A method for determining venous contribution to BOLD contrast sensory activation

While BOLD contrast reflects haemodynamic changes within capillaries serving neural tissue, it also has a venous component. Studies that have determined the relation of large blood vessels to the activation map indicate that veins are the source of the largest response, and the most delayed in time. It would be informative if the location of these large veins could be extracted from the properties of the functional responses, since vessels are not visible in BOLD contrast images. The present study describes a method for investigating whether measures taken from the functional response can reliably predict vein location, or at least be useful in down-weighting the venous contribution to the activation response, and illustrates this method using data from one subject. We combined fMRI at 3 Tesla with high-resolution anatomical imaging and MR venography to test whether the intrinsic properties of activation time courses corresponded to tissue type. Measures were taken from a gamma fit to the functional response. Mean magnitude showed a significant effect of tissue type (P veins ≈ grey matter > white matter. Mean delays displayed the same ranking across tissue types (P grey matter. However, measures for all tissue types were distributed across an overlapping range. A logistic regression model correctly discriminated 72% of the veins from grey matter in the absence of independent information of macroscopic vessels (ROC=0.72). Whilst tissue classification was not perfect for this subject, weighting the T contrast by the predicted probabilities materially reduced the venous component to the activation map

Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo

Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

Optimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-α +/- IFN-α) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-α, (iii) association between circulating T regulatory cells (Tregs) and clinical responses

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Peer reviewe

Republicanos y la Comunidad de Peruanos: Comunidades políticas inimaginadas en el Perú postcolonial.

No presenta resumen

’Republicanos’ y ’la Comunidad de Peruanos’: Comunidades políticas inimaginadas en el Perú postcolonial

El presente artículo propone formular dos preguntas relativamente simples, las que contestadas a nivel microhistórico, cuestionan nociones macrohistóricas recibidas sobre la ’historia republicana’ peruana. Primero, ¿qué es lo que se entendía por ’republicanos’ en 1818, 1846, o 1886? Y segundo, ¿cómo sonaba el neologismo sanmartiniano de ’peruanos’ en los oídos andinos postcoloniales? Estas pequeñas preguntas nos ayudan a interrogar una cuestión mayor que sigue acosando a la nebulosa historiog..