Note: This is a "pre-print" version of the paper published in Nature. It is word-for-word the same as the published version, except where noted explicitly as footnotes. Five minor typographical errors in the published version have been corrected in this version, as also a small error in Figure 3. None of the conclusions of the paper are affected by these changes. Although people's legs are capable of a broad range of muscle-use and gait patterns, they generally prefer just two. They walk, swinging their body over a relatively straight leg with each step, or run, bouncing up off a bent leg between aerial phases. Walking feels easiest when going slowly, and running feels easiest when going faster. More unusual gaits seem more tiring. Perhaps this is because walking and running use the least energy [1; 2; 3; 4; 5; 6; 7]. Addressing this classic [1] conjecture with experiments [2; 3] requires comparing walking and running with many other strange and unpracticed gaits. As an alternative, a basic understanding of gait choice might be obtained by calculating energy cost by using mechanics-based models. Here we use a minimal model that can describe walking and running as well as an infinite variety of other gaits. We use computer optimization to find which gaits are indeed energetically optimal for this model. At low speeds the optimization discovers the classic inverted-pendulum walk [8; 9; 10; 11; 12; 13], at high speeds it discovers a bouncing run [12; 14] 1 , even without springs, and at intermediate speeds it finds a new pendular-running gait that includes walking and running as extreme cases.One way of characterizing gaits is by the motions of the body (Fig. 1a). In these terms, walking seems well caricatured [13] (Fig. 1b) by the hip joint going from one circular arc to the next with push-off and heelstrike impulses in between. Similarly, running could be caricatured by a sequence of parabolic free-flight arcs (Fig. 1c) [4; 6; 7], perhaps the simplest mechanical model that is capable of exhibiting a broad range of gaits that includes walking and running. Although the model is a mechanical abstraction that is not physically realizable, it is subject to the laws of physics. Because of its simplicity, the model is amenable to interpretation. It can also be studied with exhaustive and accurate simulation experiments, far beyond what is possible with human subjects.We wish to find how a person can get from one place to another with the least muscle work W (Methods). We treat the body as a point mass m at position (x, y) at time t (Fig. 2a). The legs are massless and therefore, when not in ground contact, they can be oriented, lengthened and shortened with no energy cost. The fluctuations of the leg length l(t) due to flexion of the hip, knee and ankle are incorporated in a single telescoping axial actuator [4] that carries a compressive time-varying force F = F (t). For simplicity, we seek 1 The published version incorrectly referred to [12; 13]

No abstract

During human walking, perturbations to the upper body can be partly corrected by placing the foot appropriately on the next step. Here, we infer aspects of such foot placement dynamics using step-to-step variability over hundreds of steps of steady-state walking data. In particular, we infer dependence of the 'next' foot position on upper body state at different phases during the 'current' step. We show that a linear function of the hip position and velocity state (approximating the body center of mass state) during mid-stance explains over 80% of the next lateral foot position variance, consistent with (but not proving) lateral stabilization using foot placement. This linear function implies that a rightward pelvic deviation during a left stance results in a larger step width and smaller step length than average on the next foot placement. The absolute position on the treadmill does not add significant information about the next foot relative to current stance foot over that already available in the pelvis position and velocity. Such walking dynamics inference with steady-state data may allow diagnostics of stability and inform biomimetic exoskeleton or robot design.

The highly conserved Kinase, Endopeptidase and Other Proteins of small Size (KEOPS)/Endopeptidase‐like and Kinase associated to transcribed Chromatin (EKC) protein complex has been implicated in transcription, telomere maintenance and chromosome segregation, but its exact function remains unknown. The complex consists of five proteins, Kinase‐Associated Endopeptidase (Kae1), a highly conserved protein present in bacteria, archaea and eukaryotes, a kinase (Bud32) and three additional small polypeptides. We showed that the complex is required for a universal tRNA modification, threonyl carbamoyl adenosine (t6A), found in all tRNAs that pair with ANN codons in mRNA. We also showed that the bacterial ortholog of Kae1, YgjD, is required for t6A modification of Escherichia coli tRNAs. The ATPase activity of Kae1 and the kinase activity of Bud32 are required for the modification. The yeast protein Sua5 has been reported previously to be required for t6A synthesis. Using yeast extracts, we established an in vitro system for the synthesis of t6A that requires Sua5, Kae1, threonine, bicarbonate and ATP. It remains to be determined whether all reported defects of KEOPS/EKC mutants can be attributed to the lack of t6A, or whether the complex has multiple functions.

SummarySister chromatid cohesion conferred by entrapment of sister DNAs within a tripartite ring formed between cohesin’s Scc1, Smc1, and Smc3 subunits is created during S and destroyed at anaphase through Scc1 cleavage by separase. Cohesin’s association with chromosomes is controlled by opposing activities: loading by Scc2/4 complex and release by a separase-independent releasing activity as well as by cleavage. Coentrapment of sister DNAs at replication is accompanied by acetylation of Smc3 by Eco1, which blocks releasing activity and ensures that sisters remain connected. Because fusion of Smc3 to Scc1 prevents release and bypasses the requirement for Eco1, we suggested that release is mediated by disengagement of the Smc3/Scc1 interface. We show that mutations capable of bypassing Eco1 in Smc1, Smc3, Scc1, Wapl, Pds5, and Scc3 subunits reduce dissociation of N-terminal cleavage fragments of Scc1 (NScc1) from Smc3. This process involves interaction between Smc ATPase heads and is inhibited by Smc3 acetylation.