Muscle contraction and many other cell movements are driven by cyclic interactions between actin filaments and the motor enzyme myosin. Conformational changes in the actin-myosin binding interface occur in concert with the binding of ATP, binding to actin, and loss of hydrolytic by-products, but the effects of these conformational changes on the strength of the actomyosin bond are unknown. The force-dependent kinetics of the actomyosin bond may be particularly important at high loads, where myosin may detach from actin before achieving its full power stroke. Here we show that over a physiological range of rapidly applied loads, actomyosin behaves as a ''catch'' bond, characterized by increasing lifetimes with increasing loads up to a maximum at Ϸ6 pN. Surprisingly, we found that the myosin-ADP bond is possessed of longer lifetimes under load than rigor bonds, although the load at which bond lifetime is maximal remains unchanged. We also found that actomyosin bond lifetime is ultimately dependent not only on load, but loading history as well. These data suggest a complex relationship between the rate of actomyosin dissociation and muscle force and shortening velocity. The 6-pN load for maximum bond lifetime is near the force generated by a single myosin molecule during isometric contraction. This raises the possibility that all catch bonds between load-bearing molecules are ''mechanokinetically'' tuned to their physiological environment. catch bonds ͉ dynamic force spectroscopy ͉ laser trap ͉ myosin T he crystal structure of the myosin head (S1) (1) reveals how small-scale conformational changes within the hydrolytic site are converted into relatively large-scale changes producing movement. A globular ''motor domain'' occupies the bulk of the structure and contains both the nucleotide-and actin-binding sites (see Fig. 1). Of particular note is an ␣-helical extension of the heavy chain, or ''neck,'' protruding from the globular motor domain that acts as a rigid ''lever arm'' to amplify small movements arising in the nucleotide-binding pocket (2-5). Concomitant with phosphate release, rotation of the neck causes a step of an Ϸ5.5-nm ''working stroke'' and an isometric force of 0.7-9 pN (3, 6-10) that has been the subject of numerous single-molecule mechanics studies.Another feature of particular note within the motor domain is a cleft that divides the actin-binding site (2). This cleft is thought to close upon binding to actin (1, 2, 11-13), bringing into position residues on both sides of the cleft that are involved in strong binding to actin: the so-called R-site and A-site. Evidence suggests that there may be additional conformational changes in the actin-binding interface that accompany ADP release. The cleft at the actin-binding interface of smooth muscle myosin may close further upon ADP release (14, 15) and is accompanied by an increase in R-site flexibility (14, 16). Thus, although both the R-site and A-site are tightly bound to actin in the presence of ADP, upon ADP release from smooth muscle myosin the R-...

Sleep deprivation can impair human health and performance. Habitual total sleep time and homeostatic sleep response to sleep deprivation are quantitative traits in humans. Genetic loci for these traits have been identified in model organisms, but none of these potential animal models have a corresponding human genotype and phenotype. We have identified a mutation in a transcriptional repressor (hDEC2-P385R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time-and sleep deprivationdependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.Although sleep is an essential process for life, the brain circuits regulating sleep and the cellular and/or molecular mechanisms involved in this complex process are still enigmatic (1-3). Sleep or a "sleeplike" behavior is present in virtually every animal species where it has been studied. Total sleep deprivation can be fatal, and partial deprivation of sleep has serious consequences on cognition, mood, and health (4-6). It is obvious that situational increases in behavioral drive can transiently delay sleep, but very little is known about chronic partial sleep curtailment as a possible consequence of a persistent elevation in waking behavioral drive. The latter trait, sometimes referred to as a "hyperthymic" temperament (7), is a theoretical third influence on sleep habits. Murine Dec2 (mDec2) is a negative component of the circadian clock (8-10). It belongs to a basic helix-loop-helix (bHLH) protein family in which members can dimerize with each other and can affect gene transcription by binding to specific DNA sequences (11). While performing candidate gene resequencing in DNAs from human families, segregating alleles ‡ To whom correspondence should be addressed. for extremely early wake up times, we identified an hDEC2 point mutation in a small family with two affected individuals ( Fig. 1A) (12). Subjects carrying this mutation had lifelong shorter daily sleep times than normal individuals (Table 1). The self-reported nonworkday habitual sleep-offset times of the mutation carriers were much earlier than those of the noncarriers (including noncarrier family members and general controls). However, these two individuals have sleep-onset times that are similar to that of conventional sleepers. The habitual self-reported total sleep time per 24-hour day was much shorter in mutation carriers (average 6.25 hours) compared with the noncarriers (average 8.06 hours) in this family. Thus, they represent "natural short sleepers" who routinely sleep less than individuals with familial advanced sleep-phase syndrome (FASPS) or general controls (Table 1). The average total sleep time for American adults on nonworkdays is ∼7.4 hours (www.sleepfoundation.org). The mutation changes a C to G in the DNA seq...

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Objective: A systematic review and meta-analysis were used to directly evaluate the direct anterior approach (DAA) and the posterior approach (PA) for early efficacy and safety of total hip arthroplasty (THA). Methods: Control-led trials assessing DAA and PA for the efficacy and safety of THA were searched in the database. Articles were reviewed according to predetermined inclusion and exclusion criteria; the quality of the methodology included in a given study was strictly assessed before data extraction. Moreover, meta-analysis was performed for outcomes that can be combined; otherwise, descriptive analysis was performed. Results: There were 20 articles included, with a total of 7377 patients. Among these, 3728 and 3649 cases were in the DAA and PA groups, respectively. There was no difference between the DAA and PA groups at postoperative week 2 in the number of patients using the assistive ambulatory device or in time needed to completely discontinue all assistive ambulatory devices. Descriptive analysis found that DAA was slightly better than PA regarding early functional recovery and activity after surgery, as well as postoperative pain relief. Hospitalisation stay in the DAA group was shorter than in the PA group, in which the patients had a shorter operative time. Radiographic outcomes showed that there was little difference in prosthetic position between the DAA and PA groups. The proportions of intraoperative fractures and postoperative lateral cutaneous nerve of the thigh (LCNT) neuropraxia were significantly higher in the DAA group than in patients who underwent PA. Conclusion: Compared with PA, DAA presents superior early recovery following THA.

Original citation:Chang, Jinyuan, Guo, Bin and Yao, Qiwei (2015) We consider a multivariate time series model which represents a high dimensional vector process as a sum of three terms: a linear regression of some observed regressors, a linear combination of some latent and serially correlated factors, and a vector white noise. We investigate the inference without imposing stationary conditions on the target multivariate time series, the regressors and the underlying factors. Furthermore we deal with the the endogeneity that there exist correlations between the observed regressors and the unobserved factors. We also consider the model with nonlinear regression term which can be approximated by a linear regression function with a large number of regressors. The convergence rates for the estimators of regression coefficients, the number of factors, factor loading space and factors are established under the settings when the dimension of time series and the number of regressors may both tend to infinity together with the sample size. The proposed method is illustrated with both simulated and real data examples.

We extend the principal component analysis (PCA) to secondorder stationary vector time series in the sense that we seek for a contemporaneous linear transformation for a p-variate time series such that the transformed series is segmented into several lowerdimensional subseries, and those subseries are uncorrelated with each other both contemporaneously and serially. Therefore those lowerdimensional series can be analysed separately as far as the linear dynamic structure is concerned. Technically it boils down to an eigenanalysis for a positive definite matrix. When p is large, an additional step is required to perform a permutation in terms of either maximum cross-correlations or FDR based on multiple tests. The asymptotic theory is established for both fixed p and diverging p when the sample size n tends to infinity. Numerical experiments with both simulated and real data sets indicate that the proposed method is an effective initial step in analysing multiple time series data, which leads to substantial dimension reduction in modelling and forecasting high-dimensional linear dynamical structures. Unlike PCA for independent data, there is no guarantee that the required linear transformation exists. When it does not, the proposed method provides an approximate segmentation which leads to the advantages in, for example, forecasting for future values. The method can also be adapted to segment multiple volatility processes.

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