using-fluorescent-proteins-to-monitor-glycosome-dynamics-african

Using Fluorescent Proteins to Monitor Glycosome Dynamics in the African Trypanosome

Trypanosoma brucei is a kinetoplastid parasite that causes human African trypanosomiasis (HAT), or sleeping sickness, and a wasting disease, nagana, in ...

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with no sufficient therapeutic options to date. Falls are the most devastating feature. The causes of these falls are not well understood. To test the impact of PSP-associated motor and cognitive features on falls, 26 PSP patients were prospectively recruited and divided into frequent fallers (> one fall/month, 18 patients) and infrequent fallers (<or= one fall/month, 8 patients). Further parameters were assessed by clinical investigation and biomechanical gait and balance analysis with and without dual-task paradigms. Physical activity was measured through an ambulatory device. Frequent fallers scored higher on the total PSP rating scale and the subscales "history," "mental," "bulbar," "supranuclear ocular motor," and "gait/midline exam" but not on disease duration, the subscale "limb exam," the UPDRS motor score and the sway analysis. Frequent fallers also showed an increased probability of an altered walking pattern with shortened step lengths and increased cadence under a dual-task situation. It is concluded that the occurrence of falls in PSP seems strongly associated with the deterioration of bulbar function, but not relevantly with typical parkinsonian features like rigidity and bradykinesia. The decreased ability to deal with distraction of attention under a dual-task situation points to a relevant impact of cortical and subcortical dysfunction on the frequency of falls.

Clinical and dual-tasking aspects in frequent and infrequent fallers with progressive supranuclear palsy.

Richardson's syndrome (RS) and progressive supranuclear palsy-parkinsonism (PSP-P) are the most common subtypes of PSP. Post-mortem data suggests that the clinical presentation of the two subtypes differs especially in the first 2 years of disease and then converges. This hypothesis has, to our knowledge, never been confirmed in a living cohort. Medical history was used to define subtypes retrospectively in 23 consecutive PSP patients from our outpatient clinic specialized in movement disorders. 14 patients suffered from RS, and 9 from PSP-P. Using a prospective cross-sectional approach, clinical, cognitive, behavioral, speech and biochemical (cerebrospinal fluid tau levels) features were compared. RS patients showed shorter time from disease onset to diagnosis and more neuropsychological and neurobehavioral deficits than PSP-P patients, but differed not significantly with regard to clinical and biochemical features. RS and PSP-P show considerable symptoms overlap during the disease course when using routine assessments, with persisting differences regarding non-motor symptoms. Shorter disease duration of the comparably affected RS patients indicates that this subtype has an accelerated disease progression at early disease stages.

In vivo comparison of Richardson's syndrome and progressive supranuclear palsy-parkinsonism.

Hydrogen peroxide (H(2)O(2)) is commonly formed in microbial habitats by either chemical oxidation processes or host defense responses. H(2)O(2) can penetrate membranes and damage key intracellular biomolecules, including DNA and iron-dependent enzymes. Bacteria defend themselves against this H(2)O(2) by inducing a regulon that engages multiple defensive strategies. A previous microarray study suggested that yaaA, an uncharacterized gene found in many bacteria, was induced by H(2)O(2) in Escherichia coli as part of its OxyR regulon. Here we confirm that yaaA is a key element of the stress response to H(2)O(2). In a catalase/peroxidase-deficient (Hpx(-)) background, yaaA deletion mutants grew poorly, filamented extensively, and lost substantial viability when they were cultured in aerobic LB medium. The results from a thyA forward mutagenesis assay and the growth defect of the yaaA deletion in a recombination-deficient (recA56) background indicated that yaaA mutants accumulated high levels of DNA damage. The growth defect of yaaA mutants could be suppressed by either the addition of iron chelators or mutations that slowed iron import, indicating that the DNA damage was caused by the Fenton reaction. Spin-trapping experiments confirmed that Hpx(-) yaaA cells had a higher hydroxyl radical (HO(•)) level. Electron paramagnetic resonance spectroscopy analysis showed that the proximate cause was an unusually high level of intracellular unincorporated iron. These results demonstrate that during periods of H(2)O(2) stress the induction of YaaA is a critical device to suppress intracellular iron levels; it thereby attenuates the Fenton reaction and the DNA damage that would otherwise result. The molecular mechanism of YaaA action remains unknown.

The YaaA protein of the Escherichia coli OxyR regulon lessens hydrogen peroxide toxicity by diminishing the amount of intracellular unincorporated iron.

We hypothesized that postural instability and cognitive decline in patients with Richardsonâ€™s syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy-parkinsonism may be reflected by alterations in putaminal metabolism.

Fluorodeoxyglucose positron emission tomography in Richardsonâ€™s syndrome and progressive supranuclear palsy-parkinsonism.

Wir die Hypothese, dass posturale Instabilit&auml;t und kognitive Abnahme in Richardsons-Syndrom k&ouml;nnte eine Folge der reduzierten Stoffwechsel von Thalamus und frontal. Schwere Parkinson Anzeichen bei Patienten mit progressive supranukle&auml;re L&auml;hmung-Parkinsonismus k&ouml;nnten durch &Auml;nderungen im putaminal Stoffwechsel niederschlagen.

Fluorodeoxyglucose Positronen-Emissions-Tomographie in Richardsons-Syndrom und Progressive supranukle&auml;re L&auml;hmung-Parkinsonismus.

To assess the utility of a telephone-based interview system in providing ongoing monitoring of the developmental and functional status of children with both positive newborn screens for Krabbe disease and low galactocerebrosidase activity on confirmatory testing, and to determine whether this approach provides improved compliance with follow-up compared with formal neuropsychological testing.

Developmental and functional outcomes in children with a positive newborn screen for Krabbe disease: a pilot study of a phone-based interview surveillance technique.

Children with autism spectrum disorders (ASD) have unique developmental and behavioral phenotypes, and they have specific challenges with communication, social skills, and repetitive behaviors. At this time, no single etiology for ASD has been identified. However, evidence from family studies and linkage analyses suggests that genetic factors play a pivotal role in the etiology of ASD. However, ASD appear to be influenced by complex genetic and environmental factors, and evidence suggests that this is not a single gene disorder. In particular, ASD has a complex behavioral phenotype, and this variation reflects complex genotypes under the influence of external factors. With these considerations in mind, it is important to recognize that genetic testing is a vital component of the diagnostic evaluation of children with ASD. For example, children with ASD who have definitive etiologies may be able to access more specific resources, they may be spared long, emotionally and financially exhausting diagnostic journeys, and associated medical conditions and comorbidities can be managed proactively. Most importantly, children with disabilities of unknown origin should have an ongoing evaluation of potential etiologies for their symptoms (Crocker, 1987). Our purpose is to describe current trends in genetic testing for ASD, potential genetic etiologies of ASD, known genetic disorders associated with ASD, and recommendations for genetic testing in ASD. We will also emphasize the importance of access to informed health professionals, especially in the contexts of stigma and community supports.

Genetic testing for autism spectrum disorders.

Limited research has been conducted to describe the geographical clustering and distribution of prostate cancer (PrCA) incidence in Georgia (GA). This study describes and compares the temporal and geographic trends of PrCA incidence in GA with a specific focus on racial disparities.

Prostate cancer incidence and tumor severity in Georgia: descriptive epidemiology, racial disparity, and geographic trends.

This review summarizes peer-reviewed studies examining cancer risks among police officers. It provides an overview of existing research limitations and uncertainties and the plausible etiologic risk factors associated with cancer in this understudied occupation.

The epidemiology of cancer among police officers.

Literature has identified detrimental health effects from the indiscriminate use of artificial nighttime light. We examined the co-distribution of light at night (LAN) and breast cancer (BC) incidence in Georgia, with the goal to contribute to the accumulating evidence that exposure to LAN increases risk of BC.

A case-referent study: light at night and breast cancer risk in Georgia.

Trypanosomes compartmentalize many metabolic enzymes in glycosomes, peroxisome-related microbodies that are essential to parasite survival. While it is understood that these dynamic organelles undergo profound changes in protein composition throughout life cycle differentiation, the adaptations that occur in response to changes in environmental conditions are less appreciated. We have adopted a fluorescent-organelle reporter system in procyclic Trypanosoma brucei by expressing a fluorescent protein (FP) fused to a glycosomal targeting sequence (peroxisome-targeting sequence 2 [PTS2]). In these cell lines, PTS2-FP is localized within import-competent glycosomes, and organelle composition can be analyzed by microscopy and flow cytometry. Using this reporter system, we have characterized parasite populations that differ in their glycosome composition. In glucose-rich medium, two parasite populations are observed; one population harbors glycosomes bearing the full repertoire of glycosome proteins, while the other parasite population contains glycosomes that lack the usual glycosome-resident proteins but do contain the glycosome membrane protein TbPEX11. Interestingly, these cells lack TbPEX13, a protein essential for the import of proteins into the glycosome. This bimodal distribution is lost in low-glucose medium. Furthermore, we have demonstrated that changes in environmental conditions trigger changes in glycosome protein composition. These findings demonstrate a level of procyclic glycosome diversity heretofore unappreciated and offer a system by which glycosome dynamics can be studied in live cells. This work adds to our growing understanding of how the regulation of glycosome composition relates to environmental sensing.

Environmentally regulated glycosome protein composition in the African trypanosome.

This study sought to evaluate cardiac baroreflex sensitivity (BRS) as a predictor of response to renal sympathetic denervation (RDN).

Impaired cardiac baroreflex sensitivity predicts response to renal sympathetic denervation in patients with resistant hypertension.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Primary Immune Deficiency Treatment Consortium (PIDTC) report.

Reply: baroreflex sensitivity: a reliable predictor of response to renal denervation?

Reply: Baroreflex sensitivity and renal sympathetic denervation.

Patients' motivation to change their substance use is usually viewed as a crucial component of successful treatment. The objective of this study was to examine whether motivation contributes to drinking outcomes after residential treatment for alcohol dependence.

Article	Year
Clinical and dual-tasking aspects in frequent and infrequent fallers with progressive supranuclear palsy. Movement disorders : official journal of the Movement Disorder Society\| PubMed ID: 20131396	2010
In vivo comparison of Richardson's syndrome and progressive supranuclear palsy-parkinsonism. Journal of neural transmission (Vienna, Austria : 1996)\| PubMed ID: 21207078	2011
The YaaA protein of the Escherichia coli OxyR regulon lessens hydrogen peroxide toxicity by diminishing the amount of intracellular unincorporated iron. Journal of bacteriology\| PubMed ID: 21378183	2011
Fluorodeoxyglucose positron emission tomography in Richardsonâ€™s syndrome and progressive supranuclear palsy-parkinsonism. Movement disorders : official journal of the Movement Disorder Society\| PubMed ID: 22359740	2012
Developmental and functional outcomes in children with a positive newborn screen for Krabbe disease: a pilot study of a phone-based interview surveillance technique. The Journal of pediatrics\| PubMed ID: 22381022	2012
Genetic testing for autism spectrum disorders. Developmental disabilities research reviews\| PubMed ID: 22447748	2011
Prostate cancer incidence and tumor severity in Georgia: descriptive epidemiology, racial disparity, and geographic trends. Cancer causes & control : CCC\| PubMed ID: 23179658	2013
The epidemiology of cancer among police officers. American journal of industrial medicine\| PubMed ID: 23255299	2013
A case-referent study: light at night and breast cancer risk in Georgia. International journal of health geographics\| PubMed ID: 23594790	2013
Environmentally regulated glycosome protein composition in the African trypanosome. Eukaryotic cell\| PubMed ID: 23709182	2013
Impaired cardiac baroreflex sensitivity predicts response to renal sympathetic denervation in patients with resistant hypertension. Journal of the American College of Cardiology\| PubMed ID: 23973686	2013
Primary Immune Deficiency Treatment Consortium (PIDTC) report. The Journal of allergy and clinical immunology\| PubMed ID: 24139498	2014
Reply: baroreflex sensitivity: a reliable predictor of response to renal denervation? Journal of the American College of Cardiology\| PubMed ID: 24509282	2014
Reply: Baroreflex sensitivity and renal sympathetic denervation. Journal of the American College of Cardiology\| PubMed ID: 24632274	2014
Motivation as a predictor of drinking outcomes after residential treatment programs for alcohol dependence. Journal of addiction medicine\| PubMed ID: 24637624	2014

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