Lineage fate of ductular reactions in liver injury and carcinogenesis

Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.     

Transient elastography in DAA era. Relation between post‐SVR LSM and histology

The natural history of HCV chronic infection has drastically changed after direct‐acting antiviral treatment. Due to the high sustained virological response (SVR) achieved, noninvasive estimation of liver fibrosis regression has become a major key point. The present study tries to evaluate the relation between liver histology and liver stiffness measurement (LSM) by transient elastography (TE) after SVR.     

Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives

In this work, a novel series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated in vitro on Trypanosoma cruzi trypomastigotes and Leishmania mexicana promastigotes, and cytotoxicity activity in murine macrophages was tested. In silico molecular docking simulations of trypanothione reductase were also done. Three compounds of 33 quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better anti-T. cruzi activity than nifurtimox and beznidazole; two compounds had better anti-leishmanial activity that amphotericin-B, and two compounds showed better activity against both parasites than reference drugs. Compounds M2, M7, M8 and E5, showed low cytotoxic activity on the host cell. The in silico studies suggest that compound M2 is a potential trypanothione reductase inhibitor.     

Complex Deregulation and Expression of Cytokines and Mediators of the Immune Response in Parkinson's Disease Brain is Region Dependent

Neuroinflammation is common in neurodegenerative diseases including Parkinson disease (PD). Expression of 25 mRNAs was assessed with TaqMan‐PCR including members of the complement system, colony stimulating factors, Toll family, cytokines IL‐8, IL‐6, IL‐6ST, IL‐1B, TNF‐α family, IL‐10, TGFβ family, cathepsins and integrin family, in the substantia nigra pars compacta, putamen, frontal cortex area 8 and angular gyrus area 39, in a total of 43 controls and 56 cases with PD‐related pathology covering stages 1–6 of Braak. Up‐regulation of IL‐6ST was the only change in the substantia nigra at stages 1–2. Down‐regulation of the majority of members examined occurred in the substantia nigra from stage 4 onwards. However, region‐dependent down‐ and up‐regulation of selected mRNAs occurred in the putamen and frontal cortex, whereas only mRNA up‐regulated mRNAs were identified in the angular cortex from stage 3 onwards in PD cases. Protein studies in frontal cortex revealed increased IL6 expression and reduced IL‐10 with ELISA, and increased IL‐6 with western blotting in PD. Immunohistochemistry revealed localization of IL‐5, IL‐6 and IL‐17 receptors in glial cells, mainly microglia; IL‐5, IL‐10 and M‐CSF in neurons; TNF‐α in neurons and microglia; and active NF‐κB in the nucleus of subpopulations of neurons and glial cells in PD. Distinct inflammatory responses, involving pro‐ and anti‐inflammatory cytokines, and variegated mediators of the immune response occur in different brain regions at the same time in particular individuals. Available information shows that altered α‐synuclein solubility and aggregation, Lewy body formation, oxidative damage and neuroinflammation converge in the pathogenesis of PD.     

Interstitial 13q14 deletions detected in the karyotype and translocations with concomitant deletion at 13q14 in chronic lymphocytic leukemia: Different genetic mechanisms but equivalent poorer clinical outcome

Deletion of 13q14 as the sole abnormality is a good prognostic marker in chronic lymphocytic leukemia (CLL). Nonetheless, the prognostic value of reciprocal 13q14 translocations [t(13q)] with related 13q losses has not been fully elucidated. We described clinical and biological characteristics of 25 CLL patients with t(13q), and compared with 62 patients carrying interstitial del(13q) by conventional G‐banding cytogenetics (CGC) [i‐del(13q)] and 295 patients with del(13q) only detected by fluorescence in situ hybridization (FISH) [F‐del(13q)]. Besides from the CLL FISH panel (D13S319, CEP12, ATM, TP53), we studied RB1 deletions in all t(13q) cases and a representative group of i‐del(13q) and F‐del(13q). We analyzed NOTCH1, SF3B1, and MYD88 mutations in t(13q) cases by Sanger sequencing. In all, 25 distinct t(13q) were described. All these cases showed D13S319 deletion while 32% also lost RB1. The median percentage of 13q‐deleted nuclei did not differ from i‐del(13q) patients (73% vs. 64%), but both were significantly higher than F‐del(13q) (52%, P < 0.001). Moreover, t(13q) patients showed an increased incidence of biallelic del(13q) (52% vs. 11.3% and 14.9%, P < 0.001) and higher rates of concomitant 17p deletion (37.5% vs. 8.6% and 7.2%, P < 0.001). RB1 involvement was significantly higher in the i‐del(13q) group (79%, P < 0.001). Two t(13q) patients (11.8%) carried NOTCH1 mutations. Time to first treatment in t(13q) and i‐del(13q) was shorter than F‐del(13q) (67, 44, and 137 months, P = 0.029), and preserved significance in the multivariate analysis. In conclusion, t(13q) and del(13q) patients detected by CGC constitute a subgroup within the 13q‐deleted CLL patients associated with a worse clinical outcome. © 2014 Wiley Periodicals, Inc.     

Neuroticism and impulsivity: Their hierarchical organization in the personality characterization of drug-dependent patients from a decision tree learning perspective

Objective

Neuroticism and impulsivity are the personality variables most consistently associated with drug-dependent patients. To date, no data mining procedures have been applied to explore the differential role of personality variables in this population.

Methods

The personality profile of 336 drug-dependent patients was compared with that of a sample of community participants in the context of a decision tree learning approach using the Alternative Five Factor Model. The resulting discriminant model was cross-validated.

Results

Neuroticism and impulsivity were the most relevant variables in the resulting model, but their association appeared to be hierarchically organized. In the personality characterization of these patients, neuroticism became the main discriminant dimension, whereas impulsivity played a differential role, explained by means of an interaction effect. Decision tree learning models appear to be a heuristic theoretical and empirical approximation to the study of relevant variables, such as personality traits, in drug-dependency research.     

Heterogeneous networks do not promote cooperation when humans play a Prisoner's Dilemma

It is not fully understood why we cooperate with strangers on a daily basis. In an increasingly global world, where interaction networks and relationships between individuals are becoming more complex, different hypotheses have been put forward to explain the foundations of human cooperation on a large scale and to account for the true motivations that are behind this phenomenon. In this context, population structure has been suggested to foster cooperation in social dilemmas, but theoretical studies of this mechanism have yielded contradictory results so far; additionally, the issue lacks a proper experimental test in large systems. We have performed the largest experiments to date with humans playing a spatial Prisoner's Dilemma on a lattice and a scale-free network (1,229 subjects). We observed that the level of cooperation reached in both networks is the same, comparable with the level of cooperation of smaller networks or unstructured populations. We have also found that subjects respond to the cooperation that they observe in a reciprocal manner, being more likely to cooperate if, in the previous round, many of their neighbors and themselves did so, which implies that humans do not consider neighbors' payoffs when making their decisions in this dilemma but only their actions. Our results, which are in agreement with recent theoretical predictions based on this behavioral rule, suggest that population structure has little relevance as a cooperation promoter or inhibitor among humans.     

Aging increases mitochondrial DNA damage and oxidative stress in liver of rhesus monkeys

While the mechanisms of cellular aging remain controversial, a leading hypothesis is that mitochondrial oxidative stress and mitochondrial dysfunction play a critical role in this process. Here, we provide data in aging rhesus macaques supporting the hypothesis that increased oxidative stress is a major characteristic of aging and may be responsible for the age-associated increase in mitochondrial dysfunction. We measured mitochondrial DNA (mtDNA) damage by quantitative PCR in liver and peripheral blood mononuclear cells of young, middle age, and old monkeys and show that older monkeys have increases in the number of mtDNA lesions. There was a direct correlation between the amount of mtDNA lesions and age, supporting the role of mtDNA damage in the process of aging. Liver from older monkeys showed significant increases in lipid peroxidation, protein carbonylations and reduced antioxidant enzyme activity. Similarly, peripheral blood mononuclear cells from the middle age group showed increased levels in carbonylated proteins, indicative of high levels of oxidative stress. Together, these results suggest that the aging process is associated with defective mitochondria, where increased production of reactive oxygen species results in extensive damage at the mtDNA and protein levels. This study provides valuable data based on the rhesus macaque model further validating age-related mitochondrial functional decline with increasing age and suggesting that mtDNA damage might be a good biomarker of aging.