Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

Connexin (Cx) proteins establish intercellular gap junction channels (Cx GJCs) through coupling of two apposed hexameric Cx hemichannels (Cx HCs, connexons). Pre- and post-GJ interfaces consist of extracellular EL1 and EL2 loops, each with three conserved cysteines. Previously, we reported that known peptide inhibitors, mimicking a variety of Cx43 sequences, appear non-selective when binding to homomeric Cx43 vs. Cx36 GJC homology model subtypes. In pursuit of finding potentially Cx subtype-specific inhibitors of connexon-connexon coupling, we aimed at to understand better how the GJ interface is formed. Here we report on the discovery of Cx GJC subtype-specific protein stabilization centers (SCs) featuring GJ interface architecture. First, the Cx43 GJC homology model, embedded in two opposed membrane bilayers, has been devised. Next, we endorsed the fluctuation dynamics of SCs of the interface domain of Cx43 GJC by applying standard molecular dynamics under open and closed cystine disulfide bond (CS-SC) preconditions. The simulations confirmed the major role of of the unique trans-GJ SC pattern comprising conserved (55N, 56T) and non-conserved (57Q) residues of the apposed EL1 loops in the stabilization of the GJC complex. Importantly, clusters of SC patterns residing close to the GJ interface domain appear to orient the interface formation via the numerous SCs between EL1 and EL2. These include central 54CS-S198C or 61CS-S192C contacts with residues 53R, 54C, 55N, 197D, 199F or 64V, 191P, respectively. In addition, we revealed that GJC interface formation is favoured when the psi dihedral angle of the nearby 193P residue is stable around 180° and the interface SCs disappear when this angle moves to the 0° to −45° range. The potential of the association of non-conserved residues with SC motifs in connexon-connexon coupling makes the development of Cx subtype-specific inhibitors viable.

Comparative Analysis of the Survival Status and Treatment Outcome of Under-five Children Admitted with Severe Acute Malnutrition Among Hospital-based and Health Center Based Stabilization Centers, South Ethiopia

Background:Severe acute malnutrition has been managed at Hospital stabilization centers until the management at health center based stabilization centers was started recently. However, the treatment outcome was not assessed in relation to the existing hospital-based management. Therefore, this study comparatively assessed the treatment outcome and survival status of severe acute malnutrition among Health center-based and hospital-based stabilization centers. The finding will be used by healthcare providers, planners and policymakers at large.Methods:Randomly selected 400 records of under-five children admitted to five stabilization centers (2 hospitals and 3 health center) in Gedeo Zone was included. Data was entered by Epi Info version 7 and analyzed by STATA version 11. Survival difference was checked by life table and Kaplan-Mier with Log-Rank test. Cox proportional hazards model was built by forward stepwise procedure; compared to likely hood ratio test and Harrell’s concordance and fitness checked by the cox-snell residual plot.Result:The study showed that the cumulative probability of Survival is significantly different at Hospital stabilization center and health center stabilization centers (p.value <0.001) with shorter survival at hospitals. During the follow-up period, 28(13.86%) children from hospital and 5(2.5%) children from health center died, while 155(76.73%) children from the hospital and 145(73.23%) children from health center got cured. Eighteen (4.5%)children were defaulted. Death is significantly higher at the hospital, while default rate and cure rate are not significantly different. Altered pulse rate [AHR=2.44, 95% CI =1.47-4, p<0.001], NG tube insertion [AHR=1.8, 95% CI =1.04-3.1, p=0.038], Anemia [AHR=1.53, 95% CI =1.02-2.3, p<0.041] and Hypoglycemia [AHR=2.78, 95% CI =1.8-4.3, p<0.001] were found to be independent predictors of death.Conclusion:The survival of children in hospital is shorter and mortality is higher. An overall treatment outcome was in acceptable ranges. Intervention to further reduce deaths at hospitals has to focus on children with comorbidities and altered general conditions and early detection.

Aromatic π-networks in Sm/LSm protein interfaces

In this work, we have analyzed the influence of ?-? interactions on stability and properties of Sm/LSm assemblies. Phe residues were found to be involved in ?-? interactions much more frequently than Tyr or His. Similarly, the Phe-Phe ?-? interacting pair had the highest frequency of occurrence. Furthermore, a significant number of ?-networks were observed at the interface of Sm/LSm proteins. Generally speaking, the distance between the interacting pairs was in the range of 5-6 ?. 3? and 7?-networks were found to frequently have plane-plane angles less than 60?. Solvent accessibility pattern of Sm/LSm proteins revealed that all of the interacting residues were from buried areas. Moreover, most of the ?-? interacting residues of Sm/LSm proteins were evolutionary conserved and were in the strand regions. A high percentage of these residues could be considered as stabilization centers that (significantly) contribute to the net stability of Sm/LSm proteins.