Human immunodeficiency virus rebound after suppression to < 400 copies/mL during initial highly active antiretroviral therapy regimens, according to prior nucleoside experience and duration of suppression

This study evaluated 1433 human immunodeficiency virus (HIV)-infected patients starting highly active antiretroviral therapy (HAART), 409 (28%) of whom had prior nucleoside experience and achieved an HIV load of <400 copies/mL by 24 weeks of therapy. Three hundred seven patients experienced virus rebound during a total of 2773.3 person-years of follow-up. There was a higher rate of virus rebound among the patients with pre-HAART nucleoside experience (relative hazard [RH], 2.86; 95% confidence interval, 2.22-3.84; P < .0001) and a decreasing rate of virus rebound with increasing duration of virus suppression (i.e., time since achieving a virus load of <400 HIV RNA copies/mL) among both the nucleoside-experienced and naive patients (P < .0001), but the difference between the groups persisted into the third year of follow-up (P = .0007). Even patients who had experienced <2 months of nucleoside therapy before beginning HAART had an increased risk of virus rebound (RH, 1.95; P = .009). It appears that only a small period of pre-HAART nucleoside therapy is sufficient to confer a disadvantage, in terms of risk of virus rebound, that persists for several years

THE du / dt FILTERS PARAMETERS AND CHARACTERISTICS DETERMINATION

Проблема обеспечения электромагнитной совместимости при использовании частотно‐регулируемого электропривода является актуальной, так как влияет на надежность и безопасность его эксплуатации. Одной из разновидностей выходных фильтров электромагнитной совместимости являются фильтры du/dt – Г‐образные фильтры нижних частот. В результате анализа параметров фильтров, выпускаемых фирмой Danfoss, получены аналитические выражения для определения их индуктивности, емкости и демпфирующего сопротивления в зависимости от мощности нагрузки преобразователя частоты. Также определены численные значения важных для синтеза фильтров характеристик.The problem of ensuring electromagnetic compatibility when using a frequency‐controlled electric drive is relevant, since it affects the reliability and safety of its operation. One of the types of output filters of electromagnetic compatibility are du/dt filters L‐shaped low‐pass filters. As a result of analyzing the parameters of the filters produced by Danfoss, analytical expressions are obtained for determining their inductance, capacitance and damping resistance depending on the load power of the frequency converter. Numerical values of the characteristics important for the synthesis of filters are also determined

Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder

Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder

Identifying physiological measures of lifetime welfare status in pigs: exploring the usefulness of haptoglobin, C-reactive protein and hair cortisol sampled at the time of slaughter

Background: Physiological measures indicative of the welfare status of animals during rearing could form part of an abattoir-based animal health and welfare assessment tool. A total of 66 pigs were used in this study, the aim of which was to assess how serum concentrations of haptoglobin (Hp) and C-reactive protein (CRP) (assessed in 51 pigs), and hair concentrations of cortisol (assessed in 65 pigs), measured at or close to slaughter, reflected welfare-related indicators recorded from the animal during its lifetime. These indicators were recorded at intervals between 7 and 21 weeks of age and included assigning scores for levels of tail and skin lesions, recording the presence or absence of certain health issues, and conducting qualitative behavioural assessments (QBA). Results: Pigs recorded as having tail lesions during their lifetime had higher hair cortisol levels than those with no tail lesions (tail lesions: 47.87 ± 3.34 pg/mg, no tail lesions: 42.20 ± 3.29 pg/mg, P = 0.023), and pigs recorded as having moderate or severe tail lesions had higher Hp levels than those with no or mild tail lesions (moderate/severe: 1.711 mg/ml ± 0.74, none/mild: 0.731 mg/ml ±0.10, P = 0.010). Pigs recorded as being lame during their lifetime tended to have higher hair cortisol levels than non-lame pigs (lame: 52.72 pg/mg ± 3.83, not lame: 43.07 pg/mg ± 2.69, P = 0.062). QBA scores were not associated with any of the physiological measures (P > 0.05). Receiver Operator Curve (ROC) analysis was also carried out to get a better understanding of the usefulness of the physiological measures in discriminating animals that had had welfare-related issues recorded during their lifetime from those that had not. Hair cortisol was determined as having ‘moderate’ accuracy in discriminating pigs that were tail bitten on-farm from unbitten pigs (AUC: 0.748) while Hp and CRP were determined to have no meaningful discriminatory ability (AUC < 0.600). Conclusion: This research should be repeated on a larger scale, but the results suggest that hair cortisol measured at slaughter could provide insight into the welfare status of pigs during their lifetime. Hp may be a useful indicator of tail lesions in pigs. However, further research utilising a greater proportion of severely bitten pigs is required before conclusions can be drawn

Genetics of Mechanosensation in the Heart

Mechanosensation (the ultimate conversion of a mechanical stimulus into a biochemical signal) as well as mechanotransduction (transmission of mechanically induced signals) belong to the most fundamental processes in biology. These effects, because of their dynamic nature, are particularly important for the cardiovascular system. Therefore, it is not surprising that defects in cardiac mechanosensation, are associated with various types of cardiomyopathy and heart failure. However, our current knowledge regarding the genetic basis of impaired mechanosensation in the cardiovascular system is beginning to shed light on this subject and is at the centre of this brief review

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO

CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions

In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7- binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies