ROLE OF INHIBITION AND SPIKING VARIABILITY IN ORTHO- AND RETRONASAL OLFACTORY PROCESSING

Odor perception is the impetus for important animal behaviors, most pertinently for feeding, but also for mating and communication. There are two predominate modes of odor processing: odors pass through the front of nose (ortho) while inhaling and sniffing, or through the rear (retro) during exhalation and while eating and drinking. Despite the importance of olfaction for an animal’s well-being and specifically that ortho and retro naturally occur, it is unknown whether the modality (ortho versus retro) is transmitted to cortical brain regions, which could significantly instruct how odors are processed. Prior imaging studies show different brain activity for the two modes, even with identical odors. However, odors are first processed via coordinated spiking of neurons in the olfactory bulb (OB) before being relayed downstream to higher cortical regions. Thus, we investigate responses of mitral cells (MC), one of principle neurons in OB, to ortho and retro stimulus to elucidate how the OB processes and codes this information. We analyze our collected in vivo rat data to inform modeling of the OB circuitry and MC responses to both modes of olfaction. Our efforts show that the OB does indeed process odors differently and that the temporal profile of each stimulus route to the OB is crucial for distinguishing ortho and retro odors. Additionally, we detail the rich spiking dynamics observed in our MC model and use a phenomenological model to explain the unexpected non-monotonic spike variability observed as weak-to-moderate background noise increases. Lastly in both anesthetized and awake rodents, we show that MCs with synaptic connections to cortical regions reliably transmit ortho versus retro input stimulus information. Drug manipulation affecting GABAA-mediated synaptic inhibition leads to changes in decoding of ortho/retro and only affects firing response for one of the two modes. We have not only shown that ortho versus retro information is encoded to downstream brain regions, but with models and analysis, we uncover the network dynamics that promote this encoding

Eigenvectors of Interpoint Distance Matrices

In this paper, the eigenvectors of interpoint distance matrices will be discussed. When plotted against each other, the eigenvectors of the distance matrix of evenly spaced points in one dimension produce some interesting patterns. An explanation and description of the patterns will be discussed. After examining many aspects of the general Euclidean interpoint distance matrix of order N, D, as well as characteristics of the eigenvectors themselves,some conclusions can be made. Furthermore, research revealed a similarity between our matrices, D, and the Discrete Cosine Transform Matrix, DCT-2. This research led to additional conclusion about our matrices D and allowed for a classification of the patterns within the graphs of the eigenvectors

Spontaneous development of Epstein-Barr Virus associated human lymphomas in a prostate cancer xenograft program

Prostate cancer research is hampered by the lack of in vivo preclinical models that accurately reflect patient tumour biology and the clinical heterogeneity of human prostate cancer. To overcome these limitations we propagated and characterised a new collection of patient-derived prostate cancer xenografts. Tumour fragments from 147 unsupervised, surgical prostate samples were implanted subcutaneously into immunodeficient Rag2-/-γC-/- mice within 24 hours of surgery. Histologic and molecular characterisation of xenografts was compared with patient characteristics, including androgen-deprivation therapy, and exome sequencing. Xenografts were established from 47 of 147 (32%) implanted primary prostate cancers. Only 14% passaged successfully resulting in 20 stable lines; derived from 20 independent patient samples. Surprisingly, only three of the 20 lines (15%) were confirmed as prostate cancer; one line comprised of mouse stroma, and 16 were verified as human donor-derived lymphoid neoplasms. PCR for Epstein-Barr Virus (EBV) nuclear antigen, together with exome sequencing revealed that the lymphomas were exclusively EBV-associated. Genomic analysis determined that 14 of the 16 EBV+ lines had unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements, confirming their B-cell origin. We conclude that the generation of xenografts from tumour fragments can commonly result in B-cell lymphoma from patients carrying latent EBV. We recommend routine screening, of primary outgrowths, for latent EBV to avoid this phenomenon

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

A Novel Model of Asymptomatic Plasmodium Parasitemia That Recapitulates Elements of the Human Immune Response to Chronic Infection.

In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection

Association of diabetes with amnestic and nonamnestic mild cognitive impairment

BACKGROUND: Type 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)-related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex. METHODS: Participants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population-based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline. RESULTS: Over a median 4.0 years of follow-up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple-domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]). CONCLUSIONS: Diabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease

Blood and tissue pathology in persistently infected mice.

<p>(A) Hematocrit (mean + SEM) was measured on the indicated days (d) post infection (n = 3–5 mice per group, except n = 1 on day 352). Clearing, <i>Ifngr1</i>^<i>-/-</i> mice infected and treated with control antibody as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162132#pone.0162132.g001" target="_blank">Fig 1B</a>. Persistent, <i>Ifngr1</i>^<i>-/-</i> mice infected and treated with α-CD4 antibody as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162132#pone.0162132.g001" target="_blank">Fig 1B</a>. (B) Reticulocytes were enumerated as a percentage of total erythrocytes. 8 d.p.i., <i>Ifngr1</i>^<i>-/-</i> mice infected with <i>P</i>. <i>chabaudi</i> for 8 d. Each dot represents one mouse; means + SEM are shown. **, p < 0.01 by Kruskal-Wallis test with Dunn's post-test. n.s., not significant. (C) Mesenteric lymph nodes (arrows) in cleared and persistently infected mice, 331 d.p.i. (D) Spleens (top) and femurs (bottom) from representative mice, 331 d.p.i. (E) Tissues were excised from the indicated mice 331 d.p.i., processed, and stained with hemotoxylin and eosin. Asterisks mark representative B cell follicles in naive and cleared spleen sections.</p