Modeling gene expression regulatory networks with the sparse vector autoregressive model

Abstract Background To understand the molecular mechanisms underlying important biological processes, a detailed description of the gene products networks involved is required. In order to define and understand such molecular networks, some statistical methods are proposed in the literature to estimate gene regulatory networks from time-series microarray data. However, several problems still need to be overcome. Firstly, information flow need to be inferred, in addition to the correlation between genes. Secondly, we usually try to identify large networks from a large number of genes (parameters) originating from a smaller number of microarray experiments (samples). Due to this situation, which is rather frequent in Bioinformatics, it is difficult to perform statistical tests using methods that model large gene-gene networks. In addition, most of the models are based on dimension reduction using clustering techniques, therefore, the resulting network is not a gene-gene network but a module-module network. Here, we present the Sparse Vector Autoregressive model as a solution to these problems. Results We have applied the Sparse Vector Autoregressive model to estimate gene regulatory networks based on gene expression profiles obtained from time-series microarray experiments. Through extensive simulations, by applying the SVAR method to artificial regulatory networks, we show that SVAR can infer true positive edges even under conditions in which the number of samples is smaller than the number of genes. Moreover, it is possible to control for false positives, a significant advantage when compared to other methods described in the literature, which are based on ranks or score functions. By applying SVAR to actual HeLa cell cycle gene expression data, we were able to identify well known transcription factor targets. Conclusion The proposed SVAR method is able to model gene regulatory networks in frequent situations in which the number of samples is lower than the number of genes, making it possible to naturally infer partial Granger causalities without any a priori information. In addition, we present a statistical test to control the false discovery rate, which was not previously possible using other gene regulatory network models.

Effect of endogenous hydrogen sulfide inhibition on structural and functional renal disturbances induced by gentamicin

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg-1·day-1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein-1·h-1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation.

Assessment of the resilience of coral reefs to natural and human disturbances by means of recruitment panels in Indo-Pacific

Indo-Pacific region encompasses about 75% of world's coral reefs, but hard coral cover in this region experienced a 32% region-wide decline since 1970s. This great change is primarily ascribable to natural and anthropogenic pressures, including climate change and human activities effects. Coral reef conservation requires management strategies oriented to maintain their diversity and the capacity to provide ecosystem goods and services. Coral reef resilience, i.e. the capacity to recover after disturbances, is critical to their long-term persistence. The aims of the present study were to design and to test field experiments intended to measure changes in recruitment processes, as a fundamental aspect of the coral reef resilience. Recruitment experiments, using artificial panels suspended in the water column, were carried out in two Indo-Pacific locations affected by different disturbances: a new mine in Bangka Island (Indonesia), and the increased sedimentation due to coastal dynamics in Vavvaru Island (Maldives). One (or more) putatively disturbed site(s) was selected to be tested against 3 randomly selected control sites. Panels’ arrangement simulates 2 proximities to living corals, i.e. the sources of propagules: few centimetres and 2 meters over. Panels were deployed simultaneously at each site and left submerged for about five months. Recruits were identified to the lowest possible taxonomic level and recruited assemblages were analysed in terms of percent cover. In general it was not possible to detect significant differences between the benthic assemblages recruited in disturbed and control sites. The high variability observed in recruits assemblages structure among control sites may be so large to mask the possible disturbance effects. Only few taxa showed possible effects of the disturb they undergo. The field tests have highlighted strengths and weaknesses of the proposed approach and, based on these results, some possible improvements were suggested.

Nonmotor disturbances in Parkinson's disease

Nonmotor disturbances (NMDs) affect most patients with Parkinson's disease (PD) and often have a profound impact on their quality of life. NMDs such as depression, anxiety, fatigue, REM sleep behavior disorder, constipation, delayed gastric emptying, altered olfaction and pain can precede the onset of motor symptoms. Other NMDs, including hallucinations, dementia, excessive daytime sleepiness, insomnia, orthostatic hypotension and bladder disturbances, typically appear later in the course of PD. For most NMDs of PD, nondopaminergic and non-nigrostriatal mechanisms (e.g. neurodegeneration of other transmitter systems in the cortex and brainstem, side effects of medications, genetic and psychosocial factors) are considered more relevant than the 'classical' dopaminergic-nigrostriatal dysfunction. The recognition of NMDs requires a high degree of clinical suspicion, the use of specific questionnaires and ancillary tests. Pharmacological and nonpharmacological approaches can be effective, but for most forms of treatment of NMDs, the scientific evidence is limited.

Early detection of action potential duration alternans using an autoregressive model

Annual Meeting of the Biophysical Society, San Diego, USA

Using an adaptive autoregressive model for the early detection of action potential duration alternans

Cardiostim 2012, Nice, France

Sleep and wakefulness disturbances in Swiss pharmacy customers

BACKGROUND AND OBJECTIVE: Sleep disturbances are prevalent but often overlooked or underestimated. We suspected that sleep disorders might be particularly common among pharmacy customers, and that they could benefit from counselling. Therefore, we described the prevalence and severity of symptoms associated with sleep and wakefulness disorders among Swiss pharmacy customers, and estimated the need for counselling and treatment. METHODS: In 804 Swiss pharmacies (49% of all community pharmacies) clients were invited to complete the Stanford Sleep Disorders Questionnaire (SDQ), and the Epworth Sleepiness Scale (EPW). The SDQ was designed to classify symptoms of sleep and wakefulness into the four most prevalent disorders: sleep apnoea syndrome (SAS), insomnia in psychiatric disorders (PSY), periodic leg movement disorders/restless legs (RLS) and narcolepsy (NAR). Data were entered into an internet-linked database for analysis by an expert system as a basis for immediate counselling by the pharmacist. RESULTS: Of 4901 participants, 3238 (66.1%) were female, and 1663 (33.9%) were male. The mean age (SD) of females and males was 52.4 (18.05), and 55.1 (17.10) years, respectively. The percentages of female and male individuals above cut-off of SDQ subscales were 11.4% and 19.8% for sleep apnoea, 40.9% and 38.7% for psychiatric sleep disorders, 59.3% and 46.8% for restless legs, and 10.4% and 9.4% for narcolepsy respectively. The prevalence of an Epworth Sleepiness Scale score >11 was 16.5% in females, and 23.9% in males. Reliability assessed by Cronbach's alpha was 0.65 to 0.78 for SDQ subscales, and for the Epworth score. CONCLUSIONS: Symptoms of sleep and wakefulness disorders among Swiss pharmacy customers were highly prevalent. The SDQ and the Epworth Sleepiness Scale score had a satisfactory reliability to be useful for identification of pharmacy customers who might benefit from information and counselling while visiting pharmacies. The internet-based system proved to be a helpful tool for the pharmacist when counselling his customers in terms of diagnostic classification and severity of symptoms associated with the sleeping and waking state.

Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease

BACKGROUND: The prevalence and characteristics of sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. METHODS: Seven consecutive patients with definite sCJD underwent a systematic assessment of sleep-wake disturbances, including clinical history, video-polysomnography, and actigraphy. Extent and distribution of neurodegeneration was estimated by brain autopsy in six patients. Western blot analyses enabling classification and quantification of the protease-resistant isoform of the prion protein, PrPSc, in thalamus and occipital cortex was available in four patients. RESULTS: Sleep-wake symptoms were observed in all patients, and were prominent in four of them. All patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep. The correlation between different methods to assess sleep-wake functions (history, polysomnography, actigraphy, videography) was generally poor. Brain autopsy revealed prominent changes in cortical areas, but only mild changes in the thalamus. No mutation of the PRNP gene was found. CONCLUSIONS: This study demonstrates in sporadic Creutzfeldt-Jakob disease, first, the existence of sleep-wake disturbances similar to those reported in fatal familial insomnia in the absence of prominent and isolated thalamic neuronal loss, and second, the need of a multimodal approach for the unambiguous assessment of sleep-wake functions in these patients.

The influence of concurrent disturbances on plant community dynamics in northern hemlock-hardwood forests

Throughout the Upper Great Lakes region, alterations to historic disturbance regimes have influenced plant community dynamics in hemlock-hardwood forests. Several important mesic forest species, eastern hemlock (Tsuga canadensis), yellow birch (Betula alleghaniensis), eastern white pine (Pinus strobus), and Canada yew (Taxus canadensis), are in decline due to exploitive logging practices used at the turn of the 20th century and the wave of intense fires that followed. Continued regeneration and recruitment failure is attributed to contemporary forest management practices and overbrowsing by white-tailed deer (Odocoileus virginianus). Therefore, I examined the influence of two concurrent disturbances, overstory removal and herbivory, on plant community dynamics in two hemlock-hardwood forests. I measured the post-disturbance regeneration response (herbaceous and woody species) inside and outside of deer exclosures in 20 artificial canopy gaps (50 – 450 m2) and monitored survival and growth for hundreds of planted seedlings. The results of this research show that interacting disturbances can play a large role in shaping plant community composition and structure in hemlock-hardwood forests. White-tailed deer herbivory homogenized the post-disturbance plant communities across the experimental gradient of gap areas, essentially making species compositions in small gaps “look like” those in large gaps. Deer browsing also influenced probability of survival for planted Canada yew cuttings; all else being equal an individual was nearly seven times more likely to survive if protected from herbivory (P < 0.001). In contrast, the ability of sugar maple (Acer saccharum) to persist under high levels of herbivory and respond rapidly to overstory release appears to be related to the presence of stem layering(i.e., portions of below-ground prostrate stem). Layering occurred in 52% of excavated saplings (n = 100) and was significantly associated with increased post-disturbance height growth. Understory light was also important to planted seedling establishment and height growth. Higher levels of direct under-canopy light negatively impacted survival for shade-tolerant hemlock and Canada yew, while an increase in diffuse light was linked to a higher probability of survival for yellow birch and height growth for hemlock and Canada yew. Increases in white pine height growth were also significantly associated with a decrease in canopy cover.

High plant species richness indicates management-related disturbances rather than the conservation status of forests

There is a wealth of smaller-scale studies on the effects of forest management on plant diversity. However, studies comparing plant species diversity in forests with different management types and intensity, extending over different regions and forest stages, and including detailed information on site conditions are missing. We studied vascular plants on 1500 20 m × 20 m forest plots in three regions of Germany (Schwäbische Alb, Hainich-Dün, Schorfheide-Chorin). In all regions, our study plots comprised different management types (unmanaged, selection cutting, deciduous and coniferous age-class forests, which resulted from clear cutting or shelterwood logging), various stand ages, site conditions, and levels of management-related disturbances. We analyzed how overall richness and richness of different plant functional groups (trees, shrubs, herbs, herbaceous species typically growing in forests and herbaceous light-demanding species) responded to the different management types. On average, plant species richness was 13% higher in age-class than in unmanaged forests, and did not differ between deciduous age-class and selection forests. In age-class forests of the Schwäbische Alb and Hainich-Dün, coniferous stands had higher species richness than deciduous stands. Among age-class forests, older stands with large quantities of standing biomass were slightly poorer in shrub and light-demanding herb species than younger stands. Among deciduous forests, the richness of herbaceous forest species was generally lower in unmanaged than in managed forests, and it was even 20% lower in unmanaged than in selection forests in Hainich-Dün. Overall, these findings show that disturbances by management generally increase plant species richness. This suggests that total plant species richness is not suited as an indicator for the conservation status of forests, but rather indicates disturbances.

Flow disturbances in stent-related coronary evaginations: a computational fluid-dynamic simulation study

Aims: Angiographic ectasias and aneurysms in stented segments have been associated with late stent thrombosis. Using optical coherence tomography (OCT), some stented segments show coronary evaginations reminiscent of ectasias. The purpose of this study was to explore, using computational fluid-dynamic (CFD) simulations, whether OCT-detected coronary evaginations can induce local changes in blood flow. Methods and results: OCT-detected evaginations are defined as outward bulges in the luminal vessel contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evaginations can be characterised cross ectionally by depth and along the stented segment by total length. Assuming an ellipsoid shape, we modelled 3-D evaginations with different sizes by varying the depth from 0.2-1.0 mm, and the length from 1-9 mm. For the flow simulation we used average flow velocity data from non-diseased coronary arteries. The change in flow with varying evagination sizes was assessed using a particle tracing test where the particle transit time within the segment with evagination was compared with that of a control vessel. The presence of the evagination caused a delayed particle transit time which increased with the evagination size. The change in flow consisted locally of recirculation within the evagination, as well as flow deceleration due to a larger lumen - seen as a deflection of flow towards the evagination. Conclusions: CFD simulation of 3-D evaginations and blood flow suggests that evaginations affect flow locally, with a flow disturbance that increases with increasing evagination size.

Saccadic eye movement disturbances in whiplash patients with persistent complaints.

In order to analyse the possible basis of subjective complaints following whiplash injury, horizontal eye movements were examined in subjects with persistent complaints ('symptomatic group') and subjects who had completely recovered ('recovered group'). The results for the symptomatic and recovered groups were compared with those for age-matched, healthy volunteers (control group). A battery of different saccade paradigms was employed: two were reflexive saccade tasks including a gap and an overlap task, and two were intentional saccade tasks consisting of an antisaccade and a memory-guided saccade task. In addition, the symptomatic and recovered groups also underwent psychiatric evaluation in a structured clinical interview, and all groups were assessed for emotional functioning using the Beck Depression Inventory (BDI). The recovered group did not differ significantly from the control group in saccade performance and emotional functioning. The symptomatic group showed dissociation of their performances of reflexive and intentional saccade tasks: performance in reflexive saccade tasks was normal, but in intentional saccade tasks the symptomatic group showed significantly impaired inhibition of unwanted reflexive saccades, impaired saccade triggering (i.e. increased latency) and a higher percentage error in amplitude in memory-guided saccades. Based on clinical interviews, no signs of major depression or dysthymia were found in any of the groups. Compared with the other two groups, the symptomatic group had significantly higher overall BDI scores, but these resulted from BDI dimensions that were non-specific to depression, viz. 'physiological manifestations' (e.g. fatigue, sleep disturbance) or 'performance difficulty' (e.g. work inhibition). In summary, in the symptomatic group the pattern of eye movement disturbances together with normal performance in reflexive saccade tasks and impaired performance in the intentional saccade tasks, especially impaired inhibitory function, suggests dysfunction of prefrontal and frontal cortical structures.