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Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity. This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%-98%]) and specificity (98% [95% CI 88%-99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2. Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary.

Strawberries are a common and important fruit in the Mediterranean diet because of their high content of essential nutrients and beneficial phytochemicals, which seem to have relevant biological activity in human health. Among these phytochemicals, anthocyanin and ellagitannins are the major antioxidant compounds. Although individual phytochemical constituents of strawberries have been studied for their biological activities, human intervention studies using whole fruits are still lacking. Here, the nutritional contribution and phytochemical composition of the strawberry are reviewed, as is the role played by the maturity, genotype, and storage effects on this fruit. Specific attention is focused on fruit absorption, metabolism, and the possible beneficial biological activity on human health.

The Modern-Era Retrospective Analysis for Research and Applications-2 (MERRA2) version of the Goddard Earth Observing System-5 (GEOS-5) atmospheric general circulation model (AGCM) is currently in use in the NASA Global Modeling and Assimilation Office (GMAO) at a wide range of resolutions for a variety of applications. Details of the changes in parameterizations subsequent to the version in the original MERRA reanalysis are presented here. Results of a series of atmosphere-only sensitivity studies are shown to demonstrate changes in simulated climate associated with specific changes in physical parameterizations, and the impact of the newly implemented resolution-aware behavior on simulations at different resolutions is demonstrated. The GEOS-5 AGCM presented here is the model used as part of the GMAO MERRA2 reanalysis, global mesoscale simulations at 10 km resolution through 1.5 km resolution, the real-time numerical weather prediction system, and for atmosphere-only, coupled ocean-atmosphere and coupled atmosphere-chemistry simulations. The seasonal mean climate of the MERRA2 version of the GEOS-5 AGCM represents a substantial improvement over the simulated climate of the MERRA version at all resolutions and for all applications. Fundamental improvements in simulated climate are associated with the increased re-evaporation of frozen precipitation and cloud condensate, resulting in a wetter atmosphere. Improvements in simulated climate are also shown to be attributable to changes in the background gravity wave drag, and to upgrades in the relationship between the ocean surface stress and the ocean roughness. The series of resolution-aware parameters related to the moist physics was shown to result in improvements at higher resolutions and result in AGCM simulations that exhibit seamless behavior across different resolutions and applications.

Climate variables carry signatures of variability at multiple timescales. How these modes of variability are reflected in the state of the terrestrial biosphere is still not quantified or discussed at the global scale. Here, we set out to gain a global understanding of the relevance of different modes of variability in vegetation greenness and its covariability with climate. We used > 30 years of remote sensing records of the normalized difference vegetation index (NDVI) to characterize biosphere variability across timescales from submonthly oscillations to decadal trends using discrete Fourier decomposition. Climate data of air temperature (Tair) and precipitation (Prec) were used to characterize atmosphere-biosphere covariability at each timescale. Our results show that short-term (intra-annual) and longerterm (interannual and longer) modes of variability make regionally highly important contributions to NDVI variability: short-term oscillations focus in the tropics where they shape 27% of NDVI variability. Longer-term oscillations shape 9% of NDVI variability, dominantly in semiarid shrublands. Assessing dominant timescales of vegetation-climate covariation, a natural surface classification emerges which captures patterns not represented by conventional classifications, especially in the tropics. Finally, we find that correlations between variables can differ and even invert signs across timescales. For southern Africa for example, correlation between NDVI and Tair is positive for the seasonal signal but negative for short-term and longer-term oscillations, indicating that both short- and long-term temperature anomalies can induce stress on vegetation dynamics. Such contrasting correlations between timescales exist for 15% of vegetated areas for NDVI with Tair and 27% with Prec, indicating global relevance of scale-specific climate sensitivities. Our analysis provides a detailed picture of vegetation-climate covariability globally, characterizing ecosystems by their intrinsic modes of temporal variability. We find that (i) correlations of NDVI with climate can differ between scales, (ii) nondominant subsignals in climate variables may dominate the biospheric response, and (iii) possible links may exist between short-term and longer-term scales. These heterogeneous ecosystem responses on different timescales may depend on climate zone and vegetation type, and they are to date not well understood and do not always correspond to transitions in dominant vegetation types. These scale dependencies can be a benchmark for vegetation model evaluation and for comparing remote sensing products.

Remdesivir (RDV), a broadly acting nucleoside analogue, is the only FDA approved small molecule antiviral for the treatment of COVID-19 patients. To date, there are no reports identifying SARS-CoV-2 RDV resistance in patients, animal models or in vitro . Here, we selected drug-resistant viral populations by serially passaging SARS-CoV-2 in vitro in the presence of RDV. Using high throughput sequencing, we identified a single mutation in RNA-dependent RNA polymerase (NSP12) at a residue conserved among all coronaviruses in two independently evolved populations displaying decreased RDV sensitivity. Introduction of the NSP12 E802D mutation into our SARS-CoV-2 reverse genetics backbone confirmed its role in decreasing RDV sensitivity in vitro . Substitution of E802 did not affect viral replication or activity of an alternate nucleoside analogue (EIDD2801) but did affect virus fitness in a competition assay. Analysis of the globally circulating SARS-CoV-2 variants (>800,000 sequences) showed no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we observed an excess of substitutions in spike at corresponding sites identified in the emerging SARS-CoV-2 variants of concern (i.e., H69, E484, N501, H655) indicating that they can arise in vitro in the absence of immune selection. The identification and characterisation of a drug resistant signature within the SARS-CoV-2 genome has implications for clinical management and virus surveillance.

Today, the green synthesis of metal nanoparticles is a promising strategy in material science and nanotechnology. In this research, silver nanoparticles (AgNPs) were synthesized through the high-efficient, cost-effective green and facile process, using the Astragalus tribuloides Delile. root extract as a bioreduction and capping agent at room temperature. UV–Vis spectroscopy was applied for the investigation of the reaction proceedings. To characterize the greenly synthesized AgNPs, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction spectroscopy (XRD), and transmission electron microscopy (TEM) analyses were utilized. In addition, the total phenolics and flavonoids contents, antioxidant, antibacterial, and anti-inflammatory activities of the greenly synthesized AgNPs and the A. tribuloides root extract were evaluated. The results indicated that the AgNPs had spherical morphology and crystalline structure with the average size of 34.2 ± 8.0 nm. The total phenolics and flavonoids contents of the greenly synthesized AgNPs were lower than those for the A. tribuloides root extract. The resultant AgNPs exhibited the appropriate antioxidant activity (64%) as compared to that for the A. tribuloides root extract (47%). The antibacterial test approved the higher bactericidal activity of the resulting AgNPs on the Gram-positive and Gram-negative bacteria in comparison to the A. tribuloides root extract. Considering the anti-inflammatory activity, the greenly synthesized AgNPs showed a stranger effect than the A. tribuloides root extract (82% versus 69% at 500 μg/mL). Generally, the AgNPs that were fabricated by using the A. tribuloides root extract had appropriate antioxidant, antibacterial, and anti-inflammatory activities and, therefore, can be considered as a promising candidate for various biomedical applications.

Vaccination is a powerful tool in combating infectious diseases of humans and companion animals. In most wildlife, including reservoirs of emerging human diseases, achieving sufficient vaccine coverage to mitigate disease burdens remains logistically unattainable. Virally vectored “transmissible” vaccines that deliberately spread among hosts are a potentially transformative, but still theoretical, solution to the challenge of immunising inaccessible wildlife. Progress towards real-world application is frustrated by the absence of frameworks to guide vector selection and vaccine deployment prior to major in vitro and in vivo investments in vaccine engineering and testing. Here, we performed deep sequencing on field-collected samples of Desmodus rotundus betaherpesvirus (DrBHV), a candidate vector for a transmissible vaccine targeting vampire bat–transmitted rabies. We discovered 11 strains of DrBHV that varied in prevalence and geographic distribution across Peru. The phylogeographic structure of DrBHV strains was predictable from both host genetics and landscape topology, informing long-term DrBHV-vectored vaccine deployment strategies and identifying geographic areas for field trials where vaccine spread would be naturally contained. Multistrain infections were observed in 79% of infected bats. Resampling of marked individuals over 4 years showed within-host persistence kinetics characteristic of latency and reactivation, properties that might boost individual immunity and lead to sporadic vaccine transmission over the lifetime of the host. Further, strain acquisitions by already infected individuals implied that preexisting immunity and strain competition are unlikely to inhibit vaccine spread. Our results support the development of a transmissible vaccine targeting a major source of human and animal rabies in Latin America and show how genomics can enlighten vector selection and deployment strategies for transmissible vaccines.

The incidence of hypocalcemia and bone mineral density (BMD) changes in end-stage renal disease (ESRD) patients on denosumab remains unclear. We performed this meta-analysis to assess the incidence of denosumab-associated hypocalcemia and effects of denosumab on BMD in ESRD patients. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through November 2017 to identify studies evaluating incidence of denosumab-associated hypocalcemia and changes in serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and BMD from baseline to post-treatment course of denosumab in ESRD patients. Study results were pooled and analyzed using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017081074). Six observational studies with a total of 84 ESRD patients were enrolled. The pooled estimated incidence of hypocalcemia during denosumab treatment was 42% (95% CI 29–55%, I2 = 0%). Hypocalcemia occurred approximately 7 to 20 days after the first dose and reached nadir of low calcium levels in the first 2 weeks up to 2 months. However, there were no significant changes in serum calcium or phosphate from baseline to post-treatment course (≥ 3 months after treatment) with mean differences [MDs] of 0.20 mg/dL (95% CI, − 0.30 to 0.69 mg/dL) and − 0.10 mg/dL (95% CI, − 0.70 to 0.49 mg/dL). There were significant reductions in ALP and PTH levels with standardized mean differences (SMDs) of − 0.65 (95% CI − 1.13 to − 0.16) and − 1.89 (95% CI − 3.44 to − 0.34), respectively. There were significant increases in T-scores with MDs of 0.39 (95% CI 0.10 to 0.69) and 0.79 (95% CI 0.60 to 0.98) for lumbar spine and femoral neck, respectively. Our study demonstrates the estimated incidence of denosumab-associated hypocalcemia in dialysis patients of 42%. From baseline to post-treatment course, although there are no differences in serum calcium and phosphate, our findings suggest significant reductions in ALP and PTH and a significant increase in BMD. Currently, denosumab should not be considered as the treatment of choice in ESRD patients until more safety and efficacy data are available.

Obesity, a complex metabolic chronic illness, is commonly accompanied by an excessive production of free radicals, which influences the development of its comorbidities. Uric acid is commonly linked to pro-oxidant effects on human health. Though recent evidence suggests its potential antioxidant properties, it is possible that the increase in circulating uric acid levels is an adaptive protective response against the detrimental effects of excess free radicals and oxidative stress present in obese individuals. Hence, the purpose of this study was to evaluate the association between antioxidant capacity and oxidative damage markers with uric acid levels in overweight and obese individuals who live at sea level. This cross-sectional study included 93 adult volunteers (28 men and 65 women) from the city of Machala, El Oro, Ecuador, divided into three study groups according to Body Mass Index (normal weight, overweight, and obese). Sociodemographic characteristics, lifestyle elements, and physical measurements were evaluated, and blood samples were collected from all participants. Antioxidant and oxidant markers, including Radical-Scavenging Activity Assay (DPPH), Ferric Reducing Ability of Plasma (FRAP), Catalase (CAT) activity, Thiobarbituric Acid Reactive Substances (TBARS), and Protein Thiol Groups (SH groups), were assayed in the plasma samples. Coefficients of correlations and linear regression models were applied to evaluate the association between antioxidant/oxidant parameters and plasma uric acid levels. The antioxidant capacity, as measured by FRAP scavenging and CAT, was significantly higher in the obese group compared to the normal weight group, and uric acid levels presented a significant positive association with FRAP (b: 0.578, R: 0.459, p: 0.003) and CAT activity (b: 1.326; R: 0.432, p: 0.005) in overweight and obese individuals. Consequently, the presented evidence supports the potential antioxidant role of uric acid in the pathogenesis of obesity, contributing to our understanding of oxidative stress and inflammation that characterizes this illness.

Patient‐derived cancer organoids (PDOs) hold considerable promise for personalizing therapy selection and improving patient outcomes. However, it is challenging to generate PDOs in sufficient numbers to test therapies in standard culture platforms. This challenge is particularly acute for pancreatic ductal adenocarcinoma (PDAC) where most patients are diagnosed at an advanced stage with non‐resectable tumors and where patient tissue is in the form of needle biopsies. Here the development and characterization of microfluidic devices for testing therapies using a limited amount of tissue or PDOs available from PDAC biopsies is described. It is demonstrated that microfluidic PDOs are phenotypically and genotypically similar to the gold‐standard Matrigel organoids with the advantages of 1) spheroid uniformity, 2) minimal cell number requirement, and 3) not relying on Matrigel. The utility of microfluidic PDOs is proven by testing PDO responses to several chemotherapies, including an inhibitor of glycogen synthase kinase (GSKI). In addition, microfluidic organoid cultures are used to test effectiveness of immunotherapy comprised of NK cells in combination with a novel biologic. In summary, our microfluidic device offers considerable benefits for personalizing oncology based on cancer biopsies and may, in the future, be developed into a companion diagnostic for chemotherapy or immunotherapy treatments. Treatment of pancreatic cancer may be made more effective by selecting therapies for an individual patient. The authors developed and characterized microfluidic devices that may be used to test chemotherapies and immunotherapies using needle core biopsies from patients with pancreatic cancer.