KATNAL1 regulation of sertoli cell microtubule dynamics is essential for spermiogenesis and male fertility

Spermatogenesis is a complex process reliant upon interactions between germ cells (GC) and supporting somatic cells. Testicular Sertoli cells (SC) support GCs during maturation through physical attachment, the provision of nutrients, and protection from immunological attack. This role is facilitated by an active cytoskeleton of parallel microtubule arrays that permit transport of nutrients to GCs, as well as translocation of spermatids through the seminiferous epithelium during maturation. It is well established that chemical perturbation of SC microtubule remodelling leads to premature GC exfoliation demonstrating that microtubule remodelling is an essential component of male fertility, yet the genes responsible for this process remain unknown. Using a random ENU mutagenesis approach, we have identified a novel mouse line displaying male-specific infertility, due to a point mutation in the highly conserved ATPase domain of the novel KATANIN p60-related microtubule severing protein Katanin p60 subunit A-like1 (KATNAL1). We demonstrate that Katnal1 is expressed in testicular Sertoli cells (SC) from 15.5 days post-coitum (dpc) and that, consistent with chemical disruption models, loss of function of KATNAL1 leads to male-specific infertility through disruption of SC microtubule dynamics and premature exfoliation of spermatids from the seminiferous epithelium. The identification of KATNAL1 as an essential regulator of male fertility provides a significant novel entry point into advancing our understanding of how SC microtubule dynamics promotes male fertility. Such information will have resonance both for future treatment of male fertility and the development of non-hormonal male contraceptives.

Developed turbulence and nonlinear amplification of magnetic fields in laboratory and astrophysical plasmas

The visible matter in the universe is turbulent and magnetized. Turbulence in galaxy clusters is produced by mergers and by jets of the central galaxies and believed responsible for the amplification of magnetic fields. We report on experiments looking at the collision of two laser-produced plasma clouds, mimicking, in the laboratory, a cluster merger event. By measuring the spectrum of the density fluctuations, we infer developed, Kolmogorov-like turbulence. From spectral line broadening, we estimate a level of turbulence consistent with turbulent heating balancing radiative cooling, as it likely does in galaxy clusters. We show that the magnetic field is amplified by turbulent motions, reaching a nonlinear regime that is a precursor to turbulent dynamo. Thus, our experiment provides a promising platform for understanding the structure of turbulence and the amplification of magnetic fields in the universe.

Seismic damage detection for a steel braced frame structure

A new approach for global detection of seismic damage in a single-storey steel concentrically braced frame (CBF) structure is presented. The filtered lateral in-plane acceleration response of the CBF structure is integrated twice to provide the lateral in-plane displacement which is used to infer buckling and yielding damage. The level of interstorey drift of the CBF during a seismic excitation allows the yield and buckling of the bracing members to be identified and indirectly detects damage based on exceedance of calculated lateral in-plane displacement limits. A band-pass filter removes noise from the acceleration signal followed by baseline correction being used to reduce the drift in velocity and displacement during numerical integration. This pre-processing results in reliable numerical integration of the frame acceleration that predicts the displacement response accurately when compared to the measured lateral displacement of the CBF structure. Importantly, the structural damage is not assumed through removal of bracing members, rather damage is induced through actual seismic loading. The buckling and yielding displacement threshold limits used to identify damage are demonstrated to accurately identify the initiation of buckling and yielding.

Forward and backward least angle regression for nonlinear system identification

A forward and backward least angle regression (LAR) algorithm is proposed to construct the nonlinear autoregressive model with exogenous inputs (NARX) that is widely used to describe a large class of nonlinear dynamic systems. The main objective of this paper is to improve model sparsity and generalization performance of the original forward LAR algorithm. This is achieved by introducing a replacement scheme using an additional backward LAR stage. The backward stage replaces insignificant model terms selected by forward LAR with more significant ones, leading to an improved model in terms of the model compactness and performance. A numerical example to construct four types of NARX models, namely polynomials, radial basis function (RBF) networks, neuro fuzzy and wavelet networks, is presented to illustrate the effectiveness of the proposed technique in comparison with some popular methods.

Kernel based approaches to local nonlinear non-parametric variable selection

In this paper, we consider the variable selection problem for a nonlinear non-parametric system. Two approaches are proposed, one top-down approach and one bottom-up approach. The top-down algorithm selects a variable by detecting if the corresponding partial derivative is zero or not at the point of interest. The algorithm is shown to have not only the parameter but also the set convergence. This is critical because the variable selection problem is binary, a variable is either selected or not selected. The bottom-up approach is based on the forward/backward stepwise selection which is designed to work if the data length is limited. Both approaches determine the most important variables locally and allow the unknown non-parametric nonlinear system to have different local dimensions at different points of interest. Further, two potential applications along with numerical simulations are provided to illustrate the usefulness of the proposed algorithms.

An exploration of integrated data on the social dynamics of suicide among women

The gender based nature of suicide related behaviour is largely accepted.However, studies which report exclusively on female fatal suicides are rare.Here we demonstrate how female fatal suicide has effectively been ‘othered’ and appears ‘incidental’ in studies which compare female behaviour with that of their male counterparts. We highlight how recent studies of suicide have tended to be dominated by male only approaches,which increasingly link issues of masculinity with male death by suicide.Drawing on data collected from the GP and Coroner’s office, we then apply the Sociological Autopsy approach to a cohort of 78 deaths recorded as suicides in the UK between 2007 and 2009. By focusing on females in isolation from males, we demonstrate that as in male suicide only studies,it is similarly possible to draw out issues associated with the feminine identity which can be linked to death by suicide. We identify that bereavement, sexual violence and motherhood could all be linked to the lives and help-seeking of the females who died. In closing, we suggest are orientation towards sociological analytic approaches of female suicide may help to produce further reductions in the rate of female death by suicide.

Hypoxia response element-driven cytosine deaminase/5-fluorocytosine gene therapy system:a highly effective approach to overcome the dynamics of tumour hypoxia and enhance the radiosensitivity of prostate cancer cells in vitro

BACKGROUND: We proposed to exploit hypoxia-inducible factor (HIF)-1alpha overexpression in prostate tumours and use this transcriptional machinery to control the expression of the suicide gene cytosine deaminase (CD) through binding of HIF-1alpha to arrangements of hypoxia response elements. CD is a prodrug activation enzyme, which converts inactive 5-fluorocytosine to active 5-fluorouracil (5-FU), allowing selective killing of vector containing cells.

METHODS: We developed a pair of vectors, containing either five or eight copies of the hypoxia response element (HRE) isolated from the vascular endothelial growth factor (pH5VCD) or glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (pH8GCD) gene, respectively. The kinetics of the hypoxic induction of the vectors and sensitization effects were evaluated in 22Rv1 and DU145 cells in vitro.

RESULTS: The CD protein as selectively detected in lysates of transiently transfected 22Rv1 and DU145 cells following hypoxic exposure. This is the first evidence of GAPDH HREs being used to control a suicide gene therapy strategy. Detectable CD levels were sustained upon reoxygenation and prolonged hypoxic exposures. Hypoxia-induced chemoresistance to 5-FU was overcome in both cell lines treated with this suicide gene therapy approach. Hypoxic transfectants were sensitized to prodrug concentrations that were ten-fold lower than those that are clinically relevant. Moreover, the surviving fraction of reoxygenated transfectants could be further reduced with the concomitant delivery of clinically relevant single radiation doses.

CONCLUSIONS: This strategy thus has the potential to sensitize the hypoxic compartment of prostate tumours and improve the outcome of current therapies.

Identification of Dynamics of Surface Suction Over an Airfoil at Low Reynolds Numbers

This paper deals with identification of dynamics in suction control of airfoils for low Reynolds number regimes (8 x 10^4 - 5 x 10^5). In particular, the dynamics of interest is the map that relates suction pressure and surface pressure. Identification of such dynamics is of use to a variety of active control applications including suction control in small/medium wind turbines which operate in these Reynolds number regimes. Prior research has largely focused on higher Reynolds number regimes, creating a need for such a study. Towards identifying the said dynamic relations, experiments were conducted on NACA0012 airfoil in a wind tunnel. The dynamic relation between suction and surface pressure was identified as an overdamped second order system.

Landauer’s Principle in Multipartite Open Quantum System Dynamics

We investigate the link between information and thermodynamics embodied by Landauer’s principle in the open dynamics of a multipartite quantum system. Such irreversible dynamics is described in terms of a collisional model with a finite temperature reservoir. We demonstrate that Landauer’s principle holds, for such a configuration, in a form that involves the flow of heat dissipated into the environment and the rate of change of the entropy of the system. Quite remarkably, such a principle for heat and entropy power can be explicitly linked to the rate of creation of correlations among the elements of the multipartite system and, in turn, the non-Markovian nature of their reduced evolution. Such features are illustrated in two exemplary cases.

On Variable Selection of a Nonlinear Non-parametric System with a Limited Data Set: A Stepwise Algorithm

his paper considers a problem of identification for a high dimensional nonlinear non-parametric system when only a limited data set is available. The algorithms are proposed for this purpose which exploit the relationship between the input variables and the output and further the inter-dependence of input variables so that the importance of the input variables can be established. A key to these algorithms is the non-parametric two stage input selection algorithm.

On Infinite Time Performance of Nonlinear Model Predictive Controllers

This paper addresses the problem of infinite time performance of model predictive controllers applied to constrained nonlinear systems. The total performance is compared with a finite horizon optimal cost to reveal performance limits of closed-loop model predictive control systems. Based on the Principle of Optimality, an upper and a lower bound of the ratio between the total performance and the finite horizon optimal cost are obtained explicitly expressed by the optimization horizon. The results also illustrate, from viewpoint of performance, how model predictive controllers approaches to infinite optimal controllers as the optimization horizon increases.