Sex-Driven Differences in the Effectiveness of Individualized Clinical Management of Alzheimer's Disease Risk.

BACKGROUND: The Comparative Effectiveness Dementia and Alzheimer's Registry (CEDAR) trial demonstrated that individualized, multi-domain interventions improved cognition and reduced the risk of Alzheimer's disease (AD). As biological sex is a significant risk factor for AD, it is essential to explore the differential effectiveness of targeted clinical interventions in women vs. men. METHODS: Patients were recruited from an Alzheimer's Prevention Clinic. Subjects with normal cognition, subjective cognitive decline, or asymptomatic preclinical AD were classified as "Prevention". Subjects with mild cognitive impairment due to AD or mild AD were classified as "Early Treatment." The primary outcome was the change from baseline to 18-months on the modified-Alzheimer's Prevention Cognitive Composite. Secondary outcomes included a cognitive aging composite, AD and cardiovascular (CV) risk scales, and serum biomarkers. Subjects who adhered to > 60% of recommendations in the CEDAR trial were included in this a priori sub-group analysis to examine whether individualized intervention effects were modified by sex (n=80). RESULTS: In the Prevention group, both women (p=0.0205) and men (p=0.0044) demonstrated improvements in cognition with no sex differences (p=0.5244). In the Early Treatment group, there were also no significant sex differences in cognition (p=0.3299). In the Prevention group, women demonstrated greater improvements in the Multi-Ethnic Study of Atherosclerosis risk score (MESA-RS) than men (difference=1.5, p=0.0013). Women in the Early Treatment group demonstrated greater improvements in CV Risk Factors, Aging and Incidence of Dementia (CAIDE) risk score (difference=2.3, p=0.0067), and the MESA-RS (difference=4.1, p<0.001). CONCLUSIONS: Individualized multi-domain interventions are equally effective at improving cognition in women and men. However, personally-tailored interventions led to greater improvements in calculated AD and CV risk, and CV blood biomarkers, in women compared to men. Future study in larger cohorts is necessary to further define sex differences in AD risk reduction in clinical practice.

Costly curiosity: People pay a price to resolve an uncertain gamble early.

Humans are inherently curious creatures, continuously seeking out information about future outcomes. Such advance information is often valuable, potentially allowing people to select better courses of action. In non-human animals, this drive for information can be so strong that they forego food or water to find out a few seconds earlier whether an uncertain option will provide a reward. Here, we assess whether people will exhibit a similar sub-optimal preference for advance information. Participants played a card-flipping task where they were probabilistically rewarded based on the pattern of 3 cards that were revealed after a 5-s delay. During this delay, participants could instead pay a cost to find out the next card's identity immediately. This choice to find out early did not influence the eventual outcome. Participants preferred to find out early about 80% of the time when the information was free; they were even willing to incur an expense to get advance information about the eventual outcome. The expected magnitude of the outcome, however, had little impact on the likelihood of finding out early. These results suggest that humans, like animals, value non-instrumental information and will pay a price for such information, independent of its utility.

Non-random expression of ribosomal DNA units in a grasshopper showing high intragenomic variation for the ITS2 region.

We analyse intragenomic variation of the ITS2 internal transcribed spacer of ribosomal DNA (rDNA) in the grasshopper Eyprepocnemis plorans, by means of tagged PCR 454 amplicon sequencing performed on both genomic DNA (gDNA) and RNA-derived complementary DNA (cDNA), using part of the ITS2 flanking coding regions (5.8S and 28S rDNA) as an internal control for sequencing errors. Six different ITS2 haplotypes (i.e. variants for at least one nucleotide in the complete ITS2 sequence) were found in a single population, one of them (Hap4) being specific to a supernumerary (B) chromosome. The analysis of both gDNA and cDNA from the same individuals provided an estimate of the expression efficiency of the different haplotypes. We found random expression (i.e. about similar recovery in gDNA and cDNA) for three haplotypes (Hap1, Hap2 and Hap5), but significant underexpression for three others (Hap3, Hap4 and Hap6). Hap4 was the most extremely underexpressed and, remarkably, it showed the lowest sequence conservation for the flanking 5.8-28S coding regions in the gDNA reads but the highest conservation (100%) in the cDNA ones, suggesting the preferential expression of mutation-free rDNA units carrying this ITS2 haplotype. These results indicate that the ITS2 region of rDNA is far from complete homogenization in this species, and that the different rDNA units are not expressed at random, with some of them being severely downregulated.

A step to the gigantic genome of the desert locust: chromosome sizes and repeated DNAs.

The desert locust (Schistocerca gregaria) has been used as material for numerous cytogenetic studies. Its genome size is estimated to be 8.55 Gb of DNA comprised in 11 autosomes and the X chromosome. Its X0/XX sex chromosome determinism therefore results in females having 24 chromosomes whereas males have 23. Surprisingly, little is known about the DNA content of this locust's huge chromosomes. Here, we use the Feulgen Image Analysis Densitometry and C-banding techniques to respectively estimate the DNA quantity and heterochromatin content of each chromosome. We also identify three satellite DNAs using both restriction endonucleases and next-generation sequencing. We then use fluorescent in situ hybridization to determine the chromosomal location of these satellite DNAs as well as that of six tandem repeat DNA gene families. The combination of the results obtained in this work allows distinguishing between the different chromosomes not only by size, but also by the kind of repetitive DNAs that they contain. The recent publication of the draft genome of the migratory locust (Locusta migratoria), the largest animal genome hitherto sequenced, invites for sequencing even larger genomes. S. gregaria is a pest that causes high economic losses. It is thus among the primary candidates for genome sequencing. But this species genome is about 50 % larger than that of L. migratoria, and although next-generation sequencing currently allows sequencing large genomes, sequencing it would mean a greater challenge. The chromosome sizes and markers provided here should not only help planning the sequencing project and guide the assembly but would also facilitate assigning assembled linkage groups to actual chromosomes.

U1 snDNA clusters in grasshoppers: chromosomal dynamics and genomic organization.

The spliceosome, constituted by a protein set associated with small nuclear RNA (snRNA), is responsible for mRNA maturation through intron removal. Among snRNA genes, U1 is generally a conserved repetitive sequence. To unveil the chromosomal/genomic dynamics of this multigene family in grasshoppers, we mapped U1 genes by fluorescence in situ hybridization in 70 species belonging to the families Proscopiidae, Pyrgomorphidae, Ommexechidae, Romaleidae and Acrididae. Evident clusters were observed in all species, indicating that, at least, some U1 repeats are tandemly arrayed. High conservation was observed in the first four families, with most species carrying a single U1 cluster, frequently located in the third or fourth longest autosome. By contrast, extensive variation was observed among Acrididae, from a single chromosome pair carrying U1 to all chromosome pairs carrying it, with occasional occurrence of two or more clusters in the same chromosome. DNA sequence analysis in Eyprepocnemis plorans (species carrying U1 clusters on seven different chromosome pairs) and Locusta migratoria (carrying U1 in a single chromosome pair) supported the coexistence of functional and pseudogenic lineages. One of these pseudogenic lineages was truncated in the same nucleotide position in both species, suggesting that it was present in a common ancestor to both species. At least in E. plorans, this U1 snDNA pseudogenic lineage was associated with 5S rDNA and short interspersed elements (SINE)-like mobile elements. Given that we conclude in grasshoppers that the U1 snDNA had evolved under the birth-and-death model and that its intragenomic spread might be related with mobile elements.

B1 was the ancestor B chromosome variant in the western Mediterranean area in the grasshopper Eyprepocnemis plorans.

We analyzed the distribution of 2 repetitive DNAs, i.e. ribosomal DNA (rDNA) and a satellite DNA (satDNA), on the B chromosomes found in 17 natural populations of the grasshopper Eyprepocnemis ploransplorans sampled around the western Mediterranean region, including the Iberian Peninsula, Balearic Islands, Sicily, and Tunisia. Based on the amount of these repetitive DNAs, 4 types of B variants were found: B1, showing an equal or higher amount of rDNA than satDNA, and 3 other variants, B2, B24 and B5, bearing a higher amount of satDNA than rDNA. The variants B1 and B2 varied in size among populations: B1 was about half the size of the X chromosome in Balearic Islands, but two-thirds of the X in Iberian populations at Alicante, Murcia and Albacete provinces. Likewise, B2 was about one-third the size of the X chromosome in populations from the Granada province but half the size of the X in the populations collected at Málaga province. The widespread geographical distribution of the B1 variant makes it the best candidate for being the ancestor B chromosome in the whole western Mediterranean region.

Disparate molecular evolution of two types of repetitive DNAs in the genome of the grasshopper Eyprepocnemis plorans.

Wide arrays of repetitive DNA sequences form an important part of eukaryotic genomes. These repeats appear to evolve as coherent families, where repeats within a family are more similar to each other than to other orthologous representatives in related species. The continuous homogenization of repeats, through selective and non-selective processes, is termed concerted evolution. Ascertaining the level of variation between repeats is crucial to determining which evolutionary model best explains the homogenization observed for these sequences. Here, for the grasshopper Eyprepocnemis plorans, we present the analysis of intragenomic diversity for two repetitive DNA sequences (a satellite DNA (satDNA) and the 45S rDNA) resulting from the independent microdissection of several chromosomes. Our results show different homogenization patterns for these two kinds of paralogous DNA sequences, with a high between-chromosome structure for rDNA but no structure at all for the satDNA. This difference is puzzling, considering the adjacent localization of the two repetitive DNAs on paracentromeric regions in most chromosomes. The disparate homogenization patterns detected for these two repetitive DNA sequences suggest that several processes participate in the concerted evolution in E. plorans, and that these mechanisms might not work as genome-wide processes but rather as sequence-specific ones.

BCN Checkpoint, a community-based centre for men who have sex with men in Barcelona, Catalonia, Spain, shows high efficiency in HIV detection and linkage to care.

OBJECTIVES: We assessed the efficiency of BCN Checkpoint in detecting new cases of HIV infection and efficiently linking newly diagnosed individuals to care. METHODS: This study analysed during 2007-2012 the number of tests performed and the number of persons tested in BCN Checkpoint, the HIV prevalence, global and in first visits, the capacity of HIV detection compared to the reported cases in MSM in Catalonia, and the linkage to care rate. RESULTS: During the six years a total of 17.319 tests were performed and 618 HIV-positive cases were detected. Median prevalence of clients who visited the centre for the first time was 5.4% (4.1-5.8). BCN Checkpoint detected 36.3% (35.0-40.4) of all reported cases in MSM during 2009-2011. Linkage to care was achieved directly in 90.5% of the cases and only 2.4% of cases were lost to follow-up. CONCLUSIONS: A community-based centre, addressed to a key population at risk, can be less effort consuming (time and funding) and show high efficiency in HIV detection and linkage to care.

Manifestaciones radiológicas del síndrome de Baastrup en la edad pediátrica / Radiological manifestations of Baastrup's disease in children

Entre las causas de dolor lumbar en el niño no suele considerarse, como posibilidad diagnóstica, el síndrome de Baastrup. Clásicamente, esta entidad se caracteriza por fenómenos degenerativos secundarios al roce de apófisis espinosas adyacentes, con esclerosis de sus márgenes y disminución del espacio interespinoso. Su frecuencia aumenta con la edad y suele acompañarse de cambios degenerativos en el raquis, como pueden ser la hipertrofia facetaria lumbar o la patología discal. Determinadas actividades, como la danza o la gimnasia, pueden favorecer la aparición de esta patología a edades más tempranas. En la población infantil la enfermedad pudiera manifestarse de modo diferente, con aumento del espacio interespinoso y remodelación ósea(AU)

Baastrup's disease is not usually considered among the possible causes of low back pain in children. Classically, Baastrup's disease is characterized by degenerative phenomena secondary to friction between adjacent spinous processes, with sclerosis of the margins and decrease in the interspinous space. Baastrup's disease becomes more prevalent with age and is usually accompanied by degenerative changes in the vertebral column, such as lumbar facet hypertrophy or disc disease. Certain activities like dance or gymnastics can make Baastrup's disease more likely to appear at an earlier age. In children, Baastrup's disease can manifest in a different way, with increased interspinous spaces and bone remodeling. In this article, we present the cases of two patients with low back pain who were diagnosed with Baastrup's disease(AU)

[Radiological manifestations of Baastrup's disease in children]. / Manifestaciones radiológicas del síndrome de Baastrup en la edad pediátrica.

Baastrup's disease is not usually considered among the possible causes of low back pain in children. Classically, Baastrup's disease is characterized by degenerative phenomena secondary to friction between adjacent spinous processes, with sclerosis of the margins and decrease in the interspinous space. Baastrup's disease becomes more prevalent with age and is usually accompanied by degenerative changes in the vertebral column, such as lumbar facet hypertrophy or disc disease. Certain activities like dance or gymnastics can make Baastrup's disease more likely to appear at an earlier age. In children, Baastrup's disease can manifest in a different way, with increased interspinous spaces and bone remodeling. In this article, we present the cases of two patients with low back pain who were diagnosed with Baastrup's disease.

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions.

In this study, we describe that the PDZ protein syntenin-1 is a crucial element for the generation of signaling asymmetry during the cellular response to polarized extracellular cues. We analyze the role of syntenin-1 in the control of asymmetry in two independent models of T cell polarization--the migratory response to chemoattractants and the establishment of cognate interactions between T cells and antigen-presenting cells (APCs). A combination of mutant, biochemical and siRNA approaches demonstrate that syntenin-1 is vital for the generation of polarized actin structures such as the leading edge and the contact zone with APCs. We found that the mechanism by which syntenin-1 controls actin polymerization relies on its mandatory role for activation of the small GTPase Rac. Syntenin-1 controls Rac through a specific association with the myosin phosphatase Rho interacting protein (M-RIP), which occurs in response to phosphorylation of syntenin-1 by Src at Tyr4. Our data indicate the key role of syntenin-1 in the generation of functional asymmetry in T cells and provide a novel mechanistic link between receptor activation and actin polymerization and accumulation in response to extracellular stimulation.

DNA amount of X and B chromosomes in the grasshoppers Eyprepocnemis plorans and Locusta migratoria.

We analyzed the DNA amount in X and B chromosomes of 2 XX/X0 grasshopper species (Eyprepocnemis plorans and Locusta migratoria), by means of Feulgen image analysis densitometry (FIAD), using previous estimates in L. migratoria as standard (5.89 pg). We first analyzed spermatids of 0B males and found a bimodal distribution of integrated optical densities (IODs), suggesting that one peak corresponded to +X and the other to -X spermatids. The difference between the 2 peaks corresponded to the X chromosome DNA amount, which was 1.28 pg in E. plorans and 0.80 pg in L. migratoria. In addition, the +X peak in E. plorans gave an estimate of the C-value in this species (10.39 pg). We next analyzed diplotene cells from 1B males in E. plorans and +B males in L. migratoria (a species where Bs are mitotically unstable and no integer B number can be defined for an individual) and measured B chromosome IOD relative to X chromosome IOD, within the same cell, taking advantage of the similar degree of condensation for both positively heteropycnotic chromosomes at this meiotic stage. From this proportion, we estimated the DNA amount for 3 different B chromosome variants found in individuals from 3 E. plorans Spanish populations (0.54 pg for B1 from Saladares, 0.51 pg for B2 from Salobreña and 0.64 for B24 from Torrox). Likewise, we estimated the DNA amount of the B chromosome in L. migratoria to be 0.15 pg. To automate measurements, we wrote a GPL3 licensed Python program (pyFIA). We discuss the utility of the present approach for estimating X and B chromosome DNA amount in a variety of situations, and the meaning of the DNA amount estimates for X and B chromosomes in these 2 species.

B chromosomes and sex in animals.

Supernumerary (B) chromosomes are dispensable elements found in many eukaryote genomes in addition to standard (A) chromosomes. In many respects, B chromosomes resemble sex chromosomes, so that a common ancestry for them has frequently been suggested. For instance, B chromosomes in grasshoppers, and other insects, show a pycnotic cycle of condensation-decondensation during meiosis remarkably similar to that of the X chromosome. In some cases, B chromosome size is even very similar to that of the X chromosome. These resemblances have led to suggest the X as the B ancestor in many cases. In addition, sex chromosome origin from B chromosomes has also been suggested. In this article, we review the existing evidence for both evolutionary pathways, as well as sex differences for B frequency at adult and embryo progeny levels, B chromosome effects or B chromosome transmission. In addition, we review cases found in the literature showing sex-ratio distortion associated with B chromosome presence, the most extreme case being the paternal sex ratio (PSR) chromosomes in some Hymenoptera. We finally analyse the possibility of B chromosome regularisation within the host genome and, as a consequence of it, whether B chromosomes can become regular members of the host genome.

Level of heat shock proteins decreases in individuals carrying B-chromosomes in the grasshopper Eyprepocnemis plorans.

We analyzed the effect of B-chromosome presence on expression level of heat shock protein 70 (Hsp70) in cerebral ganglion and gonad in both males and females of the grasshopper Eyprepocnemis plorans. Two natural Spanish populations, Salobreña (Granada) and Torrox (Málaga) were assayed, the former harbouring a neutralized (non-driving) B-chromosome (B(2)) and the latter a parasitic (driving) B-chromosome (B(24)). The analysis was performed by Western blotting, immunostaining and densitometric measuring expression level of the Hsp70 family in adult individuals. The results showed that Hsp70 levels of testis were significantly higher in Salobreña than Torrox, and were significantly lower in testes of B-carrying males from both populations. A similar effect was observed in the ovary of females from Torrox. No effect was, however, observed in cerebral ganglia in any sex or population. B-chromosome effects in Torrox showed a dose-dependent pattern. The results point to an interesting interaction between B-chromosome and stress protein expression in reproductive tissue.

Abnormal spermatid formation in the presence of the parasitic B(24) chromosome in the grasshopper Eyprepocnemis plorans.

Morphology and size of spermatids were analysed in the grasshopper Eyprepocnemis plorans by means of light and electron microscopy. At light microscopy, normal and abnormal (macro- and micro-) spermatids differed in size and number of centriolar adjuncts (CAs): 1 CA in normal spermatids and 2 or more CAs, depending on ploidy level, in macrospermatids. Males carrying the additional B(24) chromosome showed significantly more macro- and microspermatids than 0B males. The frequency of macro- and microspermatids showed an odd-even pattern in respect to the number of B chromosomes, with a higher frequency of abnormal spermatids associated with odd B numbers. Transmission electron microscopy showed that macrospermatids carried more than one axoneme, depending on ploidy level: 2 for diploid, 3 for triploid, and 4 for tetraploid spermatids. In 0B males, the most frequent abnormal spermatids were diploid, whereas in 1B males they were the tetraploid spermatids and, to a lesser extent, triploid ones. This suggests that most macrospermatids derived from cytokinesis failure and nucleus restitution. The implications of aberrant spermatids on B chromosome transmission and male fertility are discussed.

Microdissection and chromosome painting of X and B chromosomes in the grasshopper Eyprepocnemis plorans.

The relative location of 2 repetitive DNAs, i.e. ribosomal (rDNA) and a tandemly repeated satellite DNA (satDNA), with respect to the centromere, suggested that B chromosomes in the grasshopper Eyprepocnemis plorans derived intraspecifically from the X chromosome. To test this hypothesis, we microdissected X and B chromosomes and amplified the obtained DNA by 2 different procedures, the conventional DOP-PCR method and the single-cell whole-genome amplification GenomePlex method. We then generated DNA probes to perform chromosome painting. Our results have confirmed that X and B chromosomes share many DNA sequences between them and with most of the autosomes, especially at locations where the satDNA and rDNA reside, in consistency with previous information. This supports the hypothesis of an intraspecific origin of B chromosomes in E. plorans. Nevertheless, the present results did not help to clarify whether Bs were derived from the X chromosome or else from 1 or more autosomes.

PI4P5-kinase Ialpha is required for efficient HIV-1 entry and infection of T cells.

HIV-1 envelope (Env) triggers membrane fusion between the virus and the target cell. The cellular mechanism underlying this process is not well known. Phosphatidylinositol 4,5-bisphosphate (PIP(2)) is known to be important for the late steps of the HIV-1 infection cycle by promoting Gag localization to the plasma membrane during viral assembly, but it has not been implicated in early stages of HIV-1 membrane-related events. In this study, we show that binding of the initial HIV-1 Env-gp120 protein induces PIP(2) production in permissive lymphocytes through the activation of phosphatidylinositol-4-phosphate 5-kinase (PI4P5-K) Ialpha. Overexpression of wild-type PI4P5-K Ialpha increased HIV-1 Env-mediated PIP(2) production and enhanced viral replication in primary lymphocytes and CEM T cells, whereas PIP(2) production and HIV-1 infection were both severely reduced in cells overexpressing the kinase-dead mutant D227A (D/A)-PI4P5-K Ialpha. Similar results were obtained with replicative and single-cycle HIV-1 particles. HIV-1 infection was also inhibited by knockdown of endogenous expression of PI4P5-K Ialpha. These data indicate that PI4P5-K Ialpha-mediated PIP(2) production is crucial for HIV-1 entry and the early steps of infection in permissive lymphocytes.

Differences in ribosomal DNA distribution on A and B chromosomes between eastern and western populations of the grasshopper Eyprepocnemis plorans plorans.

Distribution of ribosomal DNA (rDNA) on standard (A) and supernumerary (B) chromosomes of the grasshopper Eyprepocnemis plorans was analysed in specimens collected in Turkey and Armenia, belonging to the E. p. plorans subspecies, and in South Africa, belonging to the E. p. meridionalis subspecies. The latter individuals showed rDNA loci in chromosomes 9 and 11 only, whereas those from Armenia carried it in chromosomes 9 and 11 or else in chromosomes 9-11, depending on the population. The specimens from Turkey carried it in chromosomes 1, 9-11 and X. A comparison of this pattern with those previously observed in populations from Spain, Morocco, and Greece (belonging to E. p. plorans) suggests the existence of two evolutionary patterns in rDNA chromosome location in A chromosomes of this subspecies: eastern populations showing rDNA restricted to the small (9-11) chromosomes (as in E. p. meridionalis and other closely related taxa within the Eyprepocneminae subfamily) and western populations carrying rDNA in most A chromosomes (Spain) or all of them (Morocco). The intermediate pattern discerned in geographically intermediate populations (in Greece and Turkey), with rDNA also being located on the X chromosome, suggests a possible east-west cline. Additional support for east-west differentiation in the rDNA location pattern comes from the analysis of B chromosomes. In eastern populations, including Daghestan, Armenia, Turkey, and Greece, B chromosomes are composed mostly of rDNA, whereas in western populations (Spain and Morocco) they contain roughly similar amounts of rDNA and a 180-bp tandem repeat (satDNA), the latter being scarce in eastern Bs.

MTOC translocation modulates IS formation and controls sustained T cell signaling.

The translocation of the microtubule-organizing center (MTOC) toward the nascent immune synapse (IS) is an early step in lymphocyte activation initiated by T cell receptor (TCR) signaling. The molecular mechanisms that control the physical movement of the lymphocyte MTOC remain largely unknown. We have studied the role of the dynein-dynactin complex, a microtubule-based molecular motor, in the process of T cell activation during T cell antigen-presenting cell cognate immune interactions. Impairment of dynein-dynactin complex activity, either by overexpressing the p50-dynamitin component of dynactin to disrupt the complex or by knocking down dynein heavy chain expression to prevent its formation, inhibited MTOC translocation after TCR antigen priming. This resulted in a strong reduction in the phosphorylation of molecules such as zeta chain-associated protein kinase 70 (ZAP70), linker of activated T cells (LAT), and Vav1; prevented the supply of molecules to the IS from intracellular pools, resulting in a disorganized and dysfunctional IS architecture; and impaired interleukin-2 production. Together, these data reveal MTOC translocation as an important mechanism underlying IS formation and sustained T cell signaling.

HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions.

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that regulates many important biological processes, including cell migration, immune synapse formation, viral infection, and the degradation of misfolded proteins. HDAC6 deacetylates tubulin, Hsp90 and cortactin, and forms complexes with other partner proteins. Although HDAC6 enzymatic activity seems to be required for the regulation of cell morphology, the role of HDAC6 in lymphocyte chemotaxis is independent of its tubulin deacetylase activity. The diverse functions of HDAC6 suggest that it is a potential therapeutic target for the treatment of a range of diseases. This review examines the biological actions of HDAC6, focusing on its deacetylase activity and its potential scaffold functions in the regulation of cell migration and other key biological processes in which the cytoskeleton plays an important role.