The rockefeller university

We perform molecular dynamics simulations to study the effect of charged surfaces on the intermediate and long time dynamics of water in nanoconfinements. Here, we use the transferable interaction potential with five points (TIP5P) model of a water molecule confined in both hydrophobic and charged surfaces. For a single molecular layer of water between the surfaces, we find that the temperature dependence of the lateral diffusion constant of water up to very high temperatures remains Arrhenius with a high activation energy. In case of charged surfaces, however, the dynamics of water in the intermediate time regime is drastically modified presumably due to the transient coupling of dipoles of water molecules with electric field fluctuations induced by charges on the confining surfaces. Specifically, the lateral mean square displacements display a distinct super-diffusive behavior at intermediate time scale, defined as the time scale between ballistic and diffusive regimes. This change in the intermediate time-scale dynamics in the charged confinement leads to the enhancement of long-time dynamics as reflected in increasing diffusion constant. We introduce a simple model for a possible explanation of the super-diffusive behavior and find it to be in good agreement with our simulation results. Furthermore, we find that confinement and the surface polarity enhance the low frequency vibration in confinement compared to bulk water. By introducing a new effective length scale of coupling between translational and orientational motions, we find that the length scale increases with the increasing strength of the surface polarity. Further, we calculate the correlation between the diffusion constant and the excess entropy and find a disordering effect of polar surfaces on the structure of water. Finally, we find that the empirical relation between the diffusion constant and the excess entropy holds for a monolayer of water in nanoconfinement.

TRAAK channels, members of the two-pore domain K+ (potassium ion) channel family K2P, are expressed almost exclusively in the nervous system and control the resting membrane potential. Their gating is sensitive to polyunsaturated fatty acids, mechanical deformation of the membrane, and temperature changes. Physiologically, these channels appear to control the noxious input threshold for temperature and pressure sensitivity in dorsal root ganglia neurons. We present the crystal structure of human TRAAK at a resolution of 3.8 angstroms. The channel comprises two protomers, each containing two distinct pore domains, which create a two-fold symmetric K+ channel. The extracellular surface features a helical cap, 35 angstroms tall, that creates a bifurcated pore entryway and accounts for the insensitivity of two-pore domain K+ channels to inhibitory toxins. Two diagonally opposed gate-forming inner helices form membrane-interacting structures that may underlie this channel's sensitivity to chemical and mechanical properties of the cell membrane.

Introduction: Given their relative simplicity of manufacture and ability to be injected repeatedly, vaccines in a protein format are attractive for breast and other cancers. However, soluble human epidermal growth factor receptor (HER2)/neu protein as a vaccine has not been immunogenic. When protein is directly targeted to antigen uptake receptors, such as DEC205 (DEC), efficient processing and presentation of antigen take place. The aim of this study was to determine the immunogenicity of a HER2 protein vaccine that directly targets to DEC+ dendritic cells (DCs) in a mouse breast cancer model. Methods: We genetically engineered the HER2 extracellular domain into a monoclonal antibody specific for DEC (DEC-HER2). Mice of various genetic backgrounds were immunized with DEC-HER2 in combination with DC maturation stimuli (poly IC +/- CD40 Ab). Vaccine-induced T cell immunity was determined by analyzing the ability of CD4(+)/CD8(+) T cell to produce interferon (IFN)-gamma and proliferate upon antigen rechallenge. Sera were assessed for the presence of antigen specific antibody (Ab). For vaccine efficacy, FVB/N mice were immunized with DEC-HER2 in combination with poly IC and protection against neu-expressing mammary tumors was assessed. Protection mechanisms and tumor-specific T cell responses were also evaluated. Results: We demonstrate that DEC-HER2 fusion mAb, but not Ctrl Ig-HER2, elicits strong, broad and multifunctional CD4(+) T cell immunity, CD8(+) T cell responses, and humoral immunity specific for HER2 antigen. Cross-reactivity to rat neu protein was also observed. Importantly, mice xeno-primed with DEC-HER2 were protected from a neu-expressing mammary tumor challenge. Both CD4(+) and CD8(+) T cells mediated the tumor protection. Robust antitumor T cell immunity was detected in tumor protected mice. Conclusions: Immunization of mice with HER2 protein vaccine targeting DEC+ DCs in vivo induced high levels of T- and B-cell immunity. Non-targeted HER2 protein was poorly immunogenic for CD4(+) and CD8(+) T cells. This vaccination approach provided long-term survival benefit for mice challenged with neu-expressing tumor following as little as 2.7 mu g of HER2 protein incorporated in the vaccine. Vaccine-induced CD4(+) and CD8(+) T cells were both essential for tumor protection. This immunization strategy demonstrates great potential towards the development of vaccines for breast cancer patients.

A search for a narrow Higgs boson resonance in the diphoton mass spectrum is presented based on data corresponding to 7.0 fb(-1) of integrated luminosity from p (p) over bar collisions at root s = 1: 96 TeV collected by the CDF experiment. No evidence of such a resonance is observed, and upper limits are set on the cross section times branching ratio of the resonant state as a function of Higgs boson mass. The limits are interpreted in the context of the standard model and one fermiophobic benchmark model where the data exclude fermiophobic Higgs bosons with masses below 114 GeV/c(2) at a 95% Bayesian credibility level.

A search is performed for heavy particle pairs produced in root s = 7 TeV proton-proton collisions with 35 pb(-1) of data collected by the CMS experiment at the LHC. The search is sensitive to squarks and gluinos of generic supersymmetry models, provided they are kinematically accessible, with minimal assumptions on properties of the lightest superpartner particle. The kinematic consistency of the selected events is tested against the hypothesis of heavy particle pair production using the dimensionless razor variable R, related to the missing transverse energy E(T)(miss). The new physics signal is characterized by a broad peak in the distribution of M(R), an event-by-event indicator of the heavy particle mass scale. This new approach is complementary to E(T)(miss)-based searches. After background modeling based on data, and background rejection based on R and M(R), no significant excess of events is found beyond the standard model expectations. The results are interpreted in the context of the constrained minimal supersymmetric standard model as well as two simplified supersymmetry models.

Total internal reflection fluorescence (TIRF) microscopy is a high-contrast imaging technique suitable for observing biological events that occur on or near the cell membrane. The improved contrast is accomplished by restricting the thickness of the excitation field to over an order of a magnitude narrower than the z-resolution of an epi-fluorescence microscope. This technique also increases signal-to-noise, making it a valuable tool for imaging cellular events such as vesicles undergoing exocytosis or endocytosis, viral particle formation, cell signaling, and dynamics of membrane proteins. This protocol describes the basic procedures for setting up a through-the-objective TIRF illuminator and a prism-based TIRF illuminator. In addition, an alternate protocol for incorporating an automated deflection system into through-the-objective TIRF is given. This system can be used to decrease aberrations in the illumination field, to quickly switch between epi- and TIRF illumination, and to adjust the penetration depth during multicolor TIRF applications. In the commentary, a description of the total internal reflection phenomenon is given, critical parameters of a TIRF microscope are discussed, and technical challenges and considerations are reviewed.

We describe here a girl who was vaccinated at birth with BCG (Bacillus Calmette-Guerin) vaccine according to national immunization schedule in Poland. After the age of 2.5 m.o., she developed disseminated BCG infection. Primary immunodeficiencies (PID), such as severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), hyper IgM syndrome (HIGM), hyper IgE syndrome (HIES) were excluded. The diagnostic tests exploring IFN-gamma/IL-12 axis were performed. The 818del4, the most common basis of IFNGR1 deficiency was found.

Dendritic cells are professional antigen presenting cells linking the innate and the adaptive immune system. Antibody mediated antigen delivery to functionally distinct DC subpopulatdons is a promising approach to induce or inhibit antigen specific immune responses in vivo and is useful for designing therapeutic vaccination strategies. This review focuses on the state of the art of this technique and describes recent findings of antigen targeting to the subpopulation of plasmacytoid dendritic cells and the possibilities to induce immunity or attenuate autoimmunity by delivering antigens specifically to this cell type.

Cognitive and olfactory deficits occur in schizophrenia, but little is known whether sex modifies these deficits. We examined the relationship between olfaction and cognition in 55 schizophrenia patients and 32 healthy controls. Patients and controls demonstrated significant differences performing cognitive tasks. In patients, sex modified all relationships of odor identification to cognition. Female patients showed significantly stronger trends than male patients correlating better smell identification with higher scores on intelligence, memory, and attention, whereas their correlations of odor identification with executive functioning contradicted those of male patients. Odor acuity significantly correlated with several cognitive measures, especially in male patients, in whom better acuity was generally associated with better cognition. Female patients again differed significantly from males; odor acuity correlations with cognitive measures were weaker, or contradicted, those of male patients. These findings indicate significant sex differences in olfactory processing in schizophrenia. Combining the sexes in research analyses may obscure important differences. (The Journal of Neuropsychiatry and Clinical Neurosciences 2012; 24:165-175)