Protective Role of Superoxide Dismutase against Diabetogenic Drugs

Copper-zinc superoxide dismutase (SOD) is present in relatively high concentrations in the β-cells of human islets. The activity of the extracted enzyme is partially inhibited upon incubation with the diabetogenic drugs alloxan, streptozotocin, or Vacor. The role of this enzyme in protecting β-cells against chemically induced diabetes was further investigated. Incubation of intact canine islets with alloxan (0.2 mg/ml) and 4 mM glucose decreased the insulin secretory response by 87% during subsequent exposure to 28 mM glucose. Concomitantly the SOD-specific activity (units of enzyme activity per milligram immunoreactive SOD) decreased 50% in alloxan-exposed islets. When islets were protected from alloxan toxicity by including 28 mM glucose with alloxan, the insulin secretory response and SOD specific activity remained identical to controls. Thus, SOD specific activity correlates with maintenance of β-cell function. To test the effectiveness of SOD against streptozotocin in vitro, canine islets were incubated 10 min with or without streptozotocin (0.1 mg/ml) with 4 mM glucose; their functional integrity was tested subsequently as the insulin secretory response to 28 mM glucose. Exposure to streptozotocin alone decreased the response by 70%; inclusion of SOD (1.5 mg/ml) before and during exposure to streptozotocin completely prevented this effect. Cyanide-inactivated SOD was not effective. The potential of SOD to prevent streptozotocin-induced diabetes was tested in rats in vivo. SOD injected 10 s or 50 min before streptozotocin prevented or significantly attenuated diabetes. Injection of SOD and streptozotocin simultaneously was much less effective, and cyanide-inactivated SOP was ineffective. No protection was afforded by injection of SOD 12 or 24 h before streptozotocin. Our results support hypotheses that (a) oxygen radicals mediate the β-cell toxicity of both alloxan and streptozotocin, and (b) β-cells may be particularly vulnerable to oxygen radical damage

Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>The low-density lipoprotein receptor related protein 1 (LRP1) has been implicated in Alzheimer's disease (AD) but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1.</p> <p>Results</p> <p>We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split-ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP), which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b). Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two-hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human <it>APOE4 </it>gene showed significant differences in Nyggf4 expression.</p> <p>Conclusions</p> <p>These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered early in disease. Genetic and functional studies have implicated both LRP1 and NYGGF4 in obesity and cardiovascular disease and the physical association of these proteins may reflect a common mechanism. This is particularly interesting in light of the dual role of ApoE in both cardiovascular risk and AD. The results support further studies on the functional relationship between NYGGF4 and LRP1.</p

Protein Topology of Presenilin 1

AbstractMutations in a gene encoding a multitransmembrane protein, termed presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the “loop,” N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm

Cortical complexity in world trade center responders with chronic posttraumatic stress disorder

Approximately 23% of World Trade Center (WTC) responders are experiencing chronic posttraumatic stress disorder (PTSD) associated with their exposures at the WTC following the terrorist attacks of 9/11/2001, which has been demonstrated to be a risk factor for cognitive impairment raising concerns regarding their brain health. Cortical complexity, as measured by analyzing Fractal Dimension (FD) from T1 MRI brain images, has been reported to be reduced in a variety of psychiatric and neurological conditions. In this report, we hypothesized that FD would be also reduced in a case-control sample of 99 WTC responders as a result of WTC-related PTSD. The results of our surface-based morphometry cluster analysis found alterations in vertex clusters of complexity in WTC responders with PTSD, with marked reductions in regions within the frontal, parietal, and temporal cortices, in addition to whole-brain absolute bilateral and unilateral complexity. Furthermore, region of interest analysis identified that the magnitude of changes in regional FD severity was associated with increased PTSD symptoms (reexperiencing, avoidance, hyperarousal, negative affect) severity. This study confirms prior findings on FD and psychiatric disorders and extends our understanding of FD associations with posttraumatic symptom severity. The complex and traumatic experiences that led to WTC-related PTSD were associated with reductions in cortical complexity. Future work is needed to determine whether reduced cortical complexity arose prior to, or concurrently with, onset of PTSD

Association of Alleles Carried at TNFA -850 and BAT1 -22 with Alzheimer\u27s Disease

Background: Inflammatory changes are a prominent feature of brains affected by Alzheimer\u27s disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases. Methods: Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE ε4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases. Results: APOE ε4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE ε4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases. Conclusion: These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology

Reconfiguring ruins: Beyond Ruinenlust

What explains the global proliferation of interest in ruins? Can ruins be understood beyond their common framing as products of European Romanticism? Might a transdisciplinary approach allow us to see ruins differently? These questions underpinned the Arts and Humanities Research Council–funded project Reconfiguring Ruins, which deployed approaches from history, literature, East Asian studies, and geography to reflect on how ruins from different historical contexts are understood by reference to different theoretical frameworks. In recognition of the value of learning from other models of knowledge production, the project also involved a successful collaboration with the Museum of London Archaeology and the artist-led community The NewBridge Project in Newcastle. By bringing these varied sets of knowledges to bear on the project’s excavations of specific sites in the United Kingdom, the United States, and Japan, the article argues for an understanding of ruins as thresholds, with ruin sites providing unique insights into the relationship between lived pasts, presents, and futures. It does so by developing three key themes that reflect on the process of working collaboratively across the arts, humanities, and social sciences, including professional archaeology: inter- and transdisciplinarity, the limits of cocreation, and traveling meanings and praxis. Meanings of specific ruins are constructed out of specific languages and cultural resonances and read though different disciplines, but can also be reconfigured through concepts and practices that travel beyond disciplinary, cultural, and linguistic borders. As we show here, the ruin is, and should be, a relational concept that moves beyond the romantic notion of Ruinenlust

Guía de práctica clínica para el manejo de covid-19 en el seguro social del Perú (EsSalud)

Introduction: Since the beginning of the COVID-19 pandemic, different drugs and medications have been used for the prevention and treatment of COVID-19 infection. Likewise, various investigations have been carried out to evaluate the efficacy and safety of these interventions, many of which have been shown to generate more harm than benefit for the patient, for this reason it is necessary to standardize the management of adult patients with COVID-19 in our context. Objective: To provide evidence-based clinical recommendations for the management of adults with COVID-19. Methods: A guideline development group (GEG) was formed that included medical specialists and methodologists. For its elaboration, GEG decided to carry out a rapid adaptation of the Guide for the care of critical adult patients with COVID-19 in the Americas of the Pan American Health Organization (PAHO) as well as to carry out searches for novo questions. For the formulation of the recommendations, the evidence frameworks for the decision (EtD) of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology were developed. Results: This CPG addressed 28 clinical questions, divided into three topics: prevention, diagnosis and management. Based on these questions, 33 recommendations (16 strong and 17 conditional), 26 good clinical practices (GCP) and 2 flowcharts were formulated. This CPG was published in its third version in December 2021 Conclusion: This article summarizes the methodology and evidence-based conclusions of the CPG for the management of adults with COVID 19 in EsSalud.Introducción: Desde el inicio de la pandemia por el COVID-19 se han utilizado distintos fármacos y medicamentos para la prevención y tratamiento de la infección por COVID-19. Asimismo, se han desarrollado diversas investigaciones que evalúan la eficacia y seguridad de estas intervenciones, muchas de las cuales han demostrado generar más daño que beneficio para el paciente, por tal motivo es necesario estandarizar el manejo del paciente adulto con COVID-19 en nuestro contexto. Objetivo: Proveer recomendaciones clínicas basadas en evidencia para el manejo del adulto con COVID-19. Métodos: Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos. El Para su elaboración se GEG decidió realizar una adaptación rápida de la Guía para el cuidado de pacientes adultos críticos con COVID-19 en las Américas de la Organización Panamericana de la Salud (OPS) así como realizar búsquedas para preguntas de novo. Para la formulación de las recomendaciones se elaboró los marcos de evidencia para la decisión (EtD) de la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Resultados: La presente GPC abordó 28 preguntas clínicas, divididas en tres temas: prevención, diagnóstico y manejo. En base a dichas preguntas se formularon 33 recomendaciones (16 fuertes y 17 condicionales), 26 buenas prácticas clínicas (BPC) y 2 flujogramas. Esta GPC se publicó en su tercera versión en diciembre del 2021 Conclusión: El presente artículo resume la metodología y las conclusiones basadas en evidencias de la GPC para el manejo del adulto con COVID 19 en EsSalud

The Role of Presenilin and its Interacting Proteins in the Biogenesis of Alzheimer’s Beta Amyloid

The biogenesis and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterises Alzheimer’s disease. The presenilins and its interacting proteins play a pivotal role in the generation of Aβ from the amyloid precursor protein (APP). In particular, three proteins (nicastrin, aph-1 and pen-2) interact with presenilins to form a large multi-subunit enzymatic complex (γ-secretase) that cleaves APP to generate Aβ. Reconstitution studies in yeast and insect cells have provided strong evidence that these four proteins are the major components of the γ-secretase enzyme. Current research is directed at elucidating the roles that each of these protein play in the function of this enzyme. In addition, a number of presenilin interacting proteins that are not components of γ-secretase play important roles in modulating Aβ production. This review will discuss the components of the γ-secretase complex and the role of presenilin interacting proteins on γ-secretase activity