Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism.
Tissue formation, the identity of cells, and the functions they fulfill, are results of gene regulation. The male gametophyte of plants, pollen, is outstanding in this respect as several hundred genes expressed in pollen are not expressed in the sporophyte. How pollen-specific genes are down-regulated in the sporophyte has yet to be established. In this study, we have performed a bioinformatics analysis of publicly available genome-wide epigenetics data of several sporophytic tissues. By combining this analysis with DNase I footprinting data, we assessed means by which the repression of pollen-specific genes in the Arabidopsis sporophyte is conferred. Our findings show that, in seedlings, the majority of pollen-specific genes are associated with histone-3 marked by mono- or trimethylation of Lys-27 (H3K27me1/H3K27me3), both of which are repressive markers for gene expression in the sporophyte. Analysis of DNase footprint profiles of pollen-specific genes in the sporophyte displayed closed chromatin proximal to the start codon. We describe a model of two-staged gene regulation in which a lack of nucleosome-free regions in promoters and histone modifications in open reading frames repress pollen-specific genes in the sporophyte.
Individuals with major depressive disorder often experience obstructive sleep apnea. However, the relationship between depression and less severe sleep-disordered breathing is unclear. This study examined the rate of sleep-disordered breathing in depression after excluding those who had clinically significant sleep apnea (>5 apneas?h?¹). Archival data collected between 1991 and 2005 were used to assess the prevalence of sleep-disordered breathing events in 60 (31 depressed; 29 healthy controls) unmedicated participants. Respiratory events were automatically detected using a program developed in-house measuring thermal nasal air-flow and chest pressure. Results show that even after excluding participants with clinically significant sleep-disordered breathing, individuals with depression continue to exhibit higher rates of sleep-disordered breathing compared with healthy controls (depressed group: apnea-hypopnea index mean = 0.524, SE = 0.105; healthy group: apnea-hypopnea index mean = 0.179, SE = 0.108). Exploratory analyses were also conducted to assess for rates of exclusion in depression studies due to sleep-disordered breathing. Study exclusion of sleep-disordered breathing was quantified based on self-report during telephone screening, and via first night polysomnography. Results from phone screening data reveal that individuals reporting depression were 5.86 times more likely to report a diagnosis of obstructive sleep apnea than presumptive control participants. Furthermore, all of the participants excluded for severe sleep-disordered breathing detected on the first night were participants with depression. These findings illustrate the importance of understanding the relationship between sleep-disordered breathing and depression, and suggest that screening and quantification of sleep-disordered breathing should be considered in depression research.
Visually scored and power spectral analyses (PSA) of polysomnography (PSG) recordings reveal abnormalities in alcohol dependence (AD) and major depressive disorder (MDD), including deficiencies in slow wave activity (SWA) during non-rapid eye movement (NREM) sleep. SWA parameters reflect the integrity of the homeostatic sleep drive, which have not been compared in those with AD or MDD. Ten men with AD were compared with 10 men with MDD and 10 healthy controls (HCs), all aged 20-40 years. They maintained an 11 pm to 6 am sleep schedule for 5-7 days, followed by 3 consecutive nights of PSG in the laboratory: night 1 for adaptation/screening; night 2 for baseline recordings; and night 3 as the challenge night, delaying sleep until 2 am. SWA was quantified with PSA across 4 NREM periods. Men with AD generated the least SWA at baseline. In response to sleep delay, HC men showed the expected SWA enhancement and a sharper exponential decline across NREM periods. Both the MDD and the AD groups showed a significantly blunted SWA response to sleep delay. Men with MDD had the least SWA in the first NREM period (impaired accumulation of sleep drive), whereas men with AD had the slowest SWA decay rate (impaired dissipation of sleep drive). These results suggest that both SWA generation and its homeostatic regulation are impaired in men with either AD or MDD. Finding interventions that selectively improve these different components of sleep homeostasis should be a goal of treatment for AD and MDD.
Aim: Orthotopic models utilizing orthotopic implantation have been used for developing cancer models of multiple tumor entities. The aim of this study was to evaluate the role of orthotopic injection in establishing a model of esophageal cancer using a human green fluorescent protein (GFP) cell line of human esophageal carcinoma.
The recent emergence of the H5N1 influenza virus from avian reservoirs has raised concern about future influenza strains of high virulence emerging that could easily infect humans. We analyzed differential gene expression of lung epithelial cells to compare the response to H5N1 infection with a more benign infection with Respiratory Syncytial Virus (RSV). These gene expression data are then used as seeds to find important nodes by using a novel combination of the Gene Ontology database and the Human Network of gene interactions. Additional analysis of the data is conducted by training support vector machines (SVM) with the data and examining the orientations of the optimal hyperplanes generated.
Sleep disturbances are common in major depressive disorder (MDD), although polysomnographic (PSG) abnormalities are more prevalent in adults than in children and adolescents with MDD. Sleep spindle activity (SPA) is associated with neuroplasticity mechanisms during brain maturation and is more abundant in childhood and adolescence than in adulthood, and as such, may be a more sensitive measure of sleep alteration than PSG in early-onset depression. This study investigated SPA changes related to early-onset MDD, comparing individuals already ill with MDD and individuals at high-risk for MDD with healthy nondepressed controls.
Higher body mass index (BMI) has been associated with more sleep disturbance and depressive symptoms, but the combined effects of depression and BMI on sleep have not been studied in children. This study evaluated the relationship between BMI and polysomnography in children with major depressive disorder (MDD), compared to healthy controls (HCs).
The May 2009 Human Variome Project (HVP) Forum "Towards Establishing Standards" was a round table discussion attended by delegates from groups representing international efforts aimed at standardizing several aspects of the HVP: mutation nomenclature, description and annotation, clinical ontology, means to better characterize unclassified variants (UVs), and methods to capture mutations from diagnostic laboratories for broader distribution to the medical genetics research community. Methods for researchers to receive credit for their effort at mutation detection were also discussed.
The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools (e.g., microarrays) are sufficient for many if not most biomedical research efforts. A large amount of data from diverse studies proves this perception inaccurate at best, and at worst, an impediment for further efforts to characterize the variation in the human genome. Because variation in genotype and environment are the fundamental basis to understand phenotypic variability and heritability at the population level, identifying the range of human genetic variation is crucial to the development of personalized nutrition and medicine. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) was proposed initially to systematically collect mutations that cause human disease and create a cyber infrastructure to link locus specific databases (LSDB). We report here the discussions and recommendations from the 2008 HVP planning meeting held in San Feliu de Guixols, Spain, in May 2008.
The regulation of the alternation between rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) is still a matter of much debate. It is also an important topic for psychiatric research, since both sleep components show anomalies in Major Depressive Disorders (MDD) and related syndromes. In previous studies on healthy controls, we showed preferential links of the number of ultradian cycles with REMS-related variables rather than with NREMS-related variables. REMS Latency (RL), for example, was shown to be inversely related to the number of cycles. The present study replicates these analyses in a group of 29 patients with MDD (age range: 23-56; 16 females), after two adaptation nights. Results showed significant correlations between the number of cycles and REMS, and between the number of cycles and RL, whereas correlations with NREMS were not significant. This indirectly supports regulation hypotheses considering REMS as the main focus of the oscillation, inhibiting and interrupting NREMS. Also, when the RL is shorter, there are more ultradian cycles than when the RL is long. This adds an interesting element in the elucidation of the physiological meaning of anomalies of RL.
Based on theoretical reasoning it has been suggested that the reliability of findings published in the scientific literature decreases with the popularity of a research field. Here we provide empirical support for this prediction. We evaluate published statements on protein interactions with data from high-throughput experiments. We find evidence for two distinctive effects. First, with increasing popularity of the interaction partners, individual statements in the literature become more erroneous. Second, the overall evidence on an interaction becomes increasingly distorted by multiple independent testing. We therefore argue that for increasing the reliability of research it is essential to assess the negative effects of popularity and develop approaches to diminish these effects.
The role of sleep in patients diagnosed with chronic fatigue syndrome is not fully understood. Studies of polysomnographic and quantitative sleep electroencephalographic (EEG) measures have provided contradictory results, with few consistent findings in patients with Chronic Fatigue Syndrome (CFS). For the most part, it appears that delta EEG activity may provide the best discrimination between patients and healthy controls. A closer examination of delta activity in the very slow end of the frequency band is still to be considered in assessing sleep in CFS. The present preliminary study compared absolute and relative spectral power in conventional EEG bands and ultra-slow delta (0.5-0.8Hz) between 10 young female patients with the CFS and healthy controls without psychopathology. In absolute measures, the ultra-slow delta power was lower in CFS, about one-fifth that of the control group. Other frequency bands did not differ between groups. Relative ultra-slow delta power was lower in patients than in controls. CFS is associated with lower ultra-slow (0.5-0.8Hz) delta power, underscoring the importance of looking beyond conventional EEG frequency bands. From a neurophysiological standpoint, lower ultra-slow wave power may indicate abnormalities in the oscillations in membrane potential or a failure in neural recruitment in those with CFS.
Daytime deficits in children with sleep disordered breathing (SDB) are theorized to result from hypoxic insult to the developing brain or fragmented sleep. Yet, these do not explain why deficits occur in primary snorers (PS). The time course of slow wave EEG activity (SWA), a proxy of homeostatic regulation and cortical maturation, may provide insight.
The mitotic spindle is an essential molecular machine involved in cell division, whose composition has been studied extensively by detailed cellular biology, high-throughput proteomics, and RNA interference experiments. However, because of its dynamic organization and complex regulation it is difficult to obtain a complete description of its molecular composition. We have implemented an integrated computational approach to characterize novel human spindle components and have analysed in detail the individual candidates predicted to be spindle proteins, as well as the network of predicted relations connecting known and putative spindle proteins. The subsequent experimental validation of a number of predicted novel proteins confirmed not only their association with the spindle apparatus but also their role in mitosis. We found that 75% of our tested proteins are localizing to the spindle apparatus compared to a success rate of 35% when expert knowledge alone was used. We compare our results to the previously published MitoCheck study and see that our approach does validate some findings by this consortium. Further, we predict so-called "hidden spindle hub", proteins whose network of interactions is still poorly characterised by experimental means and which are thought to influence the functionality of the mitotic spindle on a large scale. Our analyses suggest that we are still far from knowing the complete repertoire of functionally important components of the human spindle network. Combining integrated bio-computational approaches and single gene experimental follow-ups could be key to exploring the still hidden regions of the human spindle system.
Sleep disturbances in alcohol-dependent (AD) individuals may persist despite abstinence from alcohol and can influence the course of the disorder. Although the mechanisms of sleep disturbances of AD are not well understood and some evidence suggests dysregulation of circadian rhythms, dim light melatonin onset (DLMO) has not previously been assessed in AD versus healthy control (HC) individuals in a sample that varied by sex and race. The authors assessed 52 AD participants (mean?±?SD age: 36.0?±?11.0 yrs of age, 10 women) who were 3-12 wks since their last drink (abstinence: 57.9?±?19.3 d) and 19 age- and sex-matched HCs (34.4?±?10.6 yrs, 5 women). Following a 23:00-06:00?h at-home sleep schedule for at least 5 d and screening/baseline nights in the sleep laboratory, participants underwent a 3-h extension of wakefulness (02:00?h bedtime) during which salivary melatonin samples were collected every 30?min beginning at 19:30?h. The time of DLMO was the primary measure of circadian physiology and was assessed with two commonly used methodologies. There was a slower rate of rise and lower maximal amplitude of the melatonin rhythm in the AD group. DLMO varied by the method used to derive it. Using 3 pg/mL as threshold, no significant differences were found between the AD and HC groups. Using 2 standard deviations above the mean of the first three samples, the DLMO in AD occurred significantly later, 21:02?±?00:41?h, than in HC, 20:44?±?00:21?h (t?=?-2.4, p?=?.02). Although melatonin in the AD group appears to have a slower rate of rise, using well-established criteria to assess the salivary DLMO did not reveal differences between AD and HC participants. Only when capturing melatonin when it is already rising was DLMO found to be significantly delayed by a mean 18?min in AD participants. Future circadian analyses on alcoholics should account for these methodological caveats.
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