specify wat-provenance using a technique we call wat-provenance specifications. Leveraging the theoretical foundations of wat-provenance, we implement a prototype distributed debugging framework called Watermelon.

Kinesin motors convert chemical energy from ATP hydrolysis into unidirectional movement. To understand how kinesin motors bind to and move along microtubules, we fit the atomic structure of the motor domain of Ncd (a kinesin motor involved in meiosis and mitosis) into three-dimensional density maps of Ncd–microtubule complexes calculated by cryo-electron microscopy and image analysis. The model reveals that Ncd shares an extensive interaction surface with the microtubule, and that a portion of the binding site involves loops that contain conserved residues. In the Ncd dimer, the microtubule-bound motor domain makes intimate contact with its partner head, which is dissociated from the microtubule. This head–head interaction may be important in positioning the dissociated head to take a step to the next binding site on the microtubule protofilament.

Muscle contraction consists of a cyclical interaction between myosin and actin driven by the concomitant hydrolysis of adenosine triphosphate (ATP). A model for the rigor complex of F actin and the myosin head was obtained by combining the molecular structures of the individual proteins with the low-resolution electron density maps of the complex derived by cryo-electron microscopy and image analysis. The spatial relation between the ATP binding pocket on myosin and the major contact area on actin suggests a working hypothesis for the crossbridge cycle that is consistent with previous independent structural and biochemical studies.

Three-dimensional data representing biological structures can be derived using several methods, including serial section reconstruction, optical sectioning, and tomography. The investigation, comprehension, and communication of structural relationships to others is greatly facilitated by computer-based visualization procedures. We describe SYNU, a suite of programs developed for interactive investigation of three-dimensional structure and for the production of high-quality three-dimensional images and animations. We illustrate the capabilities of SYNU in applications to biological data obtained by confocal light microscopy, serial section, and high-resolution electron microscopy from investigations at the cellular, subcellular, and molecular levels.

Kinesin motors power many motile processes by converting ATP energy into unidirectional motion along microtubules. The force-generating and enzymatic properties of conventional kinesin have been extensively studied; however, the structural basis of movement is unknown. Here we have detected and visualized a large conformational change of an approximately 15-amino-acid region (the neck linker) in kinesin using electron paramagnetic resonance, fluorescence resonance energy transfer, pre-steady state kinetics and cryo-electron microscopy. This region becomes immobilized and extended towards the microtubule 'plus' end when kinesin binds microtubules and ATP, and reverts to a more mobile conformation when gamma-phosphate is released after nucleotide hydrolysis. This conformational change explains both the direction of kinesin motion and processive movement by the kinesin dimer.

Myosin II crossbridges interact with F-actin producing powerstrokes of around 100 A (refs 1, 2), during which the products of ATP hydrolysis are released. This has been postulated to involve an articulation of the myosin head (S1) on actin, or substantial conformational changes in S1 itself. Small movements of the regulatory light chain have been detected (see, for example, refs 9, 10), but most data suggest that the bulk of S1 does not move on actin during crossbridge cycling. Here we present three-dimensional maps of S1-decorated F-actin in the presence and absence of MgADP. The myosin motor domain is similar in both states but there are major orientational differences in the light-chain-binding domain. This domain acts as a rigid level arm pivoting about the end of the motor domain and swinging approximately 23 degrees, resulting in a approximately 35-A step. Small, nucleotide-mediated conformational changes in the motor domain may thus be converted by the light-chain domain into large movement steps.

Comparisons of three-dimensional maps of vertebrate muscle thin filaments obtained by cryo-electron microscopy and image analysis, reveal the molecular structure of F-actin, the location of the C terminus of the monomer and the positions of the binding sites of tropomyosin, the myosin head and the N-terminal portion of the myosin A1 light chain on the filament. These data provide strong constraints for evaluating models built from the atomic structure of the monomer and the subsequent identification of molecular contacts.

A high-resolution model of the microtubule has been obtained by docking the crystal structure of tubulin into a 20 A map of the microtubule. The excellent fit indicates the similarity of the tubulin conformation in both polymers and defines the orientation of the tubulin structure within the microtubule. Long C-terminal helices form the crest on the outside of the protofilament, while long loops define the microtubule lumen. The exchangeable nucleotide in β -tubulin is exposed at the plus end of the microtubule, while the proposed catalytic residue in α -tubulin is exposed at the minus end. Extensive longitudinal interfaces between monomers have polar and hydrophobic components. At the lateral contacts, a nucleotide-sensitive helix interacts with a loop that contributes to the binding site of taxol in β -tubulin.