Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans

Order-disorder transition in the Chialvo-Bak `minibrain' controlled by network geometry

We examine a simple biologically-motivated neural network, the three-layer version of the Chialvo-Bak `minibrain' [Neurosci. 90 (1999) 1137], and present numerical results which indicate that a non-equilibrium phase transition between ordered and disordered phases occurs subject to the tuning of a control parameter. Scale-free behaviour is observed at the critical point. Notably, the transition here is due solely to network geometry and not any noise factor. The phase of the network is thus a design parameter which can be tuned. The phases are determined by differing levels of interference between active paths in the network and the consequent accidental destruction of good paths

Non‐Linear Thresholds Characterize the Relationship Between Reef Fishes and Mangrove Habitat

A significant obstacle to evaluating the importance of mangrove habitat to coral reef fishes has been the difficulty of disentangling its effects from other subtidal/nearshore habitats or human population pressures. Florida\u27s seascape, unlike most others, has been extensively surveyed and mapped, and there are reliable estimates of human population density. Despite many studies that have correlated reef fish abundance with nearby mangrove habitat, some researchers continue to question the importance of mangroves to reef fishes. Previous studies that have investigated the mangrove–reef fish subsidy effect have applied methods that either compared averages or examined linear relationships; yet there is a body of literature that indicates that the effects of habitat are characterized by thresholds and limiting functions. Here, we employed a generalized additive model to investigate whether species richness of 106 mangrove‐associated reef fishes is related to thresholds in the extent of nearby mangrove forests along the Florida Keys Reef Tract. In addition, we used linear discriminant analyses (LDAs) to examine the relationships between the occurrence of 77 reef fish species and extent of Florida mangrove forests. We found that after accounting for confounding factors, at scales \u3c20 km2, species richness declines with decreasing mangrove extent, whereas richness increases with increasing mangrove extent at scales \u3e80 km2. Results of our LDA suggested that at least 49 reef fish species (64% of focal species) were associated with higher nearby mangrove forest extent. Our results indicate that of all habitat attributes considered, mangroves played the most substantial role in the diversity of nearby reef fish populations. These apparent thresholds (i.e., non‐linearities) in the extent of mangrove forests should be incorporated into fisheries critical habitat management and emphasize the need to consider non‐linear relationships between fishes and their habitat

A Machine to Machine framework for the charging of Electric Autonomous Vehicles

Electric Autonomous Vehicles (EAVs) have gained increasing attention of industry, governments and scientific communities concerned about issues related to classic transportation including accidents and casualties, gas emissions and air pollution, intensive traffic and city viability. One of the aspects, however, that prevent a broader adoption of this technology is the need for human interference to charge EAVs, which is still mostly manual and time-consuming. This study approaches such a problem by introducing the Inno-EAV, an open-source charging framework for EAVs that employs machine-to-machine (M2M) distributed communication. The idea behind M2M is to have networked devices that can interact, exchange information and perform actions without any manual assistance of humans. The advantages of the Inno-EAV include the automation of charging processes and the collection of relevant data that can support better decision making in the spheres of energy distribution. In this paper, we present the software design of the framework, the development process, the emphasis on the distributed architecture and the networked communication, and we discuss the back-end database that is used to store information about car owners, cars, and charging stations

Before the Pandemic Ends: Making Sure This Never Happens Again

Introduction On 30 January 2020, the World Health Organization (WHO) declared a Global Health Emergency of international concern attendant to the emergence and spread of SARS-CoV-2, nearly two months after the first reported emergence of human cases in Wuhan, China. In the subsequent two months, global, national and local health personnel and infrastructures have been overwhelmed, leading to suffering and death for infected people, and the threat of socio-economic instability and potential collapse for humanity as a whole. This shows that our current and traditional mode of coping, anchored in responses after the fact, is not capable of dealing with the crisis of emerging infectious disease. Given all of our technological expertise, why is there an emerging disease crisis, and why are we losing the battle to contain and diminish emerging diseases? Part of the reason is that the prevailing paradigm explaining the biology of pathogen-host associations (coevolution, evolutionary arms races) has assumed that pathogens must evolve new capacities - special mutations – in order to colonize new hosts and produce emergent disease (e.g. Parrish and Kawaoka, 2005). In this erroneous but broadly prevalent view, the evolution of new capacities creates new opportunities for pathogens. Further, given that mutations are both rare and undirected, the highly specialized nature of pathogen-host relationships should produce an evolutionary firewall limiting dissemination; by those definitions, emergences should be rare (for a historical review see Brooks et al., 2019). Pathogens, however, have become far better at finding us than our traditional understanding predicts. We face considerable risk space for pathogens and disease that directly threaten us, our crops and livestock – through expanding interfaces bringing pathogens and hosts into increasing proximity, exacerbated by environmental disruption and urban density, fueled by globalized trade and travel. We need a new paradigm that explains what we are seeing. Additional section headers: The Stockholm Paradigm The DAMA Protocol A Sense of Urgency and Long-Term Commitment Reference

Effect of maternal Schistosoma mansoni infection and praziquantel treatment during pregnancy on Schistosoma mansoni infection and immune responsiveness among offspring at age five years.

INTRODUCTION: Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. METHODS: In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. RESULTS: Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. CONCLUSION: We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease

Increased resting state functional connectivity in the fronto-parietal and default mode network in anorexia nervosa

The etiology of anorexia nervosa (AN) is poorly understood. Results from functional brain imaging studies investigating the neural profile of AN using cognitive and emotional task paradigms are difficult to reconcile. Task-related imaging studies often require a high level of compliance and can only partially explore the distributed nature and complexity of brain function. In this study, resting state functional connectivity imaging was used to investigate well-characterized brain networks potentially relevant to understand the neural mechanisms underlying the symptomatology and etiology of AN. Resting state functional magnetic resonance imaging data was obtained from 35 unmedicated female acute AN patients and 35 closely matched healthy controls female participants (HC) and decomposed using spatial group independent component analyses (ICA). Using validated templates, we identified components covering the fronto-parietal “control” network, the default mode network (DMN), the salience network, the visual and the sensory-motor network. Group comparison revealed an increased functional connectivity between the angular gyrus and the other parts of the fronto-parietal network in patients with AN in comparison to HC. Connectivity of the angular gyrus was positively associated with self-reported persistence in HC. In the DMN, AN patients also showed an increased functional connectivity strength in the anterior insula in comparison to HC. Anterior insula connectivity was associated with self-reported problems with interoceptive awareness. This study, with one of the largest sample to date, shows that acute AN is associated with abnormal brain connectivity in two major resting state networks (RSN). The finding of an increased functional connectivity in the fronto-parietal network adds novel support for the notion of AN as a disorder of excessive cognitive control, whereas the elevated functional connectivity of the anterior insula with the DMN may reflect the high levels of self- and body-focused ruminations when AN patients are at rest

Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas

Abstract: Background: Recent studies suggest that bacterial endotoxins may be associated with various chronic diseases, including colorectal adenomas and cancer. Given the evidence linking inflammation and colorectal cancer, we sought to determine if plasma endotoxin concentrations are associated with indicators of systemic or local inflammation and colorectal adenomas. Methods: This cross-sectional study consisted of participants who underwent screening colonoscopies and included adenoma cases (n=138) and non-adenoma controls (n=324). Plasma concentrations of endotoxin were measured with Limulus Amebocyte Lysate (LAL) assay. We quantified concentrations of inflammatory cytokines, interleukin-4 (IL-4), IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-alpha (TNF-α), and interferon-γ (IFN-γ) in plasma by ELISA and mRNA expression levels in rectal mucosal biopsies by quantitative RT-PCR. Interleukin-17 was evaluated only in the rectal mucosa. Results: Compared to subjects with low plasma endotoxin concentrations, those with higher concentrations were more likely to have adenomas (OR 1.4, 95% CI 1.0-2.1). Among subjects with adenomas, those with villous histology were more likely to have higher endotoxin concentrations (5.4 vs. 4.1EU/mL, p=0.05) and lower plasma IFN-γ (0 vs. 1.64 pg/mL, p=0.02) compared to those with only tubular adenomas. Cases showed a trend of having higher plasma TNF-α levels than controls (p=0.06), but none of the other plasma or rectal mucosal cytokine levels differed between cases and controls. Elevated mucosal IL-12 levels were associated with having multiple adenomas (p=0.04). Higher concentrations of plasma endotoxin predicted increased plasma IL-12 levels (OR 1.5, 95% CI 1.0-2.2) and rectal mucosal IL-12 (OR 1.9, 95% CI 1.0-3.7) and IL-17 gene expression (OR 2.2, 95% CI 1.0-4.6). Conclusions: These findings suggest that interactions between elevated plasma endotoxin concentrations and inflammatory cytokines may be relevant to the development of colorectal adenomas

Housing policy in transition?: an analysis of two policies permeated by participation

Uno de los aspectos más criticados de los modelos tradicionales de política habitacional ha sido el escaso margen que se abre para la participación de los sectores afectados, particularmente la población destinataria, limitando su efectividad y adecuación a las necesidades habitacionales reales. Esto se ha convertido en una demanda de las organizaciones sociales vinculadas al hábitat, y en años recientes emergió cierto consenso respecto a la necesidad de contemplar esta dimensión en las políticas e intervenciones estatales en materia de hábitat. Dichas demandas están siendo recogidas con mayor frecuencia en las políticas habitacionales, que en algunos casos definen nuevos canales y mecanismos para incorporar la participación de la población destinataria y las organizaciones sociales que la representan. El presente artículo se enfoca en dos iniciativas ejemplares en este sentido: la Ley 14.449 de Acceso Justo al Hábitat de la Provincia de Buenos Aires y la experiencia del Registro Nacional de Barrios Populares y la posterior Ley Nacional 27.453. Ofrecer una mirada sobre estos casos permitirá abrir interrogantes acerca de la posibilidad de una transición incipiente hacia otro modelo de gestión de la política habitacional, en el cual la participación de las organizaciones sociales posee mayor centralidad.One of the most frequently criticized aspects of traditional models of housing policy is the lack of consideration given to the issue of citizen participation, particularly on the part of low-income groups most affected by housing problems, which is often seen as a factor that limits the effectiveness of these policies and their adequacy in resolving existing housing needs. This issue has been taken up as a demand on the part of social organizations working on issues of housing rights, and in recent years has begun to influence the decisions of policy makers. These demands increasingly shape housing policies, which in some cases create novel mechanisms for incorporating the participation of social organizations that represent the target populations. This article looks at two recent policies that share this characteristic: Law 14449 for the Just Access to Habitat (Province of Buenos Aires), and the experience of the National Registry of Popular Neighborhoods and the subsequent National Law No. 27453. The analysis of these cases will make it possible to raise questions regarding the possibility of an emerging transition toward a model of housing policy management that contemplates the participation of social organizations as a central aspect.Fil: Palumbo, Joseph Anthony. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Centro de Estudios Urbanos y Regionales; ArgentinaFil: Toscani, María de la Paz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Centro de Estudios Urbanos y Regionales; ArgentinaFil: Rosa, Paula Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Centro de Estudios Urbanos y Regionales; ArgentinaFil: Martínez Araujo, Zahiry. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Sociales. Instituto de Desarrollo Económico y Social. Centro de Investigaciones Sociales; Argentin

Influencia de las precipitaciones y la sismicidad en la aceleración del deslizamiento de Maca, Valle del Colca, Arequipa

El deslizamiento de Maca se encuentra en el flanco izquierdo del valle del Colca en el distrito de Maca, provincia de Caylloma, departamento de Arequipa. Este deslizamiento se localiza en una región con temporadas lluviosas y secas bien marcadas y de intensa actividad sísmica; características que permitieron analizar la influencia de la precipitación y la sismicidad en su aceleración considerando estas variables conjuntamente y por separado. El marco temporal en análisis comprende desde diciembre de 2015 a diciembre de 2017 en base a las series temporales de la estación GNSS permanente MAD 3 ubicada en el sector más activo del deslizamiento. Los resultados obtenidos, luego de establecerse las correlaciones, pusieron en evidencia la sensibilidad significativa del deslizamiento frente a la interacción de las precipitaciones y los sismos