2,501 research outputs found
Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo
No full textCo-author Timothy Rooney is a student in the MD/PhD program in the Morningside Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.MD/Ph
PLATE 1 in Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories
No full textPLATE 1. Serrasalmus manueli (1–9). (No photograph or voucher available for specimen 3.) (Photograph of 8-S. manueli by Frank Pezold.)Published as part of Freeman, Barbie, Nico, Leo G., Osentoski, Matthew, Jelks, Howard L. & Collins, Timothy M., 2007, Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories, pp. 1-38 in Zootaxa 1484 (1) on page 30, DOI: 10.11646/zootaxa.1484.1.1, http://zenodo.org/record/508648
FIGURE 2 in Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories
No full textFIGURE 2. Van Every and Kritsky (1992) hypothesis of the evolutionary relationships of 10 piranha species from the central Amazon based on their helminth (Anacanthorus) parasite fauna.Published as part of Freeman, Barbie, Nico, Leo G., Osentoski, Matthew, Jelks, Howard L. & Collins, Timothy M., 2007, Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories, pp. 1-38 in Zootaxa 1484 (1) on page 7, DOI: 10.11646/zootaxa.1484.1.1, http://zenodo.org/record/508648
Drosophila models of neuronal injury
No full textNeurite degeneration is a hallmark feature of nearly all neurodegenerative diseases, occurs after most brain trauma, and is thought to be the underlying cause of functional loss in patients. Understanding the genetic basis of neurite degeneration represents a major challenge in the neuroscience field. If it is possible to define key signaling pathways that promote neurite destruction, their blockade represents an exciting new potential therapeutic approach to suppressing neurological loss in patients. This review highlights recently developed models that can be used to study fundamental aspects of neuronal injury using the fruit fly Drosophila. The speed, precision, and powerful molecular-genetic tools available in the fruit fly make for an attractive system in which to dissect neuronal signaling after injury. Their use has led to the identification of some of the first molecules whose endogenous function includes promoting axonal degeneration after axotomy, and these signaling pathways appear functionally well conserved in mammals.MD/Ph
FIGURE 8 in Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories
No full textFIGURE 8. Phylogram of combined ribosomal and control region sequences. Analysis includes specimens appearing in bold font in Figure 7. Proportion of trees from posterior distribution possessing a given clade below branch, parsimony bootstrap proportions (>50%) above branch. Specimen sequences from original material appear in shadow boxes, associated number in parentheses (1–33) correspond to numbered specimens and information presented in Table 1 and elsewhere. GenBank sequences are followed by gb. Arrow marks branches with lengths that were not significantly different from zero. GenBank (gb) species with asterisk (*) indicate taxa of which we question the identification.Published as part of Freeman, Barbie, Nico, Leo G., Osentoski, Matthew, Jelks, Howard L. & Collins, Timothy M., 2007, Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories, pp. 1-38 in Zootaxa 1484 (1) on page 18, DOI: 10.11646/zootaxa.1484.1.1, http://zenodo.org/record/508648
Reponse to Freeman: The Stony Brook Perspective
No full textThe author, affiliated with the State University of New York at Stony
Brook, responds to John M. Freeman's comments on his medical center's
treatment of "Baby Jane Doe." He discloses details of the infant's anomalies
not previously available to the public or to Dr. Freeman. Newman defends the
prognosis given to Baby Jane's parents by several specialists, and the
counseling offered them by professionals familiar with her condition. (KIE
abstract
FIGURE 3 in Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories
No full textFIGURE 3. Diet and intestinal length data mapped onto Machado-Allison's (1985) proposed phylogeny (modified from Nico 1991). Diet data based on 18 serrasalmid species from the Orinoco River basin (Venezuela); number in parentheses following generic name represents numbers of species in each genus included in study; Jv = juvenile trait; ad = adult trait; long intestine defined as mean intestine length>1.2 X standard length.Published as part of Freeman, Barbie, Nico, Leo G., Osentoski, Matthew, Jelks, Howard L. & Collins, Timothy M., 2007, Molecular systematics of Serrasalmidae: Deciphering the identities of piranha species and unraveling their evolutionary histories, pp. 1-38 in Zootaxa 1484 (1) on page 8, DOI: 10.11646/zootaxa.1484.1.1, http://zenodo.org/record/508648
Goal Orientated stroke rehabilitation utilising electrical stimulation, iterative learning and Microsoft Kinect
No full textAn upper-limb stroke rehabilitation system is developed that assists patients in performing real world functionally relevant reaching tasks. The system provides de-weighting of the arm via a simple spring support whilst functional electrical stimulation is applied to the anterior deltoid and triceps via surface electrodes, and to the wrist and hand extensors via a 40 element surface electrode array. Iterative learning control (ILC) is used to mediate the electrical stimulation, and updates the stimulation signal applied to each muscle group based on the error between the ideal and actual movement in the previous attempt. The control system applies the minimum amount of stimulation required, maximising voluntary effort. Low-cost, markerless motion tracking is provided via a Microsoft Kinect, with hand and wrist data provided by an electrogoniometer or data glove. The system is described and initial experimental results are presented for a stroke patient starting treatment
Adjunctive treatment with oral AKL1, a botanical nutraceutical, in chronic obstructive pulmonary disease
No full textClaire Brockwell,1 Sundari Ampikaipakan,1,2 Darren W Sexton,1 David Price,3,4 Daryl Freeman,5 Mike Thomas,6 Muzammil Ali,4 Andrew M Wilson1,21Norwich Medical School, University of East Anglia, Norwich, UK; 2Norfolk and Norwich University Hospital Foundation Trust, Norwich, UK; 3Academic Primary Care, University of Aberdeen, Aberdeen, UK; 4Research in Real Life, Cambridge, UK; 5Mundesley Medical Centre, Mundesley, Norwich, UK; 6Primary Care Research, Aldermoor Health Centre, University of Southampton, Southampton, UKPurpose: The objective of this pilot trial was to evaluate the safety and efficacy of AKL1, a patented botanical formulation containing extracts of Picrorhiza kurroa, Ginkgo biloba, and Zingiber officinale, as add-on therapy for patients with chronic obstructive pulmonary disease (COPD) and chronic cough.Patients and methods: This randomized, double-blind, placebo-controlled trial enrolled male and female patients >18 years old with COPD and Leicester Cough Questionnaire (LCQ) score of <18. The 10-week study period comprised a 2-week single-blind placebo run-in period followed by add-on treatment with AKL1 or placebo twice daily for 8 weeks. The primary study endpoint was the change from week 0 to week 8 in cough-related health status, as assessed by the LCQ.Results: Of 33 patients enrolled, 20 were randomized to AKL1 and 13 to placebo. Patients included 19 (58%) men and 14 (42%) women of mean (standard deviation [SD]) age of 67 (9.4) years; 15 (45%) patients were smokers and 16 (49%) were ex-smokers. The mean (SD) change from baseline in LCQ score at 8 weeks was 2.3 (4.9) in the AKL1 group and 0.6 (3.7) in the placebo group, with mean difference in change of 1.8 (95% confidence interval: –1.5 to 5.1; P=0.28). The St George's Respiratory Questionnaire score improved substantially in the AKL1 treatment group by a mean (SD) of –7.7 (11.7) versus worsening in the placebo group (+1.5 [9.3]), with mean difference in change of –9.2 (95% confidence interval: –19.0 to 0.6; P=0.064). There were no significant differences between treatment groups in change from baseline to week 8 in other patient-reported measures, lung function, or the 6-minute walk distance.Conclusion: Further study is needed with a larger patient population and over a longer duration to better assess the effects of add-on therapy with AKL1 in COPD.Keywords: Leicester Cough Questionnaire, anti-inflammatory, Picrorhiza kurroa, Ginkgo biloba, Zingiber officinal
Wld(S) Prevents Axon Degeneration through Increased Mitochondrial Flux and Enhanced Mitochondrial Ca(2+) Buffering
No full textWld(S) (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses [1], but how it exerts this effect remains unclear [2]. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for Wld(S) neuroprotective function. Targeting the NAD(+) biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy Wld(S), and Wld(S) was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild-type axons induced a dramatic spike in axoplasmic Ca(2+) and termination of mitochondrial movement-Wld(S) potently suppressed both of these events. Surprisingly, Wld(S) also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of Wld(S). Intriguingly, purified mitochondria from Wld(S) mice exhibited enhanced Ca(2+) buffering capacity. We propose that the enhanced Ca(2+) buffering capacity of Wld(S+) mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca(2+) elevation in axons, and thereby suppression of Wallerian degeneration
- …
