The rockefeller university

Cognitive attention and perceptual saliency jointly govern our interaction with the environment. Yet, we still lack a universally accepted account of the interplay between attention and luminance contrast, a fundamental dimension of saliency. We measured the attentional modulation of V4 neurons' contrast response functions (CRFs) in awake, behaving macaque monkeys and applied a new approach that emphasizes the temporal dynamics of cell responses. We found that attention modulates CRFs via different gain mechanisms during subsequent epochs of visually driven activity: an early contrast-gain, strongly dependent on prestimulus activity changes (baseline shift); a time-limited stimulus-dependent multiplicative modulation, reaching its maximal expression around 150 ms after stimulus onset; and a late resurgence of contrast-gain modulation. Attention produced comparable time-dependent attentional gain changes on cells heterogeneously coding contrast, supporting the notion that the same circuits mediate attention mechanisms in V4 regardless of the form of contrast selectivity expressed by the given neuron. Surprisingly, attention was also sometimes capable of inducing radical transformations in the shape of CRFs. These findings offer important insights into the mechanisms that underlie contrast coding and attention in primate visual cortex and a new perspective on their interplay, one in which time becomes a fundamental factor. NEW & NOTEWORTHY We offer an innovative perspective on the interplay between attention and luminance contrast in macaque area V4, one in which time becomes a fundamental factor. We place emphasis on the temporal dynamics of attentional effects, pioneering the notion that attention modulates contrast response functions of V4 neurons via the sequential engagement of distinct gain mechanisms. These findings advance understanding of attentional influences on visual processing and help reconcile divergent results in the literature.

Humanized mouse models present an important tool for preclinical evaluation of new vaccines and therapeutics. Here we show the human variable repertoire of antibody sequences cloned from a previously described human immune system (HIS) mouse model that possesses functional human CD4 + T cells and B cells, namely HIS-CD4/B mice. We sequenced variable IgG genes from single memory B-cell and plasma-cell sorted from splenocytes or whole blood lymphocytes of HIS-CD4/B mice that were vaccinated with a human plasmodial antigen, a recombinant Plasmodiun falciparun circumsporozoite protein (rPfCSP). We demonstrate that rPfCSP immunization triggers a diverse B-cell IgG repertoire composed of various human VH family genes and distinct V(D)J recombinations that constitute diverse CDR3 sequences similar to humans, although low hypermutated sequences were generated. These results demonstrate the substantial genetic diversity of responding human B cells of HIS-CD4/B mice and their capacity to mount human IgG class-switched antibody response upon vaccination.

The binding of human IgG1 to human Fc gamma receptors (hFc gamma Rs) is highly sensitive to the presence of a single N-linked glycosylation site at asparagine 297 of the Fc, with deglycosylation resulting in a complete loss of hFc gamma R binding. Previously, we demonstrated that aglycosylated human IgG1 Fc variants can engage the human Fc gamma RII class of the low-affinity hFc gamma Rs, demonstrating that N-linked glycosylation of the Fc is not a strict requirement for hFc gamma R engagement. In the present study, we demonstrate that aglycosylated IgG variants can be engineered to productively engage with Fc gamma RIIIA, as well as the human Fc gamma RII subset. We also assess the biophysical properties and serum half-life of the aglycosylated IgG variants to measure stability. Aglycosylated constructs N297D/S298T (DTT)-K326I/A327Y/L328G (IYG) and N297D/S298A IYG optimally drove tumor cell phagocytosis. A mathematical model of phagocytosis suggests that hFc gamma R) and hFc gamma RIIIA dimers were the main drivers of phagocytosis. In vivo tumor control of B16F10 lung metastases further confirmed the variant DTT IYG to be the best at restoring wild-type-like properties in prevention of lung metastases. While deuterium incorporation was similar across most of the protein, several peptides within the CH2 domain of DTT IYG showed differential deuterium uptake in the peptide region of the FG loop as compared to the aglycosylated N297Q. Thus, in this study, we have found an aglycosylated variant that may effectively substitute for wild-type Fc. These aglycosylated variants have the potential to allow therapeutic antibodies to be produced in virtually any expression system and still maintain effector function. (C) 2017 Elsevier Ltd. All rights reserved.

The observation of the Y ( 4140) structure in B-+/- -> J/psi phi K-+/- decays produced in (p) over barp collisions at root s = 1.96 TeV is reported with a statistical significance greater than 5 standard deviations. A fit to the J/psi phi mass spectrum is performed assuming the presence of a Breit-Wigner resonance. The fit yields a signal of 19 +/- 6 (stat) +/- 3 (syst) resonance events, and resonance mass and width of 4143.4(-3.0)(+2.9) ( stat) +/- 0.6 (syst) MeV/c(2) and 15.3(-6.1)(+10.4) (stat) +/- 2.5 (syst) MeV/c(2), respectively. The parameters of this resonance-like structure are consistent with values reported from an earlier CDF analysis.

The photoproduction of isolated photons has been measured in diffractive events recorded by the ZEUS detector at HERA. Cross sections are evaluated in the photon transverse- energy and pseudorapidity ranges 5 < E-T(gamma) < 15 GeV and -0.7 < eta(gamma) < 0.9, inclusively, and also with a jet with transverse energy and pseudorapidity in the ranges 4 < E-T(jet) < 35 GeV and -1.5 0.9, where z(P)(meas) is the fraction of the longitudinal momentum of the colorless "Pomeron" exchange that is transferred to the photon- jet final state, giving evidence for direct Pomeron interactions.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressant drugs, but the cellular and molecular mechanisms by which their therapeutic action is initiated are poorly understood. Here we show that serotonin 5-HT1B receptors in cholecystokinin (CCK) inhibitory interneurons of the mammalian dentate gyrus (DG) initiate the therapeutic response to antidepressants. In these neurons, 5-HT1B receptors are expressed presynaptically, and their activation inhibits GABA release. Inhibition of GABA release from CCK neurons disinhibits parvalbumin (PV) interneurons and, as a consequence, reduces the neuronal activity of the granule cells. Finally, inhibition of CCK neurons mimics the antidepressant behavioral effects of SSRIs, suggesting that these cells may represent a novel cellular target for the development of fast-acting antidepressant drugs.

We present the Mesoscopic Membrane with Proteins (MesM-P) model, an extension of a previously developed elastic membrane model for mesoscale simulations of lipid membranes. MesM-P employs a discrete mesoscopic quasi-particle approach to model protein-facilitated shape and topology changes of the lipid membrane on length and time scales inaccessible to all-atom and quasimolecular coarse-grained molecular dynamics simulations. We investigate the ability of MesM-P to model the behavior of large lipid vesicles as a function of bound protein density. We find four distinct mechanisms for protein aggregation on the surface of the membrane, depending on membrane stiffness and protein spontaneous curvature. We also establish a connection between MesM-P and the results of higher resolution coarse-grained molecular dynamics simulations. Published by AIP Publishing.

It has been almost two decades since the discovery of mucosal-associated invariant T (MAIT)-cells. Several advances in the field have been made such as the discovery of the antimicrobial activity of MAIT-cells, the abundance of these cells in human mucosa and in liver and the discovery of ligands able to bind MR1 and activate MAIT-cells. MAIT-cells are a unique subset of innate-like T-cells that express a canonical T-cell receptor with the alpha chain containing hAV7S2 and AJ33 in humans (TCRV alpha 7.2J alpha 33) and respond to bacterial/fungus vitamin B2 metabolites by an MR1-dependent pathway. Indirect activation is also observed during chronic viral infections by and IL-12/IL-18 pathway. In this review, the mechanisms of activation, the timeline of MAIT-cell development in humans as well as their role in human infection are discussed. On the whole, we believe that harnessing the anti-microbial ability of MAIT-cells could contribute for the design of potent immunotherapies and vaccines against "hard-to-kill" infectious agents that remain as public health threats worldwide.

Presenilin 1 (PS1), the catalytic subunit of the gamma-secretase complex, cleaves beta CTF to produce A beta. We have shown that PS1 regulates A beta levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the.-secretase complex, selective phosphorylation of PS1 on Ser367 decreases A beta levels by increasing beta CTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates beta CTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8. Annexin A2 facilitates the binding of Vamp8 to the autophagosomal SNARE Syntaxin 17 to modulate the fusion of autophagosomes with lysosomes. Thus, PS1 phosphorylated at Ser367 has an antiamyloidogenic function, promoting autophagosome-lysosome fusion and increasing beta CTF degradation. Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer's disease.

Sickness in mammals can lead to cognition deficits, although the underlying mechanisms remain elusive. In a recent Nature Medicine article, Garreet al. (2017) report that sickness-induced cortical dendritic spine loss and impaired memory formation is mediated by CX3CR1(+) monocyte-derived TNF-alpha.