Metabolite essentiality elucidates robustness of Escherichia coli metabolism

Complex biological systems are very robust to genetic and environmental changes at all levels of organization. Many biological functions of Escherichia coli metabolism can be sustained against single-gene or even multiple-gene mutations by using redundant or alternative pathways. Thus, only a limited number of genes have been identified to be lethal to the cell. In this regard, the reaction-centric gene deletion study has a limitation in understanding the metabolic robustness. Here, we report the use of flux-sum, which is the summation of all incoming or outgoing fluxes around a particular metabolite under pseudo-steady state conditions, as a good conserved property for elucidating such robustness of E. coli from the metabolite point of view. The functional behavior, as well as the structural and evolutionary properties of metabolites essential to the cell survival, was investigated by means of a constraints-based flux analysis under perturbed conditions. The essential metabolites are capable of maintaining a steady flux-sum even against severe perturbation by actively redistributing the relevant fluxes. Disrupting the flux-sum maintenance was found to suppress cell growth. This approach of analyzing metabolite essentiality provides insight into cellular robustness and concomitant fragility, which can be used for several applications, including the development of new drugs for treating pathogens.Comment: Supplements available at http://stat.kaist.ac.kr/publication/2007/PJKim_pnas_supplement.pd

Adaptive optimal control for linear discrete time-varying systems

In this paper, adaptive optimal control is proposed for time-varying discrete linear system subject to unknown system dynamics. The idea of the method is a direct application of the Q-learning adaptive dynamic programming for time-varying system. In order to derive the optimal control policy, a actor-critic structure is constructed and time-varying least square method is adopted for parameter adaptation. It has shown that the derived control policy can robustly stabilize the time varying system and guarantee an optimal control performance at the same time. As no particular system information is required throughout the process, the proposed techniques provide a potential feasible solution to a large variety of control application. The validity of the proposed method is verified through simulation studies

Dual-acting stapled peptides target both HIV-1 entry and assembly

Background: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 μM) compared to CAI (Kd ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.<p></p> Results: In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively.<p></p> Conclusion: The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.<p></p&gt

Excited states in bilayer graphene quantum dots

We report on ground- and excited state transport through an electrostatically defined few-hole quantum dot in bilayer graphene in both parallel and perpendicular applied magnetic fields. A remarkably clear level scheme for the two-particle spectra is found by analyzing finite bias spectroscopy data within a two-particle model including spin and valley degrees of freedom. We identify the two-hole ground-state to be a spin-triplet and valley-singlet state. This spin alignment can be seen as Hund's rule for a valley-degenerate system, which is fundamentally different to quantum dots in carbon nano tubes and GaAs-based quantum dots. The spin-singlet excited states are found to be valley-triplet states by tilting the magnetic field with respect to the sample plane. We quantify the exchange energy to be 0.35meV and measure a valley and spin g-factor of 36 and 2, respectively

The Impact of a School-Based Weight Management Program Involving Parents via mHealth for Overweight and Obese Children and Adolescents with Intellectual Disability: A Randomized Controlled Trial

There is a scarcity of resources and studies that utilize targeted weight management interventions to engage parents via mHealth tools targeting obese children and adolescents with mild intellectual disabilities (MIDs) extended from school to a home setting. To test the feasibility and acceptability of a school-based weight program (SBWMP) involving parents via mHealth tools designed to reduce weight, enhance knowledge and adopt healthy lifestyles, and thereby achieve better psychosocial well-being among children and adolescents with MIDs. Four special schools were randomly assigned as intervention or control schools. Students from the intervention group (n = 63) were compared to those in the control group (n = 52), which comprised those with usual school planned activities and no parental involvement. Demographics were considered as covariates in a general linear model, an ordinal regression model and a binary logistic regression model analyzing the relationships between the SBWMP and the outcome variables at baseline (T0) and six months later (T1). Body weight, body mass index, and triceps and subscapular skinfold thickness were lower in the intervention group compared to the control group, although the differences were not statistically significant. There was a positive and direct impact of the SBWMP on students’ health knowledge and psychological impacts in the intervention group. The SBWMP extended to the home involving parents via mHealth tools is a feasible and acceptable program for this group with MIDs and their parents

Putting adversity in perspective: Purpose in life moderates the link between childhood emotional abuse and neglect and adulthood depressive symptoms

Background: Childhood emotional abuse and neglect is linked with a host of adverse outcomes later in life, including depression. However, potential psychological resources that may mitigate the adverse outcomes of childhood emotional abuse and neglect are not well-understood. Aims: Drawing from the insight that having a sense of purpose can help individuals deal with setbacks and difficulties better, we propose that purpose in life can also help sufferers of childhood maltreatment cope more effectively and reduce the onset of depressive symptoms. Methods: Participants were drawn from two large, nationally representative studies comprising a total of 3664 respondents. Purpose in life, childhood emotional abuse and neglect, and depressive symptoms were measured with validated scales. Results: We found convergent evidence that purpose in life attenuates the effect of childhood emotional abuse and neglect on subsequent depressive symptoms across a range of measures of mood and depression. Conclusions: The current study highlights the important role played by purpose in life in building resilience, coping against adverse life events, and psychological well-being