La personalidad premórbida como factor de riesgo en la aparición de síntomas psicológicos y conductuales de la demencia: revisión sistemática

The aetiology of behavioural and psychological symptoms of dementia (BPSD) is defined by a diversity of factors, and recent studies suggest that premorbid personality could be a risk factor for BPSD. This study aimed to review studies on the relationship between premorbid personality and BPSD.Studies were identified using PsycInfo, MedLine, and PubMed. The searches combined terms for premorbid personality, dementia and BPSD. Ten studies have been included in this review.Eight out of ten studies show a relationship between premorbid personality and BPSD. Neuroticism is associated with behavioural disturbances and anxiety. Extraversion is associated with wandering. Low agreeableness is associated with affective disturbance and aggression-related behaviours and high agreeableness is associated with wandering. The studies found no congruent results for openness and conscientiousness.In conclusion, premorbid personality may increase the risk of developing BPSD during the course of the disease. Even so, the relationship between personality and BPSD is complex due to multifactorial aetiology.     

The fine-scale and complex architecture of human copy-number variation

Despite considerable excitement over the potential functional significance of copy-number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at approximately 1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1020 of 1153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of currently known common human CNVs is likely smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with interindividual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously uncharacterized complexity.     

Thyroglobulin peptides associate in vivo to HLA-DR in autoimmune thyroid glands

Endocrine epithelial cells, targets of the autoimmune response in thyroid and other organ-specific autoimmune diseases, express HLA class II (HLA-II) molecules that are presumably involved in the maintenance and regulation of the in situ autoimmune response. HLA-II molecules thus expressed by thyroid cells have the "compact" conformation and are therefore expected to stably bind autologous peptides. Using a new approach to study in situ T cell responses without the characterization of self-reactive T cells and their specificity, we have identified natural HLA-DR-associated peptides in autoimmune organs that will allow finding peptide-specific T cells in situ. This study reports a first analysis of HLA-DR natural ligands from ex vivo Graves' disease-affected thyroid tissue. Using mass spectrometry, we identified 162 autologous peptides from HLA-DR-expressing cells, including thyroid follicular cells, with some corresponding to predominant molecules of the thyroid colloid. Most interestingly, eight of the peptides were derived from a major autoantigen, thyroglobulin. In vitro binding identified HLA-DR3 as the allele to which one of these peptides likely associates in vivo. Computer modeling and bioinformatics analysis suggested other HLA-DR alleles for binding of other thyroglobulin peptides. Our data demonstrate that although the HLA-DR-associated peptide pool in autoimmune tissue mostly belongs to abundant ubiquitous proteins, peptides from autoantigens are also associated to HLA-DR in vivo and therefore may well be involved in the maintenance and the regulation of the autoimmune response.     

Benthic foraminiferal turnover across the Cretaceous/Paleogene boundary at Agost (southeastern Spain): paleoenvironmental inferences

We studied Upper Cretaceous and Lower Paleogene benthic foraminifera from the Agost section (southeastern Spain) to infer paleobathymetrical changes and paleoenvironmental turnover across the Cretaceous/Paleogene (K/P) transition. Benthic foraminifera indicate uppermost bathyal depths at Agost during the Abathomphalus mayaroensis Biochron (from about 400 kyr before the K/P boundary) through the early Plummerita hantkeninoides Biochron (about 120–150 kyr before that boundary). The depth increased to middle bathyal for the remainder of the Cretaceous, and remained so for the Danian part of the studied section (Parasubbotina pseudobulloides Biochron, at least 200 kyr after the K/P boundary). There were no perceivable bathymetrical changes at the K/P boundary, where 5% of the species became extinct, and the species composition of the benthic foraminiferal fauna changed considerably. Below the boundary, infaunal morphogroups constitute up to 65–73% of the faunas. Directly above the boundary, in the black clays of the lower Guembelitria cretacea Biozone, benthic foraminifera are rare. Several opportunistic taxa (e.g. the agglutinant Haplophragmoides sp.) have short peaks in relative abundance, possibly reflecting low-oxygen conditions as well as environmental instability, with benthos receiving food from short-lived, local blooms of primary producers. Above the clays through the end of the studied interval, epifaunal morphogroups dominate (up to 70% of the assemblages) or there is an even mixture or epifaunal and infaunal morphogroups. Infaunal groups do not recover to pre-extinction relative abundances, indicating that the food supply to the benthos did not recover fully over the studied interval (about 200 kyr after the K/P boundary). The benthic foraminiferal faunal changes are compatible with the direct and indirect effects of an asteroid impact, which severely destabilized primary producers and the oceanic food web that was dependent upon them.     

Role of CXCR4/SDF-1α in the migratory phenotype of hepatoma cells that have undergone epithelial–mesenchymal transition in response to the transforming growth factor-β

Treatment of FaO rat hepatoma cells with TGF-β selects cells that survive to its apoptotic effect and undergo epithelial–mesenchymal transitions (EMT). We have established a cell line (TβT-FaO, from TGF-β-treated FaO) that shows a mesenchymal, de-differentiated, phenotype in the presence of TGF-β and is refractory to its suppressor effects. In the absence of this cytokine, cells revert to an epithelial phenotype in 3–4 weeks and recover the response to TGF-β. TβT-FaO show higher capacity to migrate than that observed in the parental FaO cells. We found that FaO cells express low levels of CXCR4 and do not respond to SDF-1α. However, TGF-β up-regulates CXCR4, through a NFkappaB-dependent mechanism, and TβT-FaO cells show elevated levels of CXCR4, which is located in the presumptive migration front. A specific CXCR4 antagonist (AMD3100) attenuates the migratory capacity of TβT-FaO cells on collagen gels. Extracellular SDF-1α activates the ERKs pathway in TβT-FaO, but not in FaO cells, increasing cell scattering and protecting cells from apoptosis induced by serum deprivation. Targeted knock-down of CXCR4 with specific siRNA blocks the TβT-FaO response to SDF-1α. Thus, the SDF-1/CXCR4 axis might play an important role in mediating cell migration and survival after a TGF-β-induced EMT in hepatoma cells.     

Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

Background

Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.

Methodology/Principal Findings

We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1–1.7]; P = 0.05).

Conclusions/Significance

Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00883480","term_id":"NCT00883480"}}NCT00883480     

Nonannual tree rings in a climate‐sensitive Prioria copaifera chronology in the Atrato River,Colombia

In temperate climates, tree growth dormancy usually ensures the annual nature of tree rings, but in tropical environments, determination of annual periodicity can be more complex. The purposes of the work are as follows: (1) to generate a reliable tree‐ring width chronology for Prioria copaifera Griseb. (Leguminoceae), a tropical tree species dwelling in the Atrato River floodplains, Colombia; (2) to assess the climate signal recorded by the tree‐ring records; and (3) to validate the annual periodicity of the tree rings using independent methods. We used standard dendrochronological procedures to generate the P. copaifera tree‐ring chronology. We used Pearson correlations to evaluate the relationship of the chronology with the meteorological records, climate regional indices, and gridded precipitation/sea surface temperature products. We also evaluated 24 high‐precision ¹⁴C measurements spread over a range of preselected tree rings, with assigned calendar years by dendrochronological techniques, before and after the bomb spike in order to validate the annual nature of the tree rings. The tree‐ring width chronology was statistically reliable, and it correlated significantly with local records of annual and October–December (OND) streamflow and precipitation across the upper river watershed (positive), and OND temperature (negative). It was also significantly related to the Oceanic Niño Index, Pacific Decadal Oscillation, and the Southern Oscillation Index, as well as sea surface temperatures over the Caribbean and the Pacific region. However, ¹⁴C high‐precision measurements over the tree rings demonstrated offsets of up to 40 years that indicate that P. copaifera can produce more than one ring in certain years. Results derived from the strongest climate–growth relationship during the most recent years of the record suggest that the climatic signal reported may be due to the presence of annual rings in some of those trees in recent years. Our study alerts about the risk of applying dendrochronology in species with challenging anatomical features defining tree rings, commonly found in the tropics, without an independent validation of annual periodicity of tree rings. High‐precision ¹⁴C measurements in multiple trees are a useful method to validate the identification of annual tree rings.     

Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance

Sirtuin 2 (SIRT2) is a member of a family of NAD⁺‐dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle‐aged, 13‐month‐old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice. In addition, these Sirt2^?/? mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT2 in orchestrating its metabolic regulation. This underscores the value of SIRT2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis.     

An HP1 isoform-specific feedback mechanism regulates Suv39h1 activity under stress conditions

The presence of H3K9me3 and heterochromatin protein 1 (HP1) are hallmarks of heterochromatin conserved in eukaryotes. The spreading and maintenance of H3K9me3 is effected by the functional interplay between the H3K9me3-specific histone methyltransferase Suv39h1 and HP1. This interplay is complex in mammals because the three HP1 isoforms, HP1α, β, and γ, are thought to play a redundant role in Suv39h1-dependent deposition of H3K9me3 in pericentric heterochromatin (PCH). Here, we demonstrate that despite this redundancy, HP1α and, to a lesser extent, HP1γ have a closer functional link to Suv39h1, compared to HP1β. HP1α and γ preferentially interact in vivo with Suv39h1, regulate its dynamics in heterochromatin, and increase Suv39h1 protein stability through an inhibition of MDM2-dependent Suv39h1-K87 polyubiquitination. The reverse is also observed, where Suv39h1 increases HP1α stability compared HP1β and γ. The interplay between Suv39h1 and HP1 isoforms appears to be relevant under genotoxic stress. Specifically, loss of HP1α and γ isoforms inhibits the upregulation of Suv39h1 and H3K9me3 that is observed under stress conditions. Reciprocally, Suv39h1 deficiency abrogates stress-dependent upregulation of HP1α and γ, and enhances HP1β levels. Our work defines a specific role for HP1 isoforms in regulating Suv39h1 function under stress via a feedback mechanism that likely regulates heterochromatin formation.