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1.  Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R 
Biochemistry  2010;49(27):5714-5725.
Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we present structures of the pathogenic SOD1 variants D124V and H80R, both of which demonstrate compromised zinc-binding sites. The disruption of the zinc-binding sites in H80R SOD1 leads to conformational changes in loop elements, permitting non-native SOD1-SOD1 interactions that mediate the assembly of these proteins into higher order filamentous arrays. Analytical ultracentrifugation sedimentation velocity experiments indicate that these SOD1 variants are more prone to monomerization than is the wild type enzyme. Although D124V and H80R SOD1 proteins appear to have fully functional copper-binding sites, inductively coupled plasma mass spectrometery (ICP-MS) and anomalous scattering X-ray diffraction analyses reveal that zinc (not copper) occupies the copper-binding sites in these variants. The absence of copper in these proteins, together with the results of covalent thiol modification experiments in yeast strains with and without the gene encoding the copper chaperone for SOD1 (CCS), suggest that CCS may not fully act on newly translated forms of these polypeptides. Overall, these findings lend support to the hypothesis that immature mutant SOD1 species contribute to toxicity in SOD1-linked ALS.
doi:10.1021/bi100314n
PMCID: PMC3037816  PMID: 20515040
2.  Innovation Networks for Improving Access and Quality Across the Healthcare Ecosystem 
Telemedicine Journal and e-Health  2010;16(1):107-111.
Abstract
Partnerships between patient communities, healthcare providers, and academic researchers are key to stepping up the pace and public health impact of clinical and translational research supported by the National Institutes of Health. With emphasis shifting toward community engagement and faster translation of research advances into clinical practice, academic researchers have a vital stake in widening the use of health information technology systems and telehealth networks to support collaboration and innovation. However, limited interaction between academic institutions and healthcare providers hinders the ability to form and sustain the integrated networks that are needed to conduct meaningful community-engaged research that improves public health outcomes. Healthcare providers, especially those affiliated with smaller practices, will need sustainable infrastructure and real incentives to utilize such networks, as well as training and additional resources for ongoing technical assistance.
doi:10.1089/tmj.2009.0157
PMCID: PMC3016866  PMID: 20043702
business administration/economics; distance learning; e-health; home health monitoring; policy
3.  Innovation in Indian Healthcare: Using Health Information Technology to Achieve Health Equity for American Indian and Alaska Native Populations 
The US Indian health system utilizes a diverse range of health information technology and innovative tools to enhance health service delivery for American Indians and Alaska Natives. This article provides an overview of efforts and experience using such tools to achieve health equity for American Indian and Alaska Native communities. Specific attention is given to the Indian Health Service Electronic Health Record and to two examples of telehealth innovation.
PMCID: PMC3035828  PMID: 21307987
Indian Health Service; American Indians; Alaska Natives; telehealth
4.  Structural and Biophysical Properties of the Pathogenic SOD1 Variant H46R/H48Q 
Biochemistry  2009;48(15):3436-3447.
Over 100 mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Two pathogenic SOD1 mutations, His46Arg (H46R) and His48Gln (H48Q), affect residues that act as copper ligands in the wild type enzyme. Transgenic mice expressing a human SOD1 variant containing both mutations develop paralytic disease akin to ALS. Here we show that H46R/H48Q SOD1 possesses multiple characteristics that distinguish it from the wild type. These properties include: 1) an ablated copper-binding site; 2) a substantially weakened affinity for zinc; 3) a binding site for calcium ion; 4) the ability to form stable heterocomplexes with the Copper Chaperone for SOD1 (CCS); and 5) compromised CCS-mediated oxidation of the intrasubunit disulfide bond in vivo. The results presented here, together with data on pathogenic SOD1 proteins coming from cell culture and transgenic mice, suggest that incomplete posttranslational modification of nascent SOD1 polypeptides via CCS may be a characteristic shared by fALS SOD1 mutants, leading to a population of destabilized, off-pathway folding intermediates that are toxic to motor neurons.
doi:10.1021/bi8021735
PMCID: PMC2757159  PMID: 19227972
5.  The Effects of Glutaredoxin and Copper Activation Pathways on the Disulfide and Stability of Cu,Zn Superoxide Dismutase*… 
The Journal of biological chemistry  2006;281(39):28648-28656.
Mutations in Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS) through mechanisms proposed to involve SOD1 misfolding, but the intracellular factors that modulate folding and stability of SOD1 are largely unknown. By using yeast and mammalian expression systems, we demonstrate here that SOD1 stability is governed by post-translational modification factors that target the SOD1 disulfide. Oxidation of the human SOD1 disulfide in vivo was found to involve both the copper chaperone for SOD1 (CCS) and the CCS-independent pathway for copper activation. When both copper pathways were blocked, wild type SOD1 stably accumulated in yeast cells with a reduced disulfide, whereas ALS SOD1 mutants A4V, G93A, and G37R were degraded. We describe here an unprecedented role for the thiol oxidoreductase glutaredoxin in reducing the SOD1 disulfide and destabilizing ALS mutants. Specifically, the major cytosolic glutaredoxin of yeast was seen to reduce the intramolecular disulfide of ALS SOD1 mutant A4V SOD1 in vivo and in vitro. By comparison, glutaredoxin was less reactive toward the disulfide of wild type SOD1. The apo-form of A4V SOD1 was highly reactive with glutaredoxin but not SOD1 containing both copper and zinc. Glutaredoxin therefore preferentially targets the immature form of ALS mutant SOD1 lacking metal co-factors. Overall, these studies implicate a critical balance between cellular reductants such as glutaredoxin and copper activation pathways in controlling the disulfide and stability of SOD1 in vivo.
doi:10.1074/jbc.M600138200
PMCID: PMC2757158  PMID: 16880213
6.  Down-Regulation of a Manganese Transporter in the Face of Metal Toxicity 
Molecular Biology of the Cell  2009;20(12):2810-2819.
The yeast Smf1p Nramp manganese transporter is posttranslationally regulated by environmental manganese. Smf1p is stabilized at the cell surface with manganese starvation, but is largely degraded in the vacuole with physiological manganese through a mechanism involving the Rsp5p adaptor complex Bsd2p/Tre1p/Tre2p. We now describe an additional level of Smf1p regulation that occurs with toxicity from manganese, but not other essential metals. This regulation is largely Smf1p-specific. As with physiological manganese, toxic manganese triggers vacuolar degradation of Smf1p by trafficking through the multivesicular body. However, regulation by toxic manganese does not involve Bsd2p/Tre1p/Tre2p. Toxic manganese triggers both endocytosis of cell surface Smf1p and vacuolar targeting of intracellular Smf1p through the exocytic pathway. Notably, the kinetics of vacuolar targeting for Smf1p are relatively slow with toxic manganese and require prolonged exposures to the metal. Down-regulation of Smf1p by toxic manganese does not require transport activity of Smf1p, whereas such transport activity is needed for Smf1p regulation by manganese starvation. Furthermore, the responses to manganese starvation and manganese toxicity involve separate cellular compartments. We provide evidence that manganese starvation is sensed within the lumen of the secretory pathway, whereas manganese toxicity is sensed within an extra-Golgi/cytosolic compartment of the cell.
doi:10.1091/mbc.E08-10-1084
PMCID: PMC2695789  PMID: 19369420
7.  The truth about proof 
Western Journal of Medicine  2000;173(2):142.
PMCID: PMC1071029  PMID: 10924447
8.  Sensing a purpose 
Western Journal of Medicine  2000;172(6):419.
PMCID: PMC1070942  PMID: 10854404
9.  Let the buyer beware 
Western Journal of Medicine  2000;172(5):347.
PMCID: PMC1070893  PMID: 18751294
10.  Our just desserts 
Western Journal of Medicine  2000;172(4):281.
PMCID: PMC1070852  PMID: 18751269
11.  A declaration of interdependence 
Western Journal of Medicine  2000;172(1):66.
PMCID: PMC1070739  PMID: 10695452
12.  Letter from the Southwest 
Western Journal of Medicine  1999;171(2):136.
Images
PMCID: PMC1305784  PMID: 18751175
13.  Letter from the Southwest 
Western Journal of Medicine  1999;170(6):384.
Images
PMCID: PMC1305714  PMID: 18751163

Results 1-13 (13)