Showing papers by "Case Western Reserve University published in 2008"

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

Abstract: Guidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide

Effects of intensive glucose lowering in type 2 diabetes

Abstract: BACKGROUND Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. METHODS In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. RESULTS At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). CONCLUSIONS As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Hyperglycemia and adverse pregnancy outcomes

Abstract: Background It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes Methods A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (58 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (111 mmol per liter) or less Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia Results For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (69 mg per deciliter [04 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (309 mg per deciliter [17 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (235 mg per deciliter [13 mmol per liter]) For birth weight above the 90th percentile, the odds ratios were 138 (95% confidence interval [CI], 132 to 144), 146 (139 to 153), and 138 (132 to 144), respectively; for cord-blood serum C-peptide level above the 90th percentile, 155 (95% CI, 147 to 164), 146 (138 to 154), and 137 (130 to 144); for primary cesarean delivery, 111 (95% CI, 106 to 115), 110 (106 to 115), and 108 (103 to 112); and for neonatal hypoglycemia, 108 (95% CI, 098 to 119), 113 (103 to 126), and 110 (100 to 112) There were no obvious thresholds at which risks increased Significant associations were also observed for secondary outcomes, although these tended to be weaker Conclusions Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels

The Potential and Challenges of Nanopore Sequencing

Abstract: A nanopore-based device provides single-molecule detection and analytical capabilities that are achieved by electrophoretically driving molecules in solution through a nano-scale pore. The nanopore provides a highly confined space within which single nucleic acid polymers can be analyzed at high throughput by one of a variety of means, and the perfect processivity that can be enforced in a narrow pore ensures that the native order of the nucleobases in a polynucleotide is reflected in the sequence of signals that is detected. Kilobase length polymers (single-stranded genomic DNA or RNA) or small molecules (e.g., nucleosides) can be identified and characterized without amplification or labeling, a unique analytical capability that makes inexpensive, rapid DNA sequencing a possibility. Further research and development to overcome current challenges to nanopore identification of each successive nucleotide in a DNA strand offers the prospect of 'third generation' instruments that will sequence a diploid mammalian genome for ∼$1,000 in ∼24 h.

What is “quality of evidence” and why is it important to clinicians?

Abstract: Guideline developers use a bewildering variety of systems to rate the quality of the evidence underlying their recommendations. Some are facile, some confused, and others sophisticated but complex

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Abstract: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms Recent reviews have described the range of assays that have been used for this purpose(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi) Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Abstract: Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

Identification of RIP1 kinase as a specific cellular target of necrostatins.

Abstract: Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.

Federal Funding for the Study of Antimicrobial Resistance in Nosocomial Pathogens: No ESKAPE

Abstract: The discovery of potent and safe antimicrobial agents is arguably the single greatest health care advance in history. The availability of these agents rapidly reduced the morbidity and mortality associated with a host of formerly fatal diseases. In addition, the confidence that infections could be prevented or treated by antibiotics allowed major leaps forward in the treatment of noninfectious diseases, including serious heart disease, cancers, and organ failure requiring transplants. Medical care, as we now know it, could not exist without the availability of effective antibiotics. The widespread use of antibiotics has been associated with what we now know to be the predictable emergence of resistance. Early confidence that infections would eventually be conquered has given way to a greater appreciation of the genetic flexibility of common human pathogens. Moreover, we have come to appreciate the role played by microorganisms in our homeostasis. Microorganisms are an intrinsic part of us, and we would do well to learn to live with them. Where we cannot live with them is in the hospital, because patients with compromised defenses are particularly vulnerable to bacterial diseases. Although many bacteria remain susceptible to most of our antimicrobial agents, a coterie has emerged that escape the lethal action of antibiotics. In hospitals in both the developed and the developing world, this small group Enterococcus faeciumy Staphylococcus aureusy Klebsiella pneumoniaey Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter species, hereafter referred to as "the ESKAPE bugs" is the same. The ESKAPE bugs are extraordinarily important, not only because they cause the lion's share of nosocomial infections but also because they represent paradigms of pathogenesis, transmission, and resistance. If we learn to control these microorganisms, our hospitals will be immeasurably safer, because the lessons learned could be applied to virtually any species that attempts to take their place. Unfortunately, the ESKAPE bugs are increasingly prevalent in our hospitals and increasingly resistant to many of our antimicrobial agents. In this issue of the Journal Peters et al. [ 1 ] detail the research agenda of the National Institute of Allergy and Infectious Diseases (NIAID) for antimicrobial resistance. As the primary federal agency for conducting and supporting medical research, the National Institutes of Health (NIH) is the standard-bearer for the federal government's commitment to health research. NIAID manages most, but certainly not all, of the work performed by the NIH in the areas of antimicrobial resistance and infectious diseases. As such, the NIAID agenda defines the weight of federal government efforts in the area of infectious diseases. One need look no further than the pivotal role played by NIAID in the enormous success of the AIDS research effort over the past 2 decades to understand the profound impact this institute's agenda can have on the growth and success of individual research areas. Peters et al. indicate that NIAID funding of antimicrobial research has grown considerably over the past decade, now totaling more than $800 million annually. In considering this very large number, it is important to realize that it represents NIAID's total commitment to all areas defined as being related to antimicrobial therapy. This category includes research on antibacterial, antifungal, antiparasitic, and antiviral therapies, whether related to the treatment of diseases or to their prevention through the use of vaccines. It is therefore difficult to get a firm grip on what level of support is devoted to antibacterial therapy and resistance, particularly in reference to the ESKAPE bugs. Regarding research specific to issues involving antimicrobial resistance, Peters Received 26 December 2007; accepted 3 January 2008; electronically published 7 March 2008. Potential conflicts of interest: none reported. Reprints or correspondence: Dr. Louis Rice, Medical Service 111(W), Louis Stokes Cleveland VA Medical Center. 10701 East Blvd.. Cleveland, OH 44106 (louis.rice@va.gov).

The Sixth Data Release of the Sloan Digital Sky Survey

Abstract: This paper describes the Sixth Data Release of the Sloan Digital Sky Survey. With this data release, the imaging of the northern Galactic cap is now complete. The survey contains images and parameters of roughly 287 million objects over 9583 deg(2), including scans over a large range of Galactic latitudes and longitudes. The survey also includes 1.27 million spectra of stars, galaxies, quasars, and blank sky ( for sky subtraction) selected over 7425 deg2. This release includes much more stellar spectroscopy than was available in previous data releases and also includes detailed estimates of stellar temperatures, gravities, and metallicities. The results of improved photometric calibration are now available, with uncertainties of roughly 1% in g, r, i, and z, and 2% in u, substantially better than the uncertainties in previous data releases. The spectra in this data release have improved wavelength and flux calibration, especially in the extreme blue and extreme red, leading to the qualitatively better determination of stellar types and radial velocities. The spectrophotometric fluxes are now tied to point-spread function magnitudes of stars rather than fiber magnitudes. This gives more robust results in the presence of seeing variations, but also implies a change in the spectrophotometric scale, which is now brighter by roughly 0.35 mag. Systematic errors in the velocity dispersions of galaxies have been fixed, and the results of two independent codes for determining spectral classifications and red-shifts are made available. Additional spectral outputs are made available, including calibrated spectra from individual 15 minute exposures and the sky spectrum subtracted from each exposure. We also quantify a recently recognized underestimation of the brightnesses of galaxies of large angular extent due to poor sky subtraction; the bias can exceed 0.2 mag for galaxies brighter than r = 14 mag.

Going from evidence to recommendations

Abstract: The GRADE system classifies recommendations made in guidelines as either strong or weak. This article explores the meaning of these descriptions and their implications for patients, clinicians, and policy makers

Short Sleep Duration and Weight Gain : A Systematic Review

Abstract: Objective The recent obesity epidemic has been accompanied by a parallel growth in chronic sleep deprivation. Physiologic studies suggest sleep deprivation may influence weight through effects on appetite, physical activity, and/or thermoregulation. This work reviews the literature regarding short sleep duration as an independent risk factor for obesity and weight gain.

The electronic origin of the visible-light absorption properties of C-, N- and S-doped TiO2 nanomaterials.

Abstract: The origin of the visible-light absorption of main-group element (C, N, S) doped TiO2 nanostructures is investigated via diffuse reflectance and valence band X-ray photoelectron spectroscopy. The synthesized C-, N-, and S-doped titania nanomaterials show an increased electron density of states above the valence band of TiO2, which explains the red-shifted light absorption of these potential photocatalysts and simultaneously suggests a lowered potential as photooxidants compared to Degussa P25 TiO2.

In search of the in vivo identity of mesenchymal stem cells

Abstract: In spite of the advances in the knowledge of adult stem cells (ASCs) during the past few years, their natural activities in vivo are still poorly understood. Mesenchymal stem cells (MSCs), one of the most promising types of ASCs for cell-based therapies, are defined mainly by functional assays using cultured cells. Defining MSCs in vitro adds complexity to their study because the artificial conditions may introduce experimental artifacts. Inserting these results in the context of the organism is difficult because the exact location and functions of MSCs in vivo remain elusive; the identification of the MSC niche is necessary to validate results obtained in vitro and to further the knowledge of the physiological functions of this ASC. Here we show an analysis of the evidence suggesting a perivascular location for MSCs, correlating these cells with pericytes, and present a model in which the perivascular zone is the MSC niche in vivo, where local cues coordinate the transition to progenitor and mature cell phenotypes. This model proposes that MSCs stabilize blood vessels and contribute to tissue and immune system homeostasis under physiological conditions and assume a more active role in the repair of focal tissue injury. The establishment of the perivascular compartment as the MSC niche provides a basis for the rational design of additional in vivo therapeutic approaches. This view connects the MSC to the immune and vascular systems, emphasizing its role as a physiological integrator and its importance in tissue repair/regeneration.

Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors

Abstract: Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa Illiteracy remains a risk factor for dementia The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia Use of traditional diets and medicinal plant extracts might aid prevention and treatment Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions

Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes

Abstract: Stroke has a greater effect on women than men because women have more events and are less likely to recover. Age-specific stroke rates are higher in men, but, because of their longer life expectancy and much higher incidence at older ages, women have more stroke events than men. With the exception of subarachnoid haemorrhage, there is little evidence of sex differences in stroke subtype or severity. Although several reports found that women are less likely to receive some in-hospital interventions, most differences disappear after age and comorbidities are accounted for. However, sex disparities persist in the use of thrombolytic treatment (with alteplase) and lipid testing. Functional outcomes and quality of life after stroke are consistently poorer in women, despite adjustment for baseline differences in age, prestroke function, and comorbidities. Here, we comprehensively review the epidemiology, clinical presentation, medical care, and outcomes of stroke in women.

Brain-computer interfaces in neurological rehabilitation.

Abstract: Summary Recent advances in analysis of brain signals, training patients to control these signals, and improved computing capabilities have enabled people with severe motor disabilities to use their brain signals for communication and control of objects in their environment, thereby bypassing their impaired neuromuscular system. Non-invasive, electroencephalogram (EEG)-based brain–computer interface (BCI) technologies can be used to control a computer cursor or a limb orthosis, for word processing and accessing the internet, and for other functions such as environmental control or entertainment. By re-establishing some independence, BCI technologies can substantially improve the lives of people with devastating neurological disorders such as advanced amyotrophic lateral sclerosis. BCI technology might also restore more effective motor control to people after stroke or other traumatic brain disorders by helping to guide activity-dependent brain plasticity by use of EEG brain signals to indicate to the patient the current state of brain activity and to enable the user to subsequently lower abnormal activity. Alternatively, by use of brain signals to supplement impaired muscle control, BCIs might increase the efficacy of a rehabilitation protocol and thus improve muscle control for the patient.

Stimuli-Responsive Polymer Nanocomposites Inspired by the Sea Cucumber Dermis

Abstract: Sea cucumbers, like other echinoderms, have the ability to rapidly and reversibly alter the stiffness of their inner dermis. It has been proposed that the modulus of this tissue is controlled by regulating the interactions among collagen fibrils, which reinforce a low-modulus matrix. We report on a family of polymer nanocomposites, which mimic this architecture and display similar chemoresponsive mechanic adaptability. Materials based on a rubbery host polymer and rigid cellulose nanofibers exhibit a reversible reduction by a factor of 40 of the tensile modulus, for example, from 800 to 20 megapascals (MPa), upon exposure to a chemical regulator that mediates nanofiber interactions. Using a host polymer with a thermal transition in the regime of interest, we demonstrated even larger modulus changes (4200 to 1.6 MPa) upon exposure to emulated physiological conditions.

Competencies in the 21st century

Abstract: Purpose – The purpose of this paper is to show that development of competencies needed to be effective managers and leaders requires program design and teaching methods focused on learning. This is the introductory essay to this special issue of JMD.Design/methodology/approach – Competencies are defined and an overview is provided for the eight papers that will follow with original research on competencies, their link to performance in various occupations, and their development.Findings – Emotional, social and cognitive intelligence competencies predict effectiveness in professional, management and leadership roles in many sectors of society. In addition, these competencies can be developed in adults.Research limitations/implications – As an introductory essay, this lays the foundation for the papers in this issue.Practical implications – Competencies needed to be effective can be developed.Originality/value – Despite widespread application, there are few published studies of the empirical link between co...

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: Associations with Neonatal Anthropometrics

Abstract: Objective: To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity. Research Design and Methods: Eligible pregnant women underwent a standard 75 gm OGTT between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skinfolds > 90th percentile or percent body fat > 90th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the baby's gender. Results: Among 23,316 HAPO study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-hour, and 2-hour plasma glucose higher by one standard deviation. Conclusions: These findings confirm the link between maternal glucose and neonatal adiposity, and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biologic relationship influencing fetal growth.

Comparative lesion sequencing provides insights into tumor evolution

Abstract: We show that the times separating the birth of benign, invasive, and metastatic tumor cells can be determined by analysis of the mutations they have in common. When combined with prior clinical observations, these analyses suggest the following general conclusions about colorectal tumorigenesis: (i) It takes 17 years for a large benign tumor to evolve into an advanced cancer but <2 years for cells within that cancer to acquire the ability to metas- tasize; (ii) it requires few, if any, selective events to transform a highly invasive cancer cell into one with the capacity to metasta- size; (iii) the process of cell culture ex vivo does not introduce new clonal mutations into colorectal tumor cell populations; and (iv) the rates at which point mutations develop in advanced cancers are similar to those of normal cells. These results have important implications for understanding human tumor pathogenesis, par- ticularly those associated with metastasis. cancer genetics colorectal cancer metastasis stem cells

Protein production and purification.

Abstract: In selecting a method to produce a recombinant protein, a researcher is faced with a bewildering array of choices as to where to start. To facilitate decision-making, we describe a consensus 'what to try first' strategy based on our collective analysis of the expression and purification of over 10,000 different proteins. This review presents methods that could be applied at the outset of any project, a prioritized list of alternate strategies and a list of pitfalls that trip many new investigators.

Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.

Abstract: Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the group's consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address.

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Abstract: Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid β on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that ≈40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with β-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or Aβ-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid β production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.

Nitrogen-doped carbon nanostructures and their composites as catalytic materials for proton exchange membrane fuel cell

Abstract: The research and development of catalysts with high activity and high durability is a significant issue for proton exchange membrane fuel cell (PEMFC). Nitrogen-doped carbon nanostructures and their composites demonstrate promising potential for PEMFC catalysts application. The nitrogen doping strategies of carbon nanostructures and the electrocatalytic aspects of nitrogen-containing carbon with and without catalytic metals on it are reviewed. Pt-based catalysts with nitrogen-doped carbon as support exhibit enhanced catalytic activity and durability toward oxygen reduction and methanol oxidation, which can be attributed to the high dispersion of Pt nanoparticles and the modified interaction between Pt nanoparticles and the support. For most of the non-Pt metal catalysts (Fe, Co, etc.) presently investigated for potential application in PEMFC, nitrogen is the indispensable element, and even though there are still controversies, the pyridinic type nitrogen is generally considered to be responsible for the catalytic sites. But the catalytic activity is still low and the stability issue is another challenging problem for non-Pt metal catalysts. Nitrogen-doped carbon, without catalytic metals on it, also shows enhanced catalytic activity. But many issues still need further investigation in order to get catalysts with targeted activity and durability.