Detecting controlling nodes of boolean regulatory networks

Boolean models of regulatory networks are assumed to be tolerant to perturbations. That qualitatively implies that each function can only depend on a few nodes. Biologically motivated constraints further show that functions found in Boolean regulatory networks belong to certain classes of functions, for example, the unate functions. It turns out that these classes have specific properties in the Fourier domain. That motivates us to study the problem of detecting controlling nodes in classes of Boolean networks using spectral techniques. We consider networks with unbalanced functions and functions of an average sensitivity less than 23k, where k is the number of controlling variables for a function. Further, we consider the class of 1-low networks which include unate networks, linear threshold networks, and networks with nested canalyzing functions. We show that the application of spectral learning algorithms leads to both better time and sample complexity for the detection of controlling nodes compared with algorithms based on exhaustive search. For a particular algorithm, we state analytical upper bounds on the number of samples needed to find the controlling nodes of the Boolean functions. Further, improved algorithms for detecting controlling nodes in large-scale unate networks are given and numerically studied

The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells. © 2013 Haas et al

The Vicorder device compared with SphygmoCor in the assessment of carotid-femoral pulse wave velocity in patients with peripheral arterial disease

To assess the reliability and reproducibility of the Vicorder's carotid-femoral pulse wave velocity (cfPWV) measurements in patients with peripheral arterial disease (PAD) and to compare between cfPWV measurements obtained using the Vicorder with those obtained using the SphygmoCor device as a reference. Some 30 patients with PAD (23 men, mean age 64.9±7.5) underwent cfPWV measurement twice by a single investigator during one visit using the Vicorder and the SphygmoCor according to the manufacturer's instructions. Intra-rater reproducibility for each device was assessed using intraclass correlation coefficients (ICC) and Bland-Altman method. The latter was also used to compare between the two devices. The mean difference (s.d.) between repeated measurements was 0.03±0.92 m s-1, P=0.85 and 0.01±0.54 m s-1, P=0.91 for the SphygmoCor and Vicorder, respectively. Measurements of cfPWV were highly reproducible using both devices (ICC=0.94 and 0.92, for the Vicorder and SphygmoCor, respectively). Limits of Agreement using the Bland-Altman method were -1.07 to 1.09 m s-1 and -1.79 to 1.85 m s-1 for the Vicorder and the SphygmoCor, respectively. Bland-Altman plots indicated that 90% of the cfPWV measurements using the Vicorder and 93% of the measurements using the SphygmoCor fell within two s.d.s of the mean difference. Transit time (TT) differed significantly between the two devices (mean difference 30±9.2 m s,

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory