Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

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Modulation of an IDP binding mechanism and rates by helix propensity and non-native interactions: association of HIF1α with CBP

Intrinsically disordered proteins that acquire their three dimensional structures only upon binding to their targets are very important in cellular signal regulation. While experimental studies have been made on the structures of both bound (structured) and unbound (disordered) states, less is known about the actual folding-binding transition. Coarse grained simulations using native-centric (i.e. Gō) potentials have been particularly useful in addressing this problem, given the large search space for IDP binding, but have well-known deficiencies in reproducing the unfolded state structure and dynamics. Here, we investigate the interaction of HIF1α with CBP using a hierarchy of coarse-grained models, in each case matching the binding affinity at 300 K to the experimental value. Starting from a pure Gō-like model based on the native structure of the complex we go on to consider a more realistic model of helix propensity in the HIF1α, and finally the effect of non-native interactions between binding partners. We find structural disorder (i.e."fuzziness") in the bound state of HIF1α in all models which is supported by the results of atomistic simulations. Correcting the over-stabilized helices in the unbound state gives rise to a more cooperative folding-binding transition (destabilizing partially bound intermediates). Adding non-native contacts lowers the free energy barrier for binding to an almost barrierless scenario, leading to higher binding/unbinding rates relative to the other models, in better agreement with the near diffusion-limited binding rates measured experimentally. Transition state structures for the three models are highly disordered, supporting a fly-casting mechanism for binding.     

INTERCELLULAR ADHESIONS IN THE POLLEN-STIGMA SYSTEM: POLLEN CAPTURE,GRAIN BINDING,AND TUBE ATTACHMENTS

Four independent pollen-stigma binding forces are differentiated after pollen contacts stigmas of Brassica oleracea var. capitata. Identification is based on their different rates and sequence of appearance during gametophyte development; on their differential occurrence after compatible and incompatible pollinations; and on their different stabilities to NaOH and hexane. The first binding force develops most rapidly, begins seconds after pollen-stigma contact, is complete within minutes, occurs on compatible or incompatible papillae, and dissociates in methanol. A second slower binding reaction begins about 15 min after contact, continues for at least 90 min (when pollen tubes emerge), results in a binding structure termed the ocreatine, develops only on compatible papillae, and is dissociated by NaOH. A third attractive mechanism binds the tip of the emerging tube to a cuticle, is detected only on incompatible papillae, and is not dissociated by NaOH or methanol. Ocreatine formation and tube development beyond the emergence stage are prevented by the incompatibility response. A fourth attraction mechanism occurs between the surfaces of papilla and elongating tubes. Reviews of physical and biochemical evidence indicate that van der Waals forces and enzymatically mediated lipid polymerization are alternatives to agglutination as mechanisms for binding male gametophyte to papilla.     

Tatlockia micdadei (Pittsburgh pneumonia agent) growth kinetics may explain its infrequent isolation from water and the low prevalence of Pittsburgh pneumonia.

Sediment and indigenous microflora taken from water distribution systems has been shown to promote the survival of Legionella pneumophila. The effect of sediment and indigenous microflora on Tatlockia micdadei (Pittsburgh pneumonia agent, PPA) was evaluated by growth curve experiments. Symbiosis between PPA and environmental bacteria was demonstrated by satellitism experiments. Unlike L. pneumophila, the concentration of PPA remained stationary in test tube suspensions containing both microflora and sediment. The difference in the ecology between the two organisms may explain the infrequent environmental recovery of PPA and, ultimately, the epidemiologic differences between Legionnaires disease and Pittsburgh pneumonia.     

Effectiveness of handwashing agents in eliminating Staphylococcus aureus from gloved hands.

The recent emphasis on gloving has resulted in accounts of healthcare workers washing gloves instead of changing them. This study evaluated the efficacy of soap and three germicidal agents in decontaminating latex and vinyl medical gloves that were experimentally contaminated with Staphylococcus aureus. Gloves were tested for perforations before and after the glove-washing procedure. Results of this study demonstrated that contamination was reduced from the glove surfaces. Although the routine washing of gloved hands cannot be recommended, it may be carried out under limited circumstances.     

ENVIRONMENTAL FACTORS INFLUENCING THE DISTRIBUTION OF SOUTHERN RIGHT WHALES (EUBALAENA AUSTRALIS) ON THE SOUTH COAST OF SOUTH AFRICA I: BROAD SCALE PATTERNS

Aerial surveys over the last 32 yr have shown that the distribution of southern right whales Eubalaena australis along the south coast of South Africa is markedly discontinuous, but highly predictable. A GIS was used at a variety of scales to investigate whether this pattern was related to environmental characteristics. Whale distribution was analyzed as density per 20-min bin of longitude over two temporal and spatial scales, namely 15 bins for 32 yr, and a wider scale but shorter time period, 23 bins for 19 yr, as well as using three years of GPS accuracy data (15 bins) for finer scale analysis. Environmental factors tested were depth, distance from shore, sea floor slope, protection from swell, protection from wind, and shore type. The majority of whales were concentrated in areas that provided reasonable protection from open ocean swell and seasonal winds, and had sedimentary floors with gentle slopes. They generally avoided exposed rocky shorelines. Cow-calf pairs were found significantly closer to shore and in shallower water than unaccompanied whales, particularly off sandy beaches. Habitat choice at this time of year may be related both to energy conservation for calves and lactating females (calm sea conditions) and to protection of the new-born.