Regulation of the bacterial cell cycle by an integrated genetic circuit

How bacteria regulate cell cycle progression at a molecular level is a fundamental but poorly understood problem. In Caulobacter crescentus, two-component signal transduction proteins are crucial for cell cycle regulation, but the connectivity of regulators involved has remained elusive and key factors are unidentified. Here we identify ChpT, an essential histidine phosphotransferase that controls the activity of CtrA, the master cell cycle regulator. We show that the essential histidine kinase CckA initiates two phosphorelays, each requiring ChpT, which lead to the phosphorylation and stabilization of CtrA. Downregulation of CckA activity therefore results in the dephosphorylation and degradation of CtrA, which in turn allow the initiation of DNA replication. Furthermore, we show that CtrA triggers its own destruction by promoting cell division and inducing synthesis of the essential regulator DivK, which feeds back to downregulate CckA immediately before S phase. Our results define a single integrated circuit whose components and connectivity can account for the cell cycle oscillations of CtrA in Caulobacter.     

Rationalization of Metaphorical Exploration: Improving the Creativity Phase of Total Systems Intervention (TSI) on the Basis of Theory and Practice

Metaphors play a significant role in the creativity phase of Total Systems Intervention (TSI). They help managers and other stakeholders to think creatively about their organizations and to highlight their organizational problems. However, in the current form of the creativity phase of TSI there are no explicit criteria in the selection of metaphors or in the disclosure and prioritization of organizational issues. This paper seeks to open a dialog with management consultants who might be interested in the consulting meta-methodology called TSI. It proposes the creativity phase of TSI to management consultants along with the theoretical improvements, as well as the context-dependent and conditional practical innovations. It emphasizes my reflections about the potential of this stage in the appreciation of organizational problems and invites new modifications. To reach this aim, the paper initially gives a brief account of the creativity phase of TSI, deals with its shortcomings, highlights its theoretical improvements and empirical findings in the PALMEK manufacturing company, Turkey, and then rationalizes this phase through proposing an appropriate method for its implementation. This method, on the whole, facilitates systematic and comprehensive analyses of problem situations, characterization of organizational issues, and disclosure and prioritization of concealed organizational problems in a structured and democratic conversational setting.     

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.     

WDR62 is associated with the spindle pole and is mutated in human microcephaly

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain.     

Forced Oscillations of a Class of Nonlinear Dispersive Wave Equations and their Stability

It has been observed in laboratory experiments that when nonlinear dispersive waves are forced periodically from one end of undisturbed stretch of the medium of propagation, the signal eventually becomes temporally periodic at each spatial point. The observation has been confirmed mathematically in the context of the damped Korteweg-de Vries （KdV） equation and the damped Benjamin-Bona-Mahony （BBM） equation. In this paper we intend to show the same results hold for the pure KdV equation （without the damping terms） posed on a finite domain. Consideration is given to the initial-boundary-value problem {ut＋ux＋uux＋uxxx=0, u（x,0）=φ（x）, 0〈x〈1, t〉0,u（0,t）=h（t）, u（1,t） = 0, ux（1,t） = 0, t〉0.It is shown that if the boundary forcing h is periodic with small ampitude, then the small amplitude solution u of （＊） becomes eventually time-periodic. Viewing （＊） （without the initial condition） as an infinite-dimensional dynamical system in the Hilbert space L^2（0, 1）, we also demonstrate that for a given periodic boundary forcing with small amplitude, the system （＊） admits a （locally） unique limit cycle, or forced oscillation, which is locally exponentially stable. A list of open problems are included for the interested readers to conduct further investigations.     

Structural Decomposition Analysis to Investigate the Changes in Energy Consumption in Pakistan

The world energy demand is increasing due to rapid growth in the global economy, industrialization, and urbanization. Pakistan is also confronted with increasing energy demand on one hand and is confronted with the challenge of energy demand-supply gap on the other hand. Since energy is the major driver for growth, it becomes important to investigate the trends of energy consumption in a country and the factors that are most affecting the changes in the use of energy. This particular study aims to investigate the use of energy by all the economic sectors of Pakistan during 2000–2012.The major contribution is the first time application of structural decomposition analysis(SDA) for energy usage along with using Input-Output data for the period of 2002–2012. The results show the fluctuation of the energy intensity of the sectors throughout the study period. Also, the overall effect of energy intensity is negative on energy consumption and it shows a negative contribution value of-80.90% for the study period. Furthermore, the focus on more energy-intensive products like cement,automobiles, iron, steel products and the increasing final demand of the economy contributes to the growth of energy consumption in Pakistan during 2000–2012.     

Chaotification in the stretch-twist-fold (STF) flow

Chaotic behavior and detailed parameter analysis of stretch-twist-fold (STF) flow are investigated. STF flow is associated with fluid particle motion which naturally arises in the dynamo theory. It proposes a mechanism, by which a celestial bodies, such as earth and sun, can maintain and amplify the magnetic field continuously. Parameter analysis is performed using linearization theory for different choices of parameters. The existence of Heteroclinic trajectory of Sil’nikov type is proved using an undetermined coefficient method. It connects two non trivial equilibrium points. As a consequence, the Sil’nikov criterion guarantees that STF flow has Smale horseshoes chaos.     

Predicting multistage financial distress: Reflections on sampling,feature and model selection criteria

This research proposes a prediction model of multistage financial distress (MSFD) after considering contextual and methodological issues regarding sampling, feature and model selection criteria. Financial distress is defined as a three‐stage process showing different nature and intensity of financial problems. It is argued that applied definition of distress is independent of legal framework and its predictability would provide more practical solutions. The final sample is selected after industry adjustments and oversampling the data. A wrapper subset data mining approach is applied to extract the most relevant features from financial statement and stock market indicators. An ensemble approach using a combination of DTNB (decision table and naïve base hybrid model), LMT (logistic model tree) and A2DE (alternative N dependence estimator) Bayesian models is used to develop the final prediction model. The performance of all the models is evaluated using a 10‐fold cross‐validation method. Results showed that the proposed model predicted MSFD with 84.06% accuracy. This accuracy increased to 89.57% when a 33.33% cut‐off value was considered. Hence the proposed model is accurate and reliable to identify the true nature and intensity of financial problems regardless of the contextual legal framework.