Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes.

BackgroundThe major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status.ResultsSomatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients' respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity.ConclusionsOur findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I

Characterizing mixed mode oscillations shaped by noise and bifurcation structure

Many neuronal systems and models display a certain class of mixed mode oscillations (MMOs) consisting of periods of small amplitude oscillations interspersed with spikes. Various models with different underlying mechanisms have been proposed to generate this type of behavior. Stochastic versions of these models can produce similarly looking time series, often with noise-driven mechanisms different from those of the deterministic models. We present a suite of measures which, when applied to the time series, serves to distinguish models and classify routes to producing MMOs, such as noise-induced oscillations or delay bifurcation. By focusing on the subthreshold oscillations, we analyze the interspike interval density, trends in the amplitude and a coherence measure. We develop these measures on a biophysical model for stellate cells and a phenomenological FitzHugh-Nagumo-type model and apply them on related models. The analysis highlights the influence of model parameters and reset and return mechanisms in the context of a novel approach using noise level to distinguish model types and MMO mechanisms. Ultimately, we indicate how the suite of measures can be applied to experimental time series to reveal the underlying dynamical structure, while exploiting either the intrinsic noise of the system or tunable extrinsic noise.Comment: 22 page

Evaluación de la estereognosia oral en pacientes completamente edéntulos con toros palatinos.

Background: The corollary is not investigated in the completely edentulous patients with palatal tori. Objective: The aim of this study was to assess the oral stereognostic ability in completely edentulous patients with palatal tori. Material and Methods: Thirty-four completely edentulous patients aged 50 to 89 years were allocated to Group 1 (without palatal tori, n=18) and Group 2 (with palatal tori, n=16). The oral stereognostic test was conducted using 6 intraoral test pieces (circle/square/rectangle/triangle/plus/toroid) that were fabricated to standard dimensions using the light cure acrylic resin. Each test piece was placed in the patient’s mouth and was asked to manipulate the test piece between the tongue and the palate. The patients identified the shapes by matching them on a shape chart. Each correct identification was assigned a score of 1. The response time taken to identify each shape was recorded. Statistical computation was done using a chi - square test and Mann-Whitney U test. Results: Significant difference was observed in the overall scoring percentages between the 2 groups (p<0.05). Group 2 had lower oral stereognostic scores compared to group 1 (p<0.05). There was no statistically significant difference in the mean response time for identifying the shapes among the groups, however group 2 patients had longer response time. Conclusion: Oral stereognostic ability of the completely edentulous patients with torus palatinus was lower when compared to completely edentulous patients without tori.Antecedentes: el corolario no se investiga en los pacientes completamente desdentados con toros palatinos. Objetivo: El objetivo de este estudio fue evaluar la capacidad estereognóstica oral en pacientes completamente edéntulos con toros palatinos. Material y Métodos: Treinta y cuatro pacientes completamente edéntulos de 50 a 89 años fueron asignados al Grupo 1 (sin toros palatinos, n = 18) y al Grupo 2 (con toros palatinos, n = 16). La prueba estereognóstica oral se realizó utilizando 6 piezas de prueba intraorales (círculo / cuadrado / rectángulo / triángulo / cruz / aro) que se fabricaron a dimensiones estándar utilizando la resina acrílica fotopolimerizable. Cada pieza de prueba se colocó en la boca del paciente y se le pidió que manipulara la pieza de prueba entre la lengua y el paladar. Los pacientes identificaron las formas haciéndolas coincidir en un gráfico de formas. A cada identificación correcta se le asignó una puntuación de 1. Se registró el tiempo de respuesta necesario para identificar cada forma. El cálculo estadístico se realizó mediante la prueba de chi-cuadrado y la prueba U de Mann-Whitney.Resultados: Se observó una diferencia significativa en los porcentajes de puntuación generales entre los 2 grupos (p<0,05). El grupo 2 tuvo puntuaciones estereognósticas orales más bajas en comparación con el grupo 1 (p<0,05). No hubo diferencia estadísticamente significativa en el tiempo medio de respuesta para identificar las formas entre los grupos, sin embargo, los pacientes del grupo 2 tuvieron un tiempo de respuesta más largo.Conclusión: La capacidad estereognóstica oral de los pacientes completamente edéntulos con torus palatino fue menor en comparación con los pacientes completamente edéntulos sin torus

A Novel Method for Training Mice in Visuo-Tactile 3-D Object Discrimination and Recognition

Perceiving, recognizing and remembering 3-dimensional (3-D) objects encountered in the environment has a very high survival value; unsurprisingly, this ability is shared among many animal species, including humans. The psychological, psychophysical and neural basis for object perception, discrimination, recognition and memory has been extensively studied in humans, monkeys, pigeons and rodents, but is still far from understood. Nearly all 3-D object recognition studies in the rodent used the “novel object recognition” paradigm, which relies on innate rather than learned behavior; however, this procedure has several important limitations. Recently, investigators have begun to recognize the power of behavioral tasks learned through reinforcement training (operant conditioning) to reveal the sensorimotor and cognitive abilities of mice and to elucidate their underlying neural mechanisms. Here, we describe a novel method for training and testing mice in visual and tactile object discrimination, recognition and memory, and use it to begin to examine the underlying sensory basis for these cognitive capacities. A custom-designed Y maze was used to train mice to associate one of two 3-D objects with a food reward. Out of nine mice trained in two cohorts, seven reached performance criterion in about 20–35 daily sessions of 20 trials each. The learned association was retained, or rapidly re-acquired, after a 6 weeks hiatus in training. When tested under low light conditions, individual animals differed in the degree to which they used tactile or visual cues to identify the objects. Switching to total darkness resulted only in a transient dip in performance, as did subsequent trimming of all large whiskers (macrovibrissae). Additional removal of the small whiskers (microvibrissae) did not degrade performance, but transiently increased the time spent inspecting the object. This novel method can be combined in future studies with the large arsenal of genetic tools available in the mouse, to elucidate the neural basis of object perception, recognition and memory

Understanding the hydrological response of a headwater-dominated catchment by analysis of distributed surface–subsurface interactions

We computationally explore the relationship between surface–subsurface exchange and hydrological response in a headwater-dominated high elevation, mountainous catchment in East River Watershed, Colorado, USA. In order to isolate the effect of surface–subsurface exchange on the hydrological response, we compare three model variations that differ only in soil permeability. Traditional methods of hydrograph analysis that have been developed for headwater catchments may fail to properly characterize catchments, where catchment response is tightly coupled to headwater inflow. Analyzing the spatially distributed hydrological response of such catchments gives additional information on the catchment functioning. Thus, we compute hydrographs, hydrological indices, and spatio-temporal distributions of hydrological variables. The indices and distributions are then linked to the hydrograph at the outlet of the catchment. Our results show that changes in the surface–subsurface exchange fluxes trigger different flow regimes, connectivity dynamics, and runoff generation mechanisms inside the catchment, and hence, affect the distributed hydrological response. Further, changes in surface–subsurface exchange rates lead to a nonlinear change in the degree of connectivity—quantified through the number of disconnected clusters of ponding water—in the catchment. Although the runoff formation in the catchment changes significantly, these changes do not significantly alter the aggregated streamflow hydrograph. This hints at a crucial gap in our ability to infer catchment function from aggregated signatures. We show that while these changes in distributed hydrological response may not always be observable through aggregated hydrological signatures, they can be quantified through the use of indices of connectivity

Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution

The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ∼43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. Here, we used a well-characterized nonimmune human Ab-phage library and a panning strategy with proteoliposomes and cells to identify seven human nAbs against the receptor-binding domain (RBD) of the MERS-CoV Spike protein. These nAbs bind to three different epitopes in the RBD and human dipeptidyl peptidase 4 (hDPP4) interface with subnanomolar/nanomolar binding affinities and block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Escape mutant assays identified five amino acid residues that are critical for neutralization escape. Despite the close proximity of the three epitopes on the RBD interface, escape from one epitope did not have a major impact on neutralization with Abs directed to a different epitope. Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers

Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

SummaryNonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D

Biomass Burning Plumes in the Vicinity of the California Coast: Airborne Characterization of Physicochemical Properties, Heating Rates, and Spatiotemporal Features

This study characterizes in situ airborne properties associated with biomass burning (BB) plumes in the vicinity of the California coast. Out of 231 total aircraft soundings in July–August 2013 and 2016, 81 were impacted by BB layers. A number of vertical characteristics of BB layers are summarized in this work (altitude, location relative to cloud top height, thickness, number of vertically adjacent layers, interlayer distances) in addition to differences in vertical aerosol concentration profiles due to either surface type (e.g., land or ocean) or time of day. Significant BB layer stratification occurred, especially over ocean versus land, with the majority of layers in the free troposphere and within 100 m of the boundary layer top. Heating rate profiles demonstrated the combined effect of cloud and BB layers and their mutual interactions, with enhanced heating in BB layers with clouds present underneath. Aerosol size distribution data are summarized below and above the boundary layer, with a notable finding being enhanced concentrations of supermicrometer particles in BB conditions. A plume aging case study revealed the dominance of organics in the free troposphere, with secondary production of inorganic and organic species and coagulation as a function of distance from fire source up to 450 km. Rather than higher horizontal and vertical resolution, a new smoke injection height method was the source of improved agreement for the vertical distribution of BB aerosol in the Navy Aerosol Analysis and Prediction System model when compared to airborne data