HLA and cancer: from research to clinical impact

The identification of different mechanisms by which tumours escape from the immune system have helped to judge the clinical relevance of several phenotypic changes that occur during tumour development. As discussed at a recent meeting³, changes in HLA class I expression play a leading role in the tumour–host scenario.     

The pivotal role of carbonic anhydrase in malaria infection

Carbon dioxide (CO₂) is essential for the growth of intraerythrocytic malaria parasites to synthesize pyrimidine through CO₂ fixation and to regulate intracellular pH. CO₂ transport across the plasma membrane of erythrocytes is facilitated by carbonic anhydrase (CA). With the use of electron microscopy and CA-specific Hansson's stain, CA is found also in all the intraerythrocytic stages of Plasmodium falciparum. When CA inhibitors, including acetazolamide, potassium iodide, and sodium deoxycholate, were added to continuous culture of P. falciparum, they, particularly sodium deoxycholate, produced a marked reduction in parasitemia. These results explain the biochemical basis of some of the clinical conditions associated with malaria and strongly suggest that CA inhibitors have potential as a new class of antimalarials.     

TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration

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Dendritic cell type 3 arises from Ly6C+ monocyte-dendritic cell progenitors

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Associations of DNA Methylation With Behavioral Problems,Gray Matter Volumes,and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study

BackgroundNegative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.MethodsTo identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.ResultsNo significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10^?8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.ConclusionsOur findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.