RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

A prospective observational study was conducted in a tertiary care hospital to study clinicoepidemiological profile of potentially rabid animal bite cases from rural India. Total of 308 children (median age 6 years) admitted to hospital, were recruited over 1 year and followed up till completion of antirabies vaccine course. Dog was the commonest (77.27%) offending animal. Of the exposures, 66.88% were scratches, 88.96% were unprovoked and 27.27% were categorized as Class III. The median times to wound toileting and reporting to health facility were 1 and 6 h, respectively. Majority received prompt PEP in hospital, and RIG was administered in 34.55% of Class II and 90.48% of Class III exposures. Compared with their older counterparts, children aged <5 years suffered more bites on face and trunk and more Class III exposures. The rabies prophylaxis scenario is encouraging, when compared with earlier studies, but there are gaps to be addressed.

RAS proteins are small membrane-anchored GTPases that regulate key cellular signaling networks. It has been recently shown that different anionic lipid types can affect the spatiotemporal properties of RAS through dimerization/clustering and signaling fidelity. To understand the effects of anionic lipids on key spatiotemporal properties of RAS, we dissected 1 ms of data from all-atom molecular dynamics simulations for KRAS4B on two model anionic lipid membranes that have 30% of POPS mixed with neutral POPC and 8% of PIP2 mixed with POPC. We unveiled the orientation space of KRAS4B, whose kinetics were slower and more distinguishable on the membrane containing PIP2 than the membrane containing POPS. Particularly, the PIP2-mixed membrane can differentiate a third kinetic orientation state from the other two known orientation states. We observed that each orientation state may yield different binding modes with an RAF kinase, which is required for activating the MAPK/ERK signaling pathway. However, an overall occluded probability, for which RAF kinases cannot bind KRAS4B, remains unchanged on the two different membranes. We identified rare fast diffusion modes of KRAS4B that appear coupled with orientations exposed to cytosolic RAF. Particularly, on the membrane having PIP2, we found nonlinear correlations between the orientation states and the conformations of the cationic farnesylated hypervariable region, which acts as an anchor in the membrane. Using diffusion coefficients estimated from the all-atom simulations, we quantified the effect of PIP2 and POPS on the KRAS4B dimerization via Green’s function reaction dynamics simulations, in which the averaged dimerization rate is 12.5% slower on PIP2-mixed membranes.

Background:Psychological stress following natural disaster is common. Despite several earthquakes in India, data on evaluation of acute stress among the child victims in the early postdisaster period is scarce. Immediately following a devastating earthquake (6.9 Richter) at Sikkim on September, 18 2011, many children attended North Bengal Medical College, the nearest government tertiary care institution, with unusual stress symptoms.Objective:Evaluation of acute stress symptoms in children in the immediate postearthquake period.Materials and Methods:This was a cross-sectional study done over 4 weeks and includes all the children from 1 to 12 years presenting with unusual physical or behavioral symptoms. Those with major injuries requiring admission were excluded. They were divided into two age groups. For older children (8-12 years) the 8-item Children Impact of Event Scale (CIES) was used for screening of stress. Unusual symptoms were recorded in younger children (1-8 years) as CIES is not validated < 8 years.Result:A total of 84 children (2.66%) out of 3154 had stress symptoms. Maximum attendance was noted in first 3 days (65.47%) and declined gradually. In children ≥ 8 years, 48.78% had psychological stress, which was statistically significant on CIES scores without any gender predilection. Static posturing (41.86%), sleeplessness (32.55%), anorexia (9.30%), recurrent vomiting (13.95%), excessive crying (13.95%), or night-awakenings (4.65%) were found in younger children (n = 43) and three required admission.Conclusion:This study represent the first Indian data showing statistically significant psychological impact in older children (8-12 years) and various forms of physical stress symptoms in young children (1-8 years) following earthquake.