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Arthropod-borne flaviviruses cause life-threatening diseases associated with endothelial hyperpermeability and vascular leak. We recently found that vascular leak can be triggered by dengue virus (DENV) non-structural protein 1 (NS1) via the disruption of the endothelial glycocalyx-like layer (EGL). However, the molecular determinants of NS1 required to trigger EGL disruption and the cellular pathway(s) involved remain unknown. Here we report that mutation of a single glycosylated residue of NS1 (N207Q) abolishes the ability of NS1 to trigger EGL disruption and induce endothelial hyperpermeability. Intriguingly, while this mutant bound to the surface of endothelial cells comparably to wild-type NS1, it was no longer internalized, suggesting that NS1 binding and internalization are distinct steps. Using endocytic pathway inhibitors and gene-specific siRNAs, we determined that NS1 was endocytosed into endothelial cells in a dynamin- and clathrin-dependent manner, which was required to trigger endothelial dysfunction in vitro and vascular leak in vivo. Finally, we found that the N207 glycosylation site is highly conserved among flaviviruses and is also essential for West Nile and Zika virus NS1 to trigger endothelial hyperpermeability via clathrin-mediated endocytosis. These data provide critical mechanistic insight into flavivirus NS1-induced pathogenesis, presenting novel therapeutic and vaccine targets for flaviviral diseases.

Zika virus (ZIKV), a mosquito-borne flavivirus with homology to Dengue virus (DENV), has become a public health emergency. By characterizing memory lymphocytes from ZIKV-infected patients, we dissected ZIKV-specific and DENV-cross-reactive immune responses. Antibodies to nonstructural protein 1 (NS1) were largely ZIKV-specific and were used to develop a serological diagnostic tool. In contrast, antibodies against E protein domain l/ll (EDI/II) were cross-reactive and, although poorly neutralizing, potently enhanced ZIKV and DENV infection in vitro and lethally enhanced DENV disease in mice. Memory T cells against NS1 or E proteins were poorly cross-reactive, even in donors preexposed to DENV. The most potent neutralizing antibodies were ZIKV-specific and targeted EDIII or quaternary epitopes on infectious virus. An EDIII-specific antibody protected mice from lethal ZIKV infection, illustrating the potential for antibody-based therapy.

Background/Objectives:The clinical relevance of the metabolically healthy overweight/obese (MHO) phenotype is controversial and the relationships between weight change and the development of cardiometabolic risk factors is unknown. Therefore, we aim to: (1) Assess the long-term risk of developing one or more components of the metabolic syndrome in MHO adults compared with metabolically healthy normal weight (MHNW); (2) Evaluate risk of a composite of death, cardiovascular disease (CVD), and risk of developing type 2 diabetes between adults defined according to baseline body mass index and metabolic health.Subjects/Methods:Retrospective cohort study of adults 18-65 years of age seen at our institution between 1998 and 2000 who lived in Olmsted County. Metabolically healthy was defined as the absence of all components of the metabolic syndrome (except for waist circumference). Main outcome was the development of metabolic risk factors. The secondary outcome was a composite of mortality, CVD and heart failure.Results:Of the 18 070 individuals with complete data at baseline, 1805 (10%) were MHO (mean age 38±11 years) and 3047 were MHNW (mean age 35±11 years). After a median follow-up of 15 years, interquartile range 10-17, 80% of MHO vs 68% of MHNW developed at least one cardiometabolic risk factor (P<0.001). In multivariate analysis, MHO individuals who gained [egs]10% of their body weight were more likely to have developed metabolic complications compared to MHO individuals that did not gain weight (P=0.001 for 10-15%, P<0.001 for >15% weight gain). The risk for the secondary composite end point was similar between MHO and MHNW, number of events 218/1805 vs 217/3048 for MHO and MHNW, respectively, (hazard ratio: 1.16, 95% confidence interval: 0.96-1.40).Conclusions:MHO are more likely to develop metabolic complications than MHNW, especially if they gain weight.

This paper deals with spatio-temporal field estimation with efficient sensor placement based on the QR decomposition. The proposed method also identifies the optimal number of sensors needed for field estimation that captures the most relevant features of the field of interest. To address the uncertainties inherent in spatio-temporal field estimation, a robust data-driven control method is utilized, providing resilience against unpredictable environmental and model changes. In particular, the approach uses the Kriged Kalman Filter (KKF) for uncertainty-aware field reconstruction. Unlike other reconstruction methods, the positional uncertainty originating from the data acquisition platform is integrated into the KKF estimator. Numerical results are presented to show the efficacy of the proposed dynamic sensor placement strategy together with the KKF field estimator.

We propose a taxonomic revision of the dixenous trypanosomatids currently classified as Endotrypanum and Leishmania, including parasites that do not fall within the subgenera L. (Leishmania) and L. (Viannia) related to human leishmaniasis or L. (Sauroleishmania) formed by leishmanias of lizards: L. colombiensis, L. equatorensis, L. herreri, L. hertigi, L. deanei, L. enriettii and L. martiniquensis. The comparison of these species with newly characterized isolates from sloths, porcupines and phlebotomines from central and South America unveiled new genera and subgenera supported by past (RNA PolII gene) and present (V7V8 SSU rRNA, Hsp70 and gGAPDH) phylogenetic analyses of the organisms. The genus Endotrypanum is restricted to Central and South America, comprising isolates from sloths and transmitted by phlebotomines that sporadically infect humans. This genus is the closest to the new genus Porcisia proposed to accommodate the Neotropical porcupine parasites originally described as L. hertigi and L. deanei. A new subgenus Leishmania (Mundinia) is created for the L. enriettii complex that includes L. martiniquensis. The new genus Zelonia harbours trypanosomatids from Neotropical hemipterans placed at the edge of the Leishmania–Endotrypanum-Porcisia clade. Finally, attention is drawn to the status of L. siamensis and L. australiensis as nomem nudums.

We use a normal mode approach to show full and partial state transfer in a class of coupled resonator networks with underlying su (2) symmetry that includes the so-called J x photonic lattice. Our approach defines an auxiliary Hermitian coupling matrix describing the network that yields the normal modes of the system and its time evolution in terms of orthogonal polynomials. Our results provide insight on the full quantum state reconstruction time in a general su (2) network of any size and the full quantum transfer time in the J x network of size 4 n + 1 with n = 1 , 2 , 3 , … For any other network sizes, the Fock state probability distribution of the initial state is conserved but the amplitudes suffer a phase shift proportional to π / 2 that results in partial quantum state transfer.

Childhood bereavement is an adverse event, yet children demonstrate considerable variability in health outcomes. Bereaved children are at risk of lower lifelong educational attainment, though the contribution of neurocognitive performance is yet to be investigated. Using data from the population-based Generation R Study wherein nearly 10,000 pregnant mothers were recruited between 2002 and 2006, we estimated the association of bereavement by age 10 years with four subtests of cognitive function and academic achievement at 13 years. Bereavement by 10 years of age was experienced by n = 796 (37.3%) of youth and was associated with a 1.12-point (SD = 0.55; p -value = 0.04) lower full-scale IQ at 13 years, which was mainly driven by lower matrix reasoning scores ( β adjusted  = −0.27, SE  = 0.11, p  < 0.02). There were no differences in academic achievement or other subtests of neurocognitive function between bereaved and non-bereaved children. Secondary analyses adjusting for pre-bereavement nonverbal cognitive ability and mental health problems revealed an overall association between bereavement and subsequent full-scale IQ and matrix reasoning, but only among those youth whose caregivers reported that the loss had an emotional influence on the child. These novel findings leveraging prospective assessments in a population-based birth cohort highlight risk and resilience mechanisms warranting further research.

The Keen model is designed to represent an economy as a dynamic system governed by the interactions between private debt, wage share, and employment rate. When certain conditions are met, the model can lead to a debt spiral, which accurately mimics the impact of a financial crisis on an economy. This manuscript presents a recipe for breaking this spiral by expressing Keen’s model as an affine nonlinear system that can be modified through policy interventions. We begin by considering critical initial conditions that resemble a financial crisis to achieve this goal. We then locate a desired point within the system’s vector field that leads to a desirable equilibrium and design a path towards it. This path is later followed using one-step-ahead optimal control. We illustrate our approach by presenting simulated control scenarios.

Obstructive Sleep Apnea (OSA) is a respiratory disorder characterized by frequent breathing pauses during sleep. The apnea–hypopnea index is a measure used to assess the severity of sleep apnea and the hourly rate of respiratory events. Despite numerous commercial devices available for apnea diagnosis and early detection, accessibility remains challenging for the general population, leading to lengthy wait times in sleep clinics. Consequently, research on monitoring and predicting OSA has surged. This comprehensive paper reviews devices, emphasizing distinctions among representative apnea devices and technologies for home detection of OSA. The collected articles are analyzed to present a clear discussion. Each article is evaluated according to diagnostic elements, the implemented automation level, and the derived level of evidence and quality rating. The findings indicate that the critical variables for monitoring sleep behavior include oxygen saturation (oximetry), body position, respiratory effort, and respiratory flow. Also, the prevalent trend is the development of level IV devices, measuring one or two signals and supported by prediction software. Noteworthy methods showcasing optimal results involve neural networks, deep learning, and regression modeling, achieving an accuracy of approximately 99%.

Currently, the management of urban waste streams in developing countries is not optimized yet, and in many cases these wastes are disposed untreated in open dumps. This fact causes serious environmental and health problems due to the presence of contaminants and pathogens. Frequently, the use of specific low-cost strategies reduces the total amount of wastes. These strategies are mainly associated to the identification, separate collection and composting of specific organic waste streams, such as vegetable and fruit refuses from food markets and urban gardening activities. Concretely, in the Chimborazo Region (Ecuador), more than 80% of municipal solid waste is dumped into environment due to the lack of an efficient waste management strategy. Therefore, the aim of this study was to develop a demonstration project at field scale in this region to evaluate the feasibility of implanting the composting technology not only for the management of the organic waste fluxes from food market and gardening activities to be scaled-up in other developing regions, but also to obtain an end-product with a commercial value as organic fertilizer. Three co-composting mixtures were prepared using market wastes mixed with pruning of trees and ornamental palms as bulking agents. Two piles were created using different proportions of market waste and prunings of trees and ornamental palms: pile 1 (50:33:17) with a C/N ratio 25; pile 2: (60:30:10) with C/N ratio 24 and pile 3 (75:0:25) with C/N ratio 33), prepared with market waste and prunings of ornamental palm. Throughout the process, the temperature of the mixtures was monitored and organic matter evolution was determined using thermogravimetric and chemical techniques. Additionally, physico-chemical, chemical and agronomic parameters were determined to evaluate compost quality. The results obtained indicated that all the piles showed a suitable development of the composting process, with a significant organic matter decomposition, reached in a shorter period of time in pile 3. At the end of the process, all the composts showed absence of phytotoxicity and suitable agronomic properties for their use as organic fertilizers. This reflects the viability of the proposed alternative to be scaled-up in developing areas, not only to manage and recycle urban waste fluxes, but also to obtain organic fertilizers, including added value in economic terms related to nutrient contents.