TOMOBFLOW: feature-preserving noise filtering for electron tomography

<p>Abstract</p> <p>Background</p> <p>Noise filtering techniques are needed in electron tomography to allow proper interpretation of datasets. The standard linear filtering techniques are characterized by a tradeoff between the amount of reduced noise and the blurring of the features of interest. On the other hand, sophisticated anisotropic nonlinear filtering techniques allow noise reduction with good preservation of structures. However, these techniques are computationally intensive and are difficult to be tuned to the problem at hand.</p> <p>Results</p> <p>TOMOBFLOW is a program for noise filtering with capabilities of preservation of biologically relevant information. It is an efficient implementation of the Beltrami flow, a nonlinear filtering method that locally tunes the strength of the smoothing according to an edge indicator based on geometry properties. The fact that this method does not have free parameters hard to be tuned makes TOMOBFLOW a user-friendly filtering program equipped with the power of diffusion-based filtering methods. Furthermore, TOMOBFLOW is provided with abilities to deal with different types and formats of images in order to make it useful for electron tomography in particular and bioimaging in general.</p> <p>Conclusion</p> <p>TOMOBFLOW allows efficient noise filtering of bioimaging datasets with preservation of the features of interest, thereby yielding data better suited for post-processing, visualization and interpretation. It is available at the web site <url>http://www.ual.es/%7ejjfdez/SW/tomobflow.html</url>.</p

A thiol redox sensor in soluble epoxide hydrolase enables oxidative activation by intra-protein disulfide bond formation

Soluble epoxide hydrolase (sEH), an enzyme that broadly regulates the cardiovascular system, hydrolyses epoxyeicosatrienoic acids (EETs) to their corresponding dihydroxyeicosatrienoic acids (DHETs). We previously showed that endogenous lipid electrophiles adduct within the catalytic domain, inhibiting sEH to lower blood pressure in angiotensin II-induced hypertensive mice. As angiotensin II increases vascular H2O2, we explored sEH redox regulation by this oxidant and how this integrates with inhibition by lipid electrophiles to regulate vasotone. Kinetics analyses revealed that H2O2 not only increased the specific activity of sEH but increased its affinity for substrate and increased its catalytic efficiency. This oxidative activation was mediated by formation of an intra-disulfide bond between C262 and C264, as determined by mass spectrometry and substantiated by biotin-phenylarsinate and thioredoxin-trapping mutant assays. C262S/264S sEH mutants were resistant to peroxide-induced activation, corroborating the disulfide-activation mechanism. The physiological impact of sEH redox state was determined in isolated arteries and the effect of the pro-oxidant vasopressor angiotensin II on arterial sEH redox state and vasodilatory EETs indexed in mice. Angiotensin II induced the activating intra-disulfide in sEH, causing a decrease in plasma EET/DHET ratios that is consistent with the pressor response to this hormone. Although sEH C262–C264 disulfide formation enhances hydrolysis of vasodilatory EETs, this modification also sensitized sEH to inhibition by lipid electrophiles. This explains why angiotensin II decreases EETs and increases blood pressure, but when lipid electrophiles are also present, that EETs are increased and blood pressure lowered

Ultraspinning instability: the missing link

We study linearized perturbations of Myers-Perry black holes in d=7, with two of the three angular momenta set to be equal, and show that instabilities always appear before extremality. Analogous results are expected for all higher odd d. We determine numerically the stationary perturbations that mark the onset of instability for the modes that preserve the isometries of the background. The onset is continuously connected between the previously studied sectors of solutions with a single angular momentum and solutions with all angular momenta equal. This shows that the near-extremality instabilities are of the same nature as the ultraspinning instability of d>5 singly-spinning solutions, for which the angular momentum is unbounded. Our results raise the question of whether there are any extremal Myers-Perry black holes which are stable in d>5.Comment: 19 pages. 1 figur

Complexity of the Inoculum Determines the Rate of Reversion of SIV Gag CD8 T Cell Mutant Virus and Outcome of Infection

Escape mutant (EM) virus that evades CD8+ T cell recognition is frequently observed following infection with HIV-1 or SIV. This EM virus is often less replicatively “fit” compared to wild-type (WT) virus, as demonstrated by reversion to WT upon transmission of HIV to a naïve host and the association of EM virus with lower viral load in vivo in HIV-1 infection. The rate and timing of reversion is, however, highly variable. We quantified reversion to WT of a series of SIV and SHIV viruses containing minor amounts of WT virus in pigtail macaques using a sensitive PCR assay. Infection with mixes of EM and WT virus containing ≥10% WT virus results in immediate and rapid outgrowth of WT virus at SIV Gag CD8 T cell epitopes within 7 days of infection of pigtail macaques with SHIV or SIV. In contrast, infection with biologically passaged SHIVmn229 viruses with much smaller proportions of WT sequence, or a molecular clone of pure EM SIVmac239, demonstrated a delayed or slow pattern of reversion. WT virus was not detectable until ≥8 days after inoculation and took ≥8 weeks to become the dominant quasispecies. A delayed pattern of reversion was associated with significantly lower viral loads. The diversity of the infecting inoculum determines the timing of reversion to WT virus, which in turn predicts the outcome of infection. The delay in reversion of fitness-reducing CD8 T cell escape mutations in some scenarios suggests opportunities to reduce the pathogenicity of HIV during very early infection

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

The effectiveness of public health interventions to reduce the health impact of climate change:a systematic review of systematic reviews

Climate change is likely to be one of the most important threats to public health in the coming years. Yet despite the large number of papers considering the health impact of climate change, few have considered what public health interventions may be of most value in reducing the disease burden. We aimed to evaluate the effectiveness of public health interventions to reduce the disease burden of high priority climate sensitive diseases

Natural Host Genetic Resistance to Lentiviral CNS Disease: A Neuroprotective MHC Class I Allele in SIV-Infected Macaques

Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease

Diarrhea is a Major killer of Children with Severe Acute Malnutrition Admitted to Inpatient Set-up in Lusaka, Zambia

<p>Abstract</p> <p>Introduction</p> <p>Mortality of children with Severe Acute Malnutrition (SAM) in inpatient set-ups in sub-Saharan Africa still remains unacceptably high. We investigated the prevalence and effect of diarrhea and HIV infection on inpatient treatment outcome of children with complicated SAM receiving treatment in inpatient units.</p> <p>Method</p> <p>A cohort of 430 children aged 6-59 months old with complicated SAM admitted to Zambia University Teaching Hospital's stabilization centre from August to December 2009 were followed. Data on nutritional status, socio-demographic factors, and admission medical conditions were collected up on enrollment. T-test and chi-square tests were used to compare difference in mean or percentage values. Logistic regression was used to assess risk of mortality by admission characteristics.</p> <p>Results</p> <p>Majority, 55.3% (238/430) were boys. The median age of the cohort was 17 months (inter-quartile range, IQR 12-22). Among the children, 68.9% (295/428) had edema at admission. The majority of the children, 67.3% (261/388), presented with diarrhea; 38.9% (162/420) tested HIV positive; and 40.5% (174/430) of the children died. The median Length of stay of the cohort was 9 days (IQR, 5-14 days); 30.6% (53/173) of the death occurred within 48 hours of admission. Children with diarrhea on admission had two and half times higher odds of mortality than those without diarrhea; Adjusted OR = 2.5 (95% CI 1.50-4.09, P < 0.001). The odds of mortality for children with HIV infection was higher than children without HIV infection; Adjusted OR = 1.6 (95% CI 0.99-2.48 P = 0.5).</p> <p>Conclusion</p> <p>Diarrhea is a major cause of complication in children with severe acute malnutrition. Under the current standard management approach, diarrhea in children with SAM was found to increase their odds of death substantially irrespective of other factors.</p

Acousto-optical Scanning-Based High-Speed 3D Two-Photon Imaging In Vivo.

Recording of the concerted activity of neuronal assemblies and the dendritic and axonal signal integration of downstream neurons pose different challenges, preferably a single recording system should perform both operations. We present a three-dimensional (3D), high-resolution, fast, acousto-optic two-photon microscope with random-access and continuous trajectory scanning modes reaching a cubic millimeter scan range (now over 950 × 950 × 3000 μm3) which can be adapted to imaging different spatial scales. The resolution of the system allows simultaneous functional measurements in many fine neuronal processes, even in dendritic spines within a central core (>290 × 290 × 200 μm3) of the total scanned volume. Furthermore, the PSF size remained sufficiently low (PSFx < 1.9 μm, PSFz < 7.9 μm) to target individual neuronal somata in the whole scanning volume for simultaneous measurement of activity from hundreds of cells. The system contains new design concepts: it allows the acoustic frequency chirps in the deflectors to be adjusted dynamically to compensate for astigmatism and optical errors; it physically separates the z-dimension focusing and lateral scanning functions to optimize the lateral AO scanning range; it involves a custom angular compensation unit to diminish off-axis angular dispersion introduced by the AO deflectors, and it uses a high-NA, wide-field objective and high-bandwidth custom AO deflectors with large apertures. We demonstrate the use of the microscope at different spatial scales by first showing 3D optical recordings of action potential back propagation and dendritic Ca2+ spike forward propagation in long dendritic segments in vitro, at near-microsecond temporal resolution. Second, using the same microscope we show volumetric random-access Ca2+ imaging of spontaneous and visual stimulation-evoked activity from hundreds of cortical neurons in the visual cortex in vivo. The selection of active neurons in a volume that respond to a given stimulus was aided by the real-time data analysis and the 3D interactive visualization accelerated selection of regions of interest

Endoscopic procedures for removal of foreign bodies of the aerodigestive tract: The Bugando Medical Centre experience

<p>Abstract</p> <p>Background</p> <p>Foreign bodies in the aerodigestive tract continue to be a common problem that contributes significantly to high morbidity and mortality worldwide. This study was conducted to describe our own experience with endoscopic procedures for removal of foreign bodies in the aerodigestive tract, in our local setting and compare with what is described in literature.</p> <p>Methods</p> <p>This was a prospective descriptive study which was conducted at Bugando Medical Centre between January 2008 and December 2009. Data were collected using a structured questionnaire and analyzed using SPSS computer software version 15.</p> <p>Results</p> <p>A total of 98 patients were studied. Males outnumbered females by a ratio of 1.1:1. Patients aged 2 years and below were the majority (75.9%). The commonest type of foreign bodies in airways was groundnuts (72.7%) and in esophagus was coins (72.7%). The trachea (52.2%) was the most common site of foreign body's lodgment in the airways, whereas cricopharyngeal sphincter (68.5%) was the commonest site in the esophagus. Rigid endoscopy with forceps removal under general anesthesia was the main treatment modality performed in 87.8% of patients. The foreign bodies were successfully removed without complications in 90.8% of cases. Complication rate was 7.1% and bronchopneumonia was the most common complication accounting for 42.8% of cases. The mean duration of hospital stay was 3.4 days and mortality rate was 4.1%.</p> <p>Conclusion</p> <p>Aerodigestive tract foreign bodies continue to be a significant cause of childhood morbidity and mortality in our setting. Rigid endoscopic procedures under general anesthesia are the main treatment modalities performed. Prevention is highly recommended whereby parents should be educated to keep a close eye on their children and keep objects which can be foreign bodies away from children's reach.</p