The 100 most-cited articles in Scientific Reports, 2018

Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2…

Multivariate time series data in practical applications, such as health care, geoscience, and biology, are characterized by a variety of missing values. In time series prediction and other related tasks, it has been noted that missing values and their missing patterns are often correlated with the target labels, a.k.a., informative missingness. There is very limited work on exploiting the missing patterns for effective imputation and improving prediction performance. In this paper, we develop novel deep learning models, namely GRU-D, as one of the early attempts. GRU-D is based on Gated Recurrent Unit (GRU), a state-of-the-art recurrent neural network. It takes two representations of missing patterns, i.e., masking and time interval, and effectively incorporates them into a deep model architecture so that it not only captures the long-term temporal dependencies in time series, but also utilizes the missing patterns to achieve better prediction results. Experiments of time series classification tasks on real-world clinical datasets (MIMIC-III, PhysioNet) and synthetic datasets…

Abstract Ocean plastic can persist in sea surface waters, eventually accumulating in remote areas of the world’s oceans. Here we characterise and quantify a major ocean plastic accumulation zone formed in subtropical waters between California and Hawaii: The Great Pacific Garbage Patch (GPGP). Our model, calibrated with data from multi-vessel and aircraft surveys, predicted at least 79 (45–129) thousand tonnes of ocean plastic are floating inside an area of 1.6 million km 2 ; a figure four to sixteen times higher than previously reported. We explain this difference through the use of more robust methods to quantify larger debris. Over three-quarters of the GPGP mass was carried by debris larger than 5 cm and at least 46% was comprised of fishing nets. Microplastics accounted for 8% of the total mass but 94% of the estimated 1.8 (1.1–3.6) trillion pieces floating in the area. Plastic collected during our study has specific characteristics such as small surface-to-volume ratio, indicating that only certain types of debris have the capacity to persist and accumulate at the surface of…

This study aims to understand through statistical learning the basic biophysical mechanisms behind three-dimensional folding of epigenomes. The 3DEpiLoop algorithm predicts three-dimensional chromatin looping interactions within topologically associating domains (TADs) from one-dimensional epigenomics and transcription factor profiles using the statistical learning. The predictions obtained by 3DEpiLoop are highly consistent with the reported experimental interactions. The complex signatures of epigenomic and transcription factors within the physically interacting chromatin regions (anchors) are similar across all genomic scales: genomic domains, chromosomal territories, cell types, and different individuals. We report the most important epigenetic and transcription factor features used for interaction identification either shared, or unique for each of sixteen (16) cell lines. The analysis shows that CTCF interaction anchors are enriched by transcription factors yet deficient in histone modifications, while the opposite is true in the case of RNAP II mediated interactions. The code…

The prevalence of depression may be affected by changes in psychiatric practices and the availability of online mental health information in the past two decades. This study aimed to evaluate the aggregate prevalence of depression in communities from different countries between 1994 and 2014 and to explore the variations in prevalence stratified by geographical, methodological and socio-economic factors. A total of 90 studies were identified and met the inclusion criteria (n = 1,112,573 adults) with 68 studies on single point prevalence, 9 studies on one-year prevalence, and 13 studies on lifetime prevalence of depression. A random-effects model meta-analysis that was performed to calculate the aggregate point, one-year and lifetime prevalence of depression calculated prevalences of 12.9%, 7.2% and 10.8% respectively. Point prevalence of depression was significantly higher in women (14.4%), countries with a medium human development index (HDI) (29.2%), studies published from 2004 to 2014 (15.4%) and when using self-reporting instruments (17.3%) to assess depression. Heterogeneity…

Coastal zones constitute one of the most heavily populated and developed land zones in the world. Despite the utility and economic benefits that coasts provide, there is no reliable global-scale assessment of historical shoreline change trends. Here, via the use of freely available optical satellite images captured since 1984, in conjunction with sophisticated image interrogation and analysis methods, we present a global-scale assessment of the occurrence of sandy beaches and rates of shoreline change therein. Applying pixel-based supervised classification, we found that 31% of the world's ice-free shoreline are sandy. The application of an automated shoreline detection method to the sandy shorelines thus identified resulted in a global dataset of shoreline change rates for the 33 year period 1984-2016. Analysis of the satellite derived shoreline data indicates that 24% of the world's sandy beaches are eroding at rates exceeding 0.5 m/yr, while 28% are accreting and 48% are stable. The majority of the sandy shorelines in marine protected areas are eroding, raising cause for serious…

Multiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and…

The biological interpretation of gene lists with interesting shared properties, such as up- or down-regulation in a particular experiment, is typically accomplished using gene ontology enrichment analysis tools. Given a list of genes, a gene ontology (GO) enrichment analysis may return hundreds of statistically significant GO results in a "flat" list, which can be challenging to summarize. It can also be difficult to keep pace with rapidly expanding biological knowledge, which often results in daily changes to any of the over 47,000 gene ontologies that describe biological knowledge. GOATOOLS, a Python-based library, makes it more efficient to stay current with the latest ontologies and annotations, perform gene ontology enrichment analyses to determine over- and under-represented terms, and organize results for greater clarity and easier interpretation using a novel GOATOOLS GO grouping method. We performed functional analyses on both stochastic simulation data and real data from a published RNA-seq study to compare the enrichment results from GOATOOLS to two other popular tools:…

The initial stage of host cell infection by influenza A viruses (IAV) is mediated through interaction of the viral haemagglutinin (HA) with cell surface glycans. The binding requirement of IAVs for Galβ(1,4)Glc/ GlcNAc (lactose/lactosamine) glycans with a terminal α(2,6)-linked (human receptors) or α(2,3)-linked (avian receptors) N-acetylneuraminic residue commonly found on N-glycans, is well-established. However the role and significance of sialylated Galβ(1,3)GalNAc (core 1) epitopes that are typical O-glycoforms in influenza virus pathogenesis remains poorly detailed. Here we report a multidisciplinary study using NMR spectroscopy, virus neutralization assays and molecular modelling, into the potential for IAV to engage sialyl-Galβ(1,3)GalNAc O-glycoforms for cell attachment. H5 containing virus like particles (VLPs) derived from an H5N1 avian IAV strain show a significant involvement of the O-glycan-specific GalNAc residue, coordinated by a EQTKLY motif conserved in highly pathogenic avian influenza (HPAI) strains. Notably, human pandemic H1N1 influenza viruses shift the…

Bulk equiatomic (Hf-Ta-Zr-Ti)C and (Hf-Ta-Zr-Nb)C high entropy Ultra-High Temperature Ceramic (UHTC) carbide compositions were fabricated by ball milling and Spark Plasma Sintering (SPS). It was found that the lattice parameter mismatch of the component monocarbides is a key factor for predicting single phase solid solution formation. The processing route was further optimised for the (Hf-Ta-Zr-Nb)C composition to produce a high purity, single phase, homogeneous, bulk high entropy material (99% density); revealing a vast new compositional space for the exploration of new UHTCs. One sample was observed to chemically decompose; indicating the presence of a miscibility gap. While this suggests the system is not thermodynamically stable to room temperature, it does reveal further potential for the development of new in situ formed UHTC nanocomposites. The optimised material was subjected to nanoindentation testing and directly compared to the constituent mono/binary carbides, revealing a significantly enhanced hardness (36.1 ± 1.6 GPa,) compared to the hardest monocarbide (HfC, 31.5 ±…

Microplastic contamination of aquatic ecosystems is a high priority research topic, whereas the issue on terrestrial ecosystems has been widely neglected. At the same time, terrestrial ecosystems under human influence, such as agroecosystems, are likely to be contaminated by plastic debris. However, the extent of this contamination has not been determined at present. Via Fourier transform infrared (FTIR) analysis, we quantified for the first time the macro- and microplastic contamination on an agricultural farmland in southeast Germany. We found 206 macroplastic pieces per hectare and 0.34 ± 0.36 microplastic particles per kilogram dry weight of soil. In general, polyethylene was the most common polymer type, followed by polystyrene and polypropylene. Films and fragments were the dominating categories found for microplastics, whereas predominantly films were found for macroplastics. Since we intentionally chose a study site where microplastic-containing fertilizers and agricultural plastic applications were never used, our findings report on plastic contamination on a site which…

Abstract Changes in coastal morphology have broad consequences for the sustainability of coastal communities, structures and ecosystems. Although coasts are monitored locally in many places, understanding long-term changes at a global scale remains a challenge. Here we present a global and consistent evaluation of coastal morphodynamics over 32 years (1984–2015) based on satellite observations. Land losses and gains were estimated from the changes in water presence along more than 2 million virtual transects. We find that the overall surface of eroded land is about 28,000 km 2 , twice the surface of gained land, and that often the extent of erosion and accretion is in the order of km. Anthropogenic factors clearly emerge as the dominant driver of change, both as planned exploitation of coastal resources, such as building coastal structures, and as unforeseen side effects of human activities, for example the installment of dams, irrigation systems and structures that modify the flux of sediments, or the clearing of coastal ecosystems, such as mangrove forests. Another important…

Phytochemicals of medicinal plants encompass a diverse chemical space for drug discovery. India is rich with a flora of indigenous medicinal plants that have been used for centuries in traditional Indian medicine to treat human maladies. A comprehensive online database on the phytochemistry of Indian medicinal plants will enable computational approaches towards natural product based drug discovery. In this direction, we present, IMPPAT, a manually curated database of 1742 Indian Medicinal Plants, 9596 Phytochemicals, And 1124 Therapeutic uses spanning 27074 plant-phytochemical associations and 11514 plant-therapeutic associations. Notably, the curation effort led to a non-redundant in silico library of 9596 phytochemicals with standard chemical identifiers and structure information. Using cheminformatic approaches, we have computed the physicochemical, ADMET (absorption, distribution, metabolism, excretion, toxicity) and drug-likeliness properties of the IMPPAT phytochemicals. We show that the stereochemical complexity and shape complexity of IMPPAT phytochemicals differ from…

Here we describe a method for fabricating a primary human Small Intestine-on-a-Chip (Intestine Chip) containing epithelial cells isolated from healthy regions of intestinal biopsies. The primary epithelial cells are expanded as 3D organoids, dissociated, and cultured on a porous membrane within a microfluidic device with human intestinal microvascular endothelium cultured in a parallel microchannel under flow and cyclic deformation. In the Intestine Chip, the epithelium forms villi-like projections lined by polarized epithelial cells that undergo multi-lineage differentiation similar to that of intestinal organoids, however, these cells expose their apical surfaces to an open lumen and interface with endothelium. Transcriptomic analysis also indicates that the Intestine Chip more closely mimics whole human duodenum in vivo when compared to the duodenal organoids used to create the chips. Because fluids flowing through the lumen of the Intestine Chip can be collected continuously, sequential analysis of fluid samples can be used to quantify nutrient digestion, mucus secretion and…

Abstract Introduction Missing values exist widely in mass-spectrometry (MS) based metabolomics data. Various methods have been applied for handling missing values, but the selection of methods can significantly affect following data analyses and interpretations. According to the definition, there are three types of missing values, missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). Objectives The aim of this study was to comprehensively compare common imputation methods for different types of missing values using two separate metabolomics data sets (977 and 198 serum samples respectively) to propose a strategy to deal with missing values in metabolomics studies. Methods Imputation methods included zero, half minimum (HM), mean, median, random forest (RF), singular value decomposition (SVD), k-nearest neighbors (kNN), and quantile regression imputation of left-censored data (QRILC). Normalized root mean squared error (NRMSE) and NRMSE-based sum of ranks (SOR) were applied to evaluate the imputation accuracy for MCAR/MAR and MNAR…

In the last two decades, Computer Aided Detection (CAD) systems were developed to help radiologists analyse screening mammograms, however benefits of current CAD technologies appear to be contradictory, therefore they should be improved to be ultimately considered useful. Since 2012, deep convolutional neural networks (CNN) have been a tremendous success in image recognition, reaching human performance. These methods have greatly surpassed the traditional approaches, which are similar to currently used CAD solutions. Deep CNN-s have the potential to revolutionize medical image analysis. We propose a CAD system based on one of the most successful object detection frameworks, Faster R-CNN. The system detects and classifies malignant or benign lesions on a mammogram without any human intervention. The proposed method sets the state of the art classification performance on the public INbreast database, AUC = 0.95. The approach described here has achieved 2nd place in the Digital Mammography DREAM Challenge with AUC = 0.85. When used as a detector, the system reaches high sensitivity…

We identify the physical mechanism through which newly developed quaternary ammonium salt (QAS) deposit control additives (DCAs) affect the rheological properties of cavitating turbulent flows, resulting in an increase in the volumetric efficiency of clean injectors fuelled with diesel or biodiesel fuels. Quaternary ammonium surfactants with appropriate counterions can be very effective in reducing the turbulent drag in aqueous solutions, however, less is known about the effect of such surfactants in oil-based solvents or in cavitating flow conditions. Small-angle neutron scattering (SANS) investigations show that in traditional DCA fuel compositions only reverse spherical micelles form, whereas reverse cylindrical micelles are detected by blending the fuel with the QAS additive. Moreover, experiments utilising X-ray micro computed tomography (micro-CT) in nozzle replicas, quantify that in cavitation regions the liquid fraction is increased in the presence of the QAS additive. Furthermore, high-flux X-ray phase contrast imaging (XPCI) measurements identify a flow stabilization…

Iron oxide nanoparticles (IONPs) have been increasingly used in biomedical applications, but the comprehensive understanding of their interactions with biological systems is relatively limited. In this study, we systematically investigated the in vitro cell uptake, cytotoxicity, in vivo distribution, clearance and toxicity of commercially available and well-characterized IONPs with different sizes and coatings. Polyethylenimine (PEI)-coated IONPs exhibited significantly higher uptake than PEGylated ones in both macrophages and cancer cells, and caused severe cytotoxicity through multiple mechanisms such as ROS production and apoptosis. 10 nm PEGylated IONPs showed higher cellular uptake than 30 nm ones, and were slightly cytotoxic only at high concentrations. Interestingly, PEGylated IONPs but not PEI-coated IONPs were able to induce autophagy, which may play a protective role against the cytotoxicity of IONPs. Biodistribution studies demonstrated that all the IONPs tended to distribute in the liver and spleen, and the biodegradation and clearance of PEGylated IONPs in these tissues…

Abstract Herein, a simple approach based on tailoring the surface charge of nanoparticles, NPs, during the preparation to boost the electrostatic attraction between NPs and the organic pollutant was investigated. In this study, chargeable titania nanoparticles (TiΟ 2 NPs) were synthesized via a hydrothermal route under different pH conditions (pH = 1.6, 7.0 and 10). The prepared TiΟ 2 NPs were fully characterized via various techniques including; transmission electron microscopy (TEM), X-ray diffraction (XRD), N 2 adsorption/desorption, X-ray photoelectron spectroscopy (XPS), Ultraviolet–visible spectroscopy (UV-Vis) and dynamic light scattering (DLS). The influence of the preparation pH on the particle size, surface area and band gap was investigated and showed pH-dependent behavior. The results revealed that upon increasing the pH value, the particle size decreases and lead to larger surface area with less particles agglomeration. Additionally, the effect of pH on the surface charge was monitored by XPS to determine the amount of hydroxyl groups on the TiO 2 NPs surface.…

Image-based machine learning and deep learning in particular has recently shown expert-level accuracy in medical image classification. In this study, we combine convolutional and recurrent architectures to train a deep network to predict colorectal cancer outcome based on images of tumour tissue samples. The novelty of our approach is that we directly predict patient outcome, without any intermediate tissue classification. We evaluate a set of digitized haematoxylin-eosin-stained tumour tissue microarray (TMA) samples from 420 colorectal cancer patients with clinicopathological and outcome data available. The results show that deep learning-based outcome prediction with only small tissue areas as input outperforms (hazard ratio 2.3; CI 95% 1.79-3.03; AUC 0.69) visual histological assessment performed by human experts on both TMA spot (HR 1.67; CI 95% 1.28-2.19; AUC 0.58) and whole-slide level (HR 1.65; CI 95% 1.30-2.15; AUC 0.57) in the stratification into low- and high-risk patients. Our results suggest that state-of-the-art deep learning techniques can extract more prognostic…

Abstract Development of conformal n-channel organic phototransistor (OPT) array is urgent for future applications of organic complementary circuits in portable and wearable electronics and optoelectronics. In this work, the ultrathin conformal OPT array based on air-stable n-type PTCDI-C13H27 was fabricated. The OPT array shows excellent electrical and photoelectrical performance, good device uniformity, and remains stable in electron mobility by 83% after 90 days compared to the initial values. Eventhough mobility, on-state current, off-state current, and photocurrent of PTCDI-C13H27 thin film phototransistor show slight decrease with the decreased bending radius, the device still remains the stable photosensitivity as high as 104 when the device is freely adhered on the 2D surfaces and 3D hemispherical sphere, which is in a class with the highest photosensitivity for perylene diimide derivatives. These results present the promising application potential of our conformable air-stable n-type PTCDI-C13H27 OPTs as the photodetection system of curved artificial compound eyes in…

Abstract We carried out systematic review and meta-analysis to evaluate whether peripheral levels of pro-inflammatory markers including Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF- α) and C-Reactive Protein (CRP) are significantly higher in elderly with depression and Alzheimer’s disease. We searched Pubmed, PsycINFO and Embase, and thirty-four relevant studies (2609 with Depression, 1645 with Alzheimer’s disease and 14363 Controls) were included. Compared with controls, IL-1β (pooled standardized mean difference [SMD]: 0.642; 95% confidence interval [CI]: 0.078–1.206; significant heterogeneity: I 2 = 86.28%) and IL-6 (pooled SMD: 0.377; 95% CI: 0.156–0.598; significant heterogeneity: I 2 = 88.75%) were significantly elevated in depression. There was no difference in TNF-α (p = 0.351) and CRP (p = 0.05) between those with depression and controls. Compared with controls, IL-1β (pooled SMD: 1.37, 95% CI: 0.06–2.68, significant heterogeneity: I 2 = 96.01%) was significantly elevated in Alzheimer’s disease. There were no differences in IL-6 (p =…

Defining the metabolic strategies used by wheat to tolerate and recover from drought events will be important for ensuring yield stability in the future, but studies addressing this critical research topic are limited. To this end, the current study quantified the physiological, biochemical, and agronomic responses of a drought tolerant and drought sensitive cultivar to periods of water deficit and recovery. Drought stress caused a reversible decline in leaf water relations, membrane stability, and photosynthetic activity, leading to increased reactive oxygen species (ROS) generation, lipid peroxidation and membrane injury. Plants exhibited osmotic adjustment through the accumulation of soluble sugars, proline, and free amino acids and increased enzymatic and non-enzymatic antioxidant activities. After re-watering, leaf water potential, membrane stability, photosynthetic processes, ROS generation, anti-oxidative activities, lipid peroxidation, and osmotic potential completely recovered for moderately stressed plants and did not fully recover in severely stressed plants. Higher…

Convolutional neural networks (CNNs) excel in a wide variety of computer vision applications, but their high performance also comes at a high computational cost. Despite efforts to increase efficiency both algorithmically and with specialized hardware, it remains difficult to deploy CNNs in embedded systems due to tight power budgets. Here we explore a complementary strategy that incorporates a layer of optical computing prior to electronic computing, improving performance on image classification tasks while adding minimal electronic computational cost or processing time. We propose a design for an optical convolutional layer based on an optimized diffractive optical element and test our design in two simulations: a learned optical correlator and an optoelectronic two-layer CNN. We demonstrate in simulation and with an optical prototype that the classification accuracies of our optical systems rival those of the analogous electronic implementations, while providing substantial savings on computational cost.

Wrist worn raw-data accelerometers are used increasingly in large-scale population research. We examined whether sleep parameters can be estimated from these data in the absence of sleep diaries. Our heuristic algorithm uses the variance in estimated z-axis angle and makes basic assumptions about sleep interruptions. Detected sleep period time window (SPT-window) was compared against sleep diary in 3752 participants (range = 60-82 years) and polysomnography in sleep clinic patients (N = 28) and in healthy good sleepers (N = 22). The SPT-window derived from the algorithm was 10.9 and 2.9 minutes longer compared with sleep diary in men and women, respectively. Mean C-statistic to detect the SPT-window compared to polysomnography was 0.86 and 0.83 in clinic-based and healthy sleepers, respectively. We demonstrated the accuracy of our algorithm to detect the SPT-window. The value of this algorithm lies in studies such as UK Biobank where a sleep diary was not used.

Thyroid plays an important role in the endocrine system of the human body. Its characterization by diffuse optics can open new path ways in the non-invasive diagnosis of thyroid pathologies. Yet, the absorption spectra of tyrosine and thyroglobulin-key tissue constituents specific to the thyroid organ-in the visible to near infrared range are not fully available. Here, we present the optical characterization of tyrosine (powder), thyroglobulin (granular form) and iodine (aqueous solution) using a time domain broadband diffuse optical spectrometer in the 550-1350 nm range. Various systematic errors caused by physics of photo migration and sample inherent properties were effectively suppressed by means of advanced time domain diffuse optical methods. A brief comparison with various other known tissue constituents is presented, which reveals key spectral regions for the quantification of the thyroid absorbers in an in vivo scenario.

We propose a new anthropometric index, weight-adjusted-waist index (WWI), to assess adiposity by standardizing waist circumference (WC) for weight. WWI, calculated as WC (cm) divided by the square root of weight (kg) (cm/√kg), was measured from 465,629 subjects in the Korean nationwide cohort (2008-2013). Cox regression analysis was used to compare WWI with BMI, WC, waist-to-height ratio (WHtR), and a body shape index (ABSI) for cardiometabolic morbidity and mortality risk in diagnostic and prognostic prediction models. For incident hypertension, type 2 diabetes and cardiovascular disease (CVD), BMI had the strongest predictive power, followed by WWI and WC. However, WWI showed the best predictive performance for CVD mortality. Also, a linear positive association between adiposity indices and cardiovascular and all-cause mortality was only shown in WWI and ABSI, not BMI, WC and WHtR which showed inverse J-shaped patterns. In the test of joint effects of each index, WWI combined with BMI was the strongest in both diagnostic and prognostic models. WWI is a unique adiposity index that…

Conventional machine learning approaches for predicting material properties from elemental compositions have emphasized the importance of leveraging domain knowledge when designing model inputs. Here, we demonstrate that by using a deep learning approach, we can bypass such manual feature engineering requiring domain knowledge and achieve much better results, even with only a few thousand training samples. We present the design and implementation of a deep neural network model referred to as ElemNet; it automatically captures the physical and chemical interactions and similarities between different elements using artificial intelligence which allows it to predict the materials properties with better accuracy and speed. The speed and best-in-class accuracy of ElemNet enable us to perform a fast and robust screening for new material candidates in a huge combinatorial space; where we predict hundreds of thousands of chemical systems that could contain yet-undiscovered compounds.

Abstract Measurements of skeletal muscle cross-sectional area, index, and radiation attenuation utilizing clinical computed tomography (CT) scans are used in assessments of sarcopenia, the loss of skeletal muscle mass and function associated with aging. To classify individuals as sarcopenic, sex-specific cutoffs for ‘low’ values are used. Conventionally, cutoffs for skeletal muscle measurements at the level of the third lumbar (L3) vertebra are used, however L3 is not included in several clinical CT protocols. Non-contrast-enhanced CT scans from healthy kidney donor candidates (age 18–40) at Michigan Medicine were utilized. Skeletal muscle area (SMA), index (SMI), and mean attenuation (SMRA) were measured at each vertebral level between the tenth thoracic (T10) and the fifth lumbar (L5) vertebra. Sex-specific means, standard deviations (s.d.), and sarcopenia cutoffs (mean-2 s.d.) at each vertebral level were computed. Associations between vertebral levels were assessed using Pearson correlations and Tukey’s difference test. Classification agreement between different vertebral level…

We report here the identification of α1 Na/K-ATPase as a major regulator of the proto-oncogene Src kinase and the role of this regulation in control of Warburg effect and tumor growth. Specifically, we discovered Y260 in α1 Na/K-ATPase as a Src-specific phosphorylation and binding site and that Y260 phosphorylation is required for Src-mediated signal transduction in response to a number of stimuli including EGF. As such, it enables a dynamic control of aerobic glycolysis. However, such regulation appears to be lost or attenuated in human cancers as the expression of Na/K-ATPase α1 was significantly decreased in prostate, breast and kidney cancers, and further reduced in corresponding metastatic lesions in patient samples. Consistently, knockdown of α1 Na/K-ATPase led to a further increase in lactate production and the growth of tumor xenograft. These findings suggest that α1 Na/K-ATPase works as a tumor suppressor and that a loss of Na/K-ATPase-mediated Src regulation may lead to Warburg phenotype in cancer.

Abstract Techniques for electrical brain stimulation (EBS), in which weak electrical stimulation is applied to the brain, have been extensively studied in various therapeutic brain functional applications. The extracellular fluid in the brain is a complex electrolyte that is composed of different types of ions, such as sodium (Na+), potassium (K+), and calcium (Ca+). Abnormal levels of electrolytes can cause a variety of pathological disorders. In this paper, we present a novel technique to visualize the total electrolyte concentration in the extracellular compartment of biological tissues. The electrical conductivity of biological tissues can be expressed as a product of the concentration and the mobility of the ions. Magnetic resonance electrical impedance tomography (MREIT) investigates the electrical properties in a region of interest (ROI) at low frequencies (below 1 kHz) by injecting currents into the brain region. Combining with diffusion tensor MRI (DT-MRI), we analyze the relation between the concentration of ions and the electrical properties extracted from the magnetic…

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS…

Elucidating brain cell type specific gene expression patterns is critical towards a better understanding of how cell-cell communications may influence brain functions and dysfunctions. We set out to compare and contrast five human and murine cell type-specific transcriptome-wide RNA expression data sets that were generated within the past several years. We defined three measures of brain cell type-relative expression including specificity, enrichment, and absolute expression and identified corresponding consensus brain cell "signatures," which were well conserved across data sets. We validated that the relative expression of top cell type markers are associated with proxies for cell type proportions in bulk RNA expression data from postmortem human brain samples. We further validated novel marker genes using an orthogonal ATAC-seq dataset. We performed multiscale coexpression network analysis of the single cell data sets and identified robust cell-specific gene modules. To facilitate the use of the cell type-specific genes for cell type proportion estimation and deconvolution from…

The inner structure of a material is called microstructure. It stores the genesis of a material and determines all its physical and chemical properties. While microstructural characterization is widely spread and well known, the microstructural classification is mostly done manually by human experts, which gives rise to uncertainties due to subjectivity. Since the microstructure could be a combination of different phases or constituents with complex substructures its automatic classification is very challenging and only a few prior studies exist. Prior works focused on designed and engineered features by experts and classified microstructures separately from the feature extraction step. Recently, Deep Learning methods have shown strong performance in vision applications by learning the features from data together with the classification step. In this work, we propose a Deep Learning method for microstructural classification in the examples of certain microstructural constituents of low carbon steel. This novel method employs pixel-wise segmentation via Fully Convolutional Neural…

This study investigated the trophic transfer, individual impact, and embryonic uptake of fluorescent nano-sized polystyrene plastics (nanoplastics) through direct exposure in a freshwater ecosystem, with a food chain containing four species. The alga Chlamydomonas reinhardtii, water flea Daphnia magna, secondary-consumer fish Oryzias sinensis, and end-consumer fish Zacco temminckii were used as test species. In the trophic transfer test, algae were exposed to 50 mg/L nanoplastics, defined as plastic particles <100 nm in diameter; higher trophic level organisms were exposed through their diet. In the direct exposure test, each species was directly exposed to nanoplastics. Microscopic analysis confirmed that the nanoplastics adhered to the surface of the primary producer and were present in the digestive organs of the higher trophic level species. Nanoplastics also negatively affected fish activity, as measured by distance traveled and area covered, and induced histopathological changes in the livers of fish that were directly exposed. Additionally, nanoplastics penetrated the embryo…

Despite the ecological and societal importance of large rivers, fish sampling remains costly and limited to specific habitats (e.g., river banks). Using an eDNA metabarcoding approach, we regularly sampled 500 km of a large river (Rhône River). Comparisons with long-term electrofishing surveys demonstrated the ability of eDNA metabarcoding to qualitatively and quantitatively reveal fish assemblage structures (relative species abundance) but eDNA integrated a larger space than the classical sampling location. Combination of a literature review and field data showed that eDNA behaves in the water column like fine particulate organic matter. Its detection distance varied from a few km in a small stream to more than 100 km in a large river. To our knowledge, our results are the first demonstration of the capacity of eDNA metabarcoding to describe longitudinal fish assemblage patterns in a large river, and metabarcoding appears to be a reliable, cost-effective method for future monitoring.

Abstract Baloxavir acid (BXA), derived from the prodrug baloxavir marboxil (BXM), potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In clinical trials, single doses of BXM profoundly decrease viral titers as well as alleviating influenza symptoms. Here, we characterize the impact on BXA susceptibility and replicative capacity of variant viruses detected in the post-treatment monitoring of the clinical studies. We find that the PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC 50 changes in A and B viruses, respectively. The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro . Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor. A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease. These…

Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 as a highly transmissible pathogenic human betacoronavirus. The viral spike glycoprotein (S) utilizes angiotensin-converting enzyme 2 (ACE2) as a host protein receptor and mediates fusion of the viral and host membranes, making S essential to viral entry into host cells and host species tropism. As SARS-CoV enters host cells, the viral S is believed to undergo a number of conformational transitions as it is cleaved by host proteases and binds to host receptors. We recently developed stabilizing mutations for coronavirus spikes that prevent the transition from the pre-fusion to post-fusion states. Here, we present cryo-EM analyses of a stabilized trimeric SARS-CoV S, as well as the trypsin-cleaved, stabilized S, and its interactions with ACE2. Neither binding to ACE2 nor cleavage by trypsin at the S1/S2 cleavage site impart large conformational changes within stabilized SARS-CoV S or expose the secondary cleavage site, S2'.

The Gleason grading system remains the most powerful prognostic predictor for patients with prostate cancer since the 1960s. Its application requires highly-trained pathologists, is tedious and yet suffers from limited inter-pathologist reproducibility, especially for the intermediate Gleason score 7. Automated annotation procedures constitute a viable solution to remedy these limitations. In this study, we present a deep learning approach for automated Gleason grading of prostate cancer tissue microarrays with Hematoxylin and Eosin (H&E) staining. Our system was trained using detailed Gleason annotations on a discovery cohort of 641 patients and was then evaluated on an independent test cohort of 245 patients annotated by two pathologists. On the test cohort, the inter-annotator agreements between the model and each pathologist, quantified via Cohen's quadratic kappa statistic, were 0.75 and 0.71 respectively, comparable with the inter-pathologist agreement (kappa = 0.71). Furthermore, the model's Gleason score assignments achieved pathology expert-level stratification of patients…

Peptide-YY (PYY) and Glucagon-Like Peptide-1 (GLP-1) play important roles in the regulation of food intake and insulin secretion, and are of translational interest in the field of obesity and diabetes. PYY production is highest in enteroendocrine cells located in the distal intestine, mirroring the sites where high concentrations of short chain fatty acids (SCFAs) are produced by gut microbiota. We show here that propionate and butyrate strongly increased expression of PYY but not GCG in human cell line and intestinal primary culture models. The effect was predominantly attributable to the histone deacetylase inhibitory activity of SCFA and minor, but significant contributions of FFA2 (GPR43). Consistent with the SCFA-dependent elevation of PYY gene expression, we also observed increased basal and stimulated PYY hormone secretion. Interestingly, the transcriptional stimulation of PYY was specific to human-derived cell models and not reproduced in murine primary cultures. This is likely due to substantial differences in PYY gene structure between mouse and human. In summary, this…

Hydrothermal reduction is a promising approach for graphene oxide (GO) reduction since it is environmentally friendly, simple, and cost effective. We present a detailed study of structural changes occurring in graphene oxide during the reduction process. The correlations between the interlayer spacing, chemical states, work functions, surface morphology, level of disorders, the number of layers, and processing time are elucidated. The results reveal that GO flakes remain in the early stage of the reduction process and that they are fully reduced after a 4-h hydrothermal treatment. With an increase in the reduction time, the resulting product, i.e., reduced graphene oxide, has a low oxygen content, small interlayer spacing, and crumbled and wrinkled structures. We are convinced that these properties can be tuned to a desired level for various applications.

In this study, we report transcription of genes involved in aerobic and anaerobic benzene degradation pathways in a benzene-degrading denitrifying continuous culture. Transcripts associated with the family Peptococcaceae dominated all samples (21-36% relative abundance) indicating their key role in the community. We found a highly transcribed gene cluster encoding a presumed anaerobic benzene carboxylase (AbcA and AbcD) and a benzoate-coenzyme A ligase (BzlA). Predicted gene products showed >96% amino acid identity and similar gene order to the corresponding benzene degradation gene cluster described previously, providing further evidence for anaerobic benzene activation via carboxylation. For subsequent benzoyl-CoA dearomatization, bam-like genes analogous to the ones found in other strict anaerobes were transcribed, whereas gene transcripts involved in downstream benzoyl-CoA degradation were mostly analogous to the ones described in facultative anaerobes. The concurrent transcription of genes encoding enzymes involved in oxygenase-mediated aerobic benzene degradation suggested…

We aimed to assess the impact of timing of surgery in elderly patients with acute hip fracture on morbidity and mortality. We systematically searched MEDLINE, the Cochrane Library, Embase, PubMed, and trial registries from 01/1997 to 05/2017, as well as reference lists of relevant reviews, archives of orthopaedic conferences, and contacted experts. Eligible studies had to be randomised controlled trials (RCTs) or prospective cohort studies, including patients 60 years or older with acute hip fracture. Two authors independently assessed study eligibility, abstracted data, and critically appraised study quality. We conducted meta-analyses using the generic inverse variance model. We included 28 prospective observational studies reporting data of 31,242 patients. Patients operated on within 48 hours had a 20% lower risk of dying within 12 months (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.66-0.97). No statistical significant different mortality risk was observed when comparing patients operated on within or after 24 hours (RR 0.82, 95% CI 0.67-1.01). Adjusted data…

Abstract Fine particulate matters less than 2.5 µm (PM2.5) in the ambient atmosphere are strongly associated with adverse health effects. However, it is unlikely that all fine particles are equally toxic in view of their different sizes and chemical components. Toxicity of fine particles produced from various combustion sources (diesel engine, gasoline engine, biomass burning (rice straw and pine stem burning), and coal combustion) and non-combustion sources (road dust including sea spray aerosols, ammonium sulfate, ammonium nitrate, and secondary organic aerosols (SOA)), which are known major sources of PM2.5, was determined. Multiple biological and chemical endpoints were integrated for various source-specific aerosols to derive toxicity scores for particles originating from different sources. The highest toxicity score was obtained for diesel engine exhaust particles, followed by gasoline engine exhaust particles, biomass burning particles, coal combustion particles, and road dust, suggesting that traffic plays the most critical role in enhancing the toxic effects of fine…

Mangroves are amongst the most productive marine ecosystems on Earth, providing a unique habitat opportunity for many species and key goods and services for human beings. Mangrove habitats are regressing at an alarming rate, due to direct anthropogenic impacts and global change. Here, in order to assess the effects of mangrove habitat degradation on benthic biodiversity and ecosystem functioning, we investigated meiofaunal biodiversity (as proxy of benthic biodiversity), benthic biomass and prokaryotic heterotrophic production (as proxies of ecosystem functioning) and trophic state in a disturbed and an undisturbed mangrove forests. We report here that disturbed mangrove area showed a loss of 20% of benthic biodiversity, with the local extinction of four Phyla (Cladocera, Kynorincha, Priapulida, Tanaidacea), a loss of 80% of microbial-mediated decomposition rates, of the benthic biomass and of the trophic resources. The results of this study strengthen the need to preserve mangrove forests and to restore those degraded to guarantee the provision of goods and services needed to…

Abstract In β titanium alloys, the β stabilizers segregate easily and considerable effort has been devoted to alleviate/eliminate the segregation. In this work, instead of addressing the segregation problems, the segregation was utilized to develop a novel microstructure consisting of a nanometre-grained duplex (α+β) structure and micrometre scale β phase with superior mechanical properties. An as-cast Ti-9Mo-6W alloy exhibited segregation of Mo and W at the tens of micrometre scale. This was subjected to cold rolling and flash annealing at 820 oC for 2 and 5 mins. The solidification segregation of Mo and W leads to a locally different microstructure after cold rolling (i.e., nanostructured β phase in the regions rich in Mo and W and plate-like martensite and β phase in regions relatively poor in Mo and W), which play a decisive role in the formation of the heterogeneous microstructure. Tensile tests showed that this alloy exhibited a superior combination of high yield strength (692 MPa), high tensile strength (1115 MPa), high work hardening rate and large uniform elongation…

Abstract For frequently used engineered nanomaterials (ENMs) CeO2-, SiO2-, and Ag, past, current, and future use and environmental release are investigated. Considering an extended period (1950 to 2050), we assess ENMs released through commercial activity as well as found in natural and technical settings. Temporal dynamics, including shifts in release due to ENM product application, stock (delayed use), and subsequent end-of-life product treatment were taken into account. We distinguish predicted concentrations originating in ENM use phase and those originating from end-of-life release. Furthermore, we compare Ag- and CeO2-ENM predictions with existing measurements. The correlations and limitations of the model, and the analytic validity of our approach are discussed in the context of massive use of assumptive model data and high uncertainty on the colloidal material captured by the measurements. Predictions for freshwater CeO2-ENMs range from 1 pg/l (2017) to a few hundred ng/l (2050). Relative to CeO2, the SiO2-ENMs estimates are approximately 1,000 times higher, and those for…

The Xiamaling Formation in the North China Block contains a well-preserved 1400 Ma sedimentary sequence with a low degree of thermal maturity. Previous studies have confirmed the dynamic and complex nature of this evolving marine setting, including the existence of an oxygen-minimum zone, using multi-proxy approaches, including iron speciation, trace metal dynamics, and organic geochemistry. Here, we investigate the prevailing redox conditions during diagenesis via the biomarkers of rearranged hopanes from the finely laminated sediments of the organic-rich black shales in Units 2 and 3 of the Xiamaling Formation. We find that rearranged hopanes are prominent in the biomarker composition of the oxygen-minimum zone sediment, which is completely different from that of the sediment in the overlying anoxic strata. Since the transition process from hopanes to rearranged hopanes requires oxygen via oxidation at the C-l6 alkyl position of 17α(H)-hopanes, we infer that dissolved oxygen led to the transformation of hopane precursors into rearranged hopanes during the early stages of…

Abstract Airborne-mediated microbial diseases such as influenza and tuberculosis represent major public health challenges. A direct approach to prevent airborne transmission is inactivation of airborne pathogens, and the airborne antimicrobial potential of UVC ultraviolet light has long been established; however, its widespread use in public settings is limited because conventional UVC light sources are both carcinogenic and cataractogenic. By contrast, we have previously shown that far-UVC light (207–222 nm) efficiently kills bacteria without harm to exposed mammalian skin. This is because, due to its strong absorbance in biological materials, far-UVC light cannot penetrate even the outer (non living) layers of human skin or eye; however, because bacteria and viruses are of micrometer or smaller dimensions, far-UVC can penetrate and inactivate them. We show for the first time that far-UVC efficiently kills airborne aerosolized viruses, a very low dose of 2 mJ/cm 2 of 222-nm light inactivating >95% of aerosolized H1N1 influenza virus. Continuous very low dose-rate far-UVC light in…

Affective Computing has emerged as an important field of study that aims to develop systems that can automatically recognize emotions. Up to the present, elicitation has been carried out with non-immersive stimuli. This study, on the other hand, aims to develop an emotion recognition system for affective states evoked through Immersive Virtual Environments. Four alternative virtual rooms were designed to elicit four possible arousal-valence combinations, as described in each quadrant of the Circumplex Model of Affects. An experiment involving the recording of the electroencephalography (EEG) and electrocardiography (ECG) of sixty participants was carried out. A set of features was extracted from these signals using various state-of-the-art metrics that quantify brain and cardiovascular linear and nonlinear dynamics, which were input into a Support Vector Machine classifier to predict the subject's arousal and valence perception. The model's accuracy was 75.00% along the arousal dimension and 71.21% along the valence dimension. Our findings validate the use of Immersive Virtual…

Abstract The study was performed to explore physiological, non-enzymatic and enzymatic detoxification pathways of reactive oxygen species (ROS) in tolerance ofAmaranthus tricolorunder drought stress. The tolerant genotype VA13 exhibited lower reduction in growth, photosynthetic pigments, relative water content (RWC) and negligible increment in electrolyte leakage (EL), lower increment in proline, guaiacol peroxidase (GPOX) activity compared to sensitive genotype VA15. This genotype also had higher catalase (CAT), superoxide dismutase (SOD), remarkable and dramatic increment in ascorbate-glutathione content, ascorbate-glutathione redox and ascorbate-glutathione cycle enzymes activity compared to sensitive genotype VA15. The negligible increment of ascorbate-glutathione content, ascorbate-glutathione redox and ascorbate-glutathione cycle enzymes activities and dramatic increment in malondialdehyde (MDA), hydrogen peroxide (H2O2) and EL were observed in the sensitive genotype VA15. SOD contributed superoxide radical dismutation and CAT contributed H2O2detoxification in both sensitive…

Root exudates comprise a large variety of compounds released by plants into the rhizosphere, including low-molecular-weight primary metabolites (particularly saccharides, amino acids and organic acids) and secondary metabolites (phenolics, flavonoids and terpenoids). Changes in exudate composition could have impacts on the plant itself, on other plants, on soil properties (e.g. amount of soil organic matter), and on soil organisms. The effects of drought on the composition of root exudates, however, have been rarely studied. We used an ecometabolomics approach to identify the compounds in the exudates of Quercus ilex (holm oak) under an experimental drought gradient and subsequent recovery. Increasing drought stress strongly affected the composition of the exudate metabolome. Plant exudates under drought consisted mainly of secondary metabolites (71% of total metabolites) associated with plant responses to drought stress, whereas the metabolite composition under recovery shifted towards a dominance of primary metabolites (81% of total metabolites). These results strongly suggested…

Abstract System xc− was recently described as the most upstream node in a novel form of regulated necrotic cell death, called ferroptosis. In this context, the small molecule erastin was reported to target and inhibit system xc−, leading to cysteine starvation, glutathione depletion and consequently ferroptotic cell death. Although the inhibitory effect of erastin towards system xc− is well-documented, nothing is known about its mechanism of action. Therefore, we sought to interrogate in more detail the underlying mechanism of erastin’s pro-ferroptotic effects. When comparing with some well-known inhibitors of system xc−, erastin was the most efficient inhibitor acting at low micromolar concentrations. Notably, only a very short exposure of cells with low erastin concentrations was sufficient to cause a strong and persistent inhibition of system xc−, causing glutathione depletion. These inhibitory effects towards system xc− did not involve cysteine modifications of the transporter. More importantly, short exposure of tumor cells with erastin strongly potentiated the cytotoxic…

Abstract Microplastic is a contaminant of concern worldwide. Rivers are implicated as major pathways of microplastic transport to marine and lake ecosystems, and microplastic ingestion by freshwater biota is a risk associated with microplastic contamination, but there is little research on microplastic ecology within freshwater ecosystems. Microplastic uptake by fish is likely affected by environmental microplastic abundance and aspects of fish ecology, but these relationships have rarely been addressed. We measured the abundance and composition of microplastic in fish and surface waters from 3 major tributaries of Lake Michigan, USA. Microplastic was detected in fish and surface waters from all 3 sites, but there was no correlation between microplastic concentrations in fish and surface waters. Rather, there was a significant effect of functional feeding group on microplastic concentration in fish. Neogobius melanostomus (round goby, a zoobenthivore) had the highest concentration of gut microplastic (19 particles fish −1 ) compared to 10 other fish taxa measured, and had a positive…

Exosomes participate in cell-to-cell communication, facilitated by the transfer of RNAs, proteins and lipids from donor to recipient cells. Exosomes and their RNA cargos do not exclusively originate from endogenous synthesis but may also be obtained from dietary sources such as the inter-species transfer of exosomes and RNAs in bovine milk to humans. Here, we assessed the bioavailability and distribution of exosomes and their microRNA cargos from bovine, porcine and murine milk within and across species boundaries. Milk exosomes labeled with fluorophores or fluorescent fusion proteins accumulated in liver, spleen and brain following suckling, oral gavage and intravenous administration in mice and pigs. When synthetic, fluorophore-labeled microRNAs were transfected into bovine milk exosomes and administered to mice, distinct species of microRNAs demonstrated unique distribution profiles and accumulated in intestinal mucosa, spleen, liver, heart or brain. Administration of bovine milk exosomes failed to rescue Drosha homozygous knockout mice, presumably due to low bioavailability or…

Climate variability and trends affect global crop yields and are characterized as highly dependent on location, crop type, and irrigation. U.S. Great Plains, due to its significance in national food production, evident climate variability, and extensive irrigation is an ideal region of investigation for climate impacts on food production. This paper evaluates climate impacts on maize, sorghum, and soybean yields and effect of irrigation for individual counties in this region by employing extensive crop yield and climate datasets from 1968-2013. Variability in crop yields was a quarter of the regional average yields, with a quarter of this variability explained by climate variability, and temperature and precipitation explained these in singularity or combination at different locations. Observed temperature trend was beneficial for maize yields, but detrimental for sorghum and soybean yields, whereas observed precipitation trend was beneficial for all three crops. Irrigated yields demonstrated increased robustness and an effective mitigation strategy against climate impacts than…

Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR-/-; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific…

High whole-body fat percentage is independently associated with increased mortality. We aimed to identify a simple anthropometric linear equation that is more accurate than the body mass index (BMI) to estimate whole-body fat percentage among adult individuals. National Health and Nutrition Examination Survey (NHANES) 1999-2004 data (n = 12,581) were used for model development and NHANES 2005-2006 data (n = 3,456) were used for model validation. From the 365 anthropometric indices generated, the final selected equation was as follows: 64 - (20 × height/waist circumference) + (12 × sex), named as the relative fat mass (RFM); sex = 0 for men and 1 for women. In the validation dataset, compared with BMI, RFM better predicted whole-body fat percentage, measured by dual energy X-ray absorptiometry (DXA), among women and men. RFM showed better accuracy than the BMI and had fewer false negative cases of body fat-defined obesity among women and men. RFM reduced total obesity misclassification among all women and all men and, overall, among Mexican-Americans, European-Americans and…

Abstract A simple approach for growing porous electrochemically reduced graphene oxide (pErGO) networks on copper wire, modified with galvanostatically deposited copper foam is demonstrated. The as-prepared pErGO networks on the copper wire are directly used to fabricate solid-state supercapacitor. The pErGO-based supercapacitor can deliver a specific capacitance (C sp ) as high as 81±3 F g −1 at 0.5 A g −1 with polyvinyl alcohol/H 3 PO 4 gel electrolyte. The C sp per unit length and area are calculated as 40.5 mF cm −1 and 283.5 mF cm −2 , respectively. The shape of the voltammogram retained up to high scan rate of 100 V s −1 . The pErGO-based supercapacitor device exhibits noticeably high charge-discharge cycling stability, with 94.5% C sp retained even after 5000 cycles at 5 A g −1 . Nominal change in the specific capacitance, as well as the shape of the voltammogram, is observed at different bending angles of the device even after 5000 cycles. The highest energy density of 11.25 W h kg −1 and the highest power density of 5 kW kg −1 are also achieved with this device. The…

Extrusion processing of carbon tubes can be problematic due to their poor interfacial interactions with polymeric matrices. Surface chemical modification of carbon tubes can be utilized to create bonding sites to form networks with polymer chains. However, chemical reactions resulting in intermolecular primary bonding limit processability of extrudate, since they cause unstable rheological behaviour, and thus decrease the stock holding time, which is determinative in extrusion. This study presents a method for the synthesis of carbon microtubes with physically modified surface area to improve the filler and matrix interfacial interactions. The key concept is the formation of a nanogrooved topography, through acoustic cavitation on the surface of processing fibres. The effect of nanogrooving on roughness parameters is described, along with the role of surface modified carbon tubes on rheological behaviour, homogeneity, and coherency of extrudate. The measurements showed that nanogrooving increases the surface area of carbon microtubes, as a result, die swelling of the extrudate is…

Abstract We report a facile and cost-effective approach to develop self-standing reduced Graphene Oxide (rGO) film based optical sensor and its low-temperature performance analysis where midgap defect states play a key role in tuning the crucial sensor parameters. Graphite oxide (GO) is produced by modified Hummers’ method and reduced thermally at 250 °C for 1 h in Argon atmosphere to obtain rGO. Self-standing rGO film is prepared via vacuum filtration. The developed film is characterized by HRTEM, FESEM, Raman, and XRD techniques. The developed sensor exhibits highest sensitivity towards 635 nm illumination wavelength, irrespective of the operating temperature. For a given excitation wavelength, photoresponse study at low temperature (123K–303K) reveals inverse relationship between sensitivity and operating temperature. Highest sensitivity of 49.2% is obtained at 123 K for 635 nm laser at power density of 1.4 mW/mm2. Unlike sensitivity, response- and recovery-time demonstrate directly proportional dependence with operating temperature. Power dependent studies establish linear…

As part of efforts to reduce pressure on the Amazon and other biomes, one approach considered by Brazilian authorities and scientists is more intensive use of the soils of the interior of the northeast of the country, which are generally sandy, with low contents of organic matter and low water holding capacity and are frequently affected by severe droughts. In this work, biochars produced from waste biomasses were tested for the improvement of these soils. The highest BET (Brunauer-Emmett-Teller) specific surface areas were observed for all biochars. In the pH range studied, the water hyacinth plants (WH) sample showed the most negative zeta potentials, as well as the highest water holding capacity (WHC) values, while the zeta potentials of two quartzarenic neosol soils were consistent with their WHC values. The results suggested that despite the effect of porosity on water retention, the zeta potential could be associated with the presence of negative charges by which hydrated cationic counterions were absorbed and retained. The surface energy and its polar and dispersive…

Herein, we investigate the morphology, structure and piezoelectric performances of neat polyvinylidene fluoride hexafluoropropylene (PVDF-HFP) and PVDF-HFP/Co-ZnO nanofibers, fabricated by electrospinning. An increase in the amount of crystalline β-phase of PVDF-HFP has been observed with the increase in Co-doped ZnO nanofiller concentration in the PVDF-HFP matrix. The dielectric constants of the neat PVDF-HFP and PVDF-HFP/2 wt.% Co-ZnO nanofibers are derived as 8 and 38 respectively. The flexible nanogenerator manipulated from the polymer nanocomposite (PVDF-HFP/Co-ZnO) exhibits an output voltage as high as 2.8 V compared with the neat PVDF-HFP sample (~120 mV). These results indicate that the investigated nanocomposite is appropriate for fabricating various flexible and wearable self-powered electrical devices and systems.

Abstract Gravimetry is a well-established technique for the determination of sub-surface mass distribution needed in several fields of geoscience, and various types of gravimeters have been developed over the last 50 years. Among them, quantum gravimeters based on atom interferometry have shown top-level performance in terms of sensitivity, long-term stability and accuracy. Nevertheless, they have remained confined to laboratories due to their complex operation and high sensitivity to the external environment. Here we report on a novel, transportable, quantum gravimeter that can be operated under real world conditions by non-specialists, and measure the absolute gravitational acceleration continuously with a long-term stability below 10 nm.s −2 (1 μ Gal). It features several technological innovations that allow for high-precision gravity measurements, while keeping the instrument light and small enough for field measurements. The instrument was characterized in detail and its stability was evaluated during a month-long measurement campaign.

The controlled preparation of Au nanoparticles (NPs) in the size range of 6 to 22 nm is explored in this study. The Au NPs were prepared by the reduction of tetrachloroauric acid using maltose in the presence of nonionic surfactant Tween 80 at various concentrations to control the size of the resulting Au NPs. With increasing concentration of Tween 80 a decrease in the size of produced Au NPs was observed, along with a significant decrease in their size distribution. The size-dependent catalytic activity of the synthesized Au NPs was tested in the reduction of 4-nitrophenol with sodium borohydride, resulting in increasing catalytic activity with decreasing size of the prepared nanoparticles. Eley-Rideal catalytic mechanism emerges as the more probable, in contrary to the Langmuir-Hinshelwood mechanism reported for other noble metal nanocatalysts.

Autism spectrum disorder (ASD) is a complex and heterogeneous disorder, diagnosed on the basis of behavioral symptoms during the second year of life or later. Finding scalable biomarkers for early detection is challenging because of the variability in presentation of the disorder and the need for simple measurements that could be implemented routinely during well-baby checkups. EEG is a relatively easy-to-use, low cost brain measurement tool that is being increasingly explored as a potential clinical tool for monitoring atypical brain development. EEG measurements were collected from 99 infants with an older sibling diagnosed with ASD, and 89 low risk controls, beginning at 3 months of age and continuing until 36 months of age. Nonlinear features were computed from EEG signals and used as input to statistical learning methods. Prediction of the clinical diagnostic outcome of ASD or not ASD was highly accurate when using EEG measurements from as early as 3 months of age. Specificity, sensitivity and PPV were high, exceeding 95% at some ages. Prediction of ADOS calibrated severity…

The employment of functional near-infrared spectroscopy (fNIRS) as a method of brain imaging has increased over the last few years due to its portability, low-cost and robustness to subject movement. Experiments with fNIRS are designed in the face of a limited number of sources and detectors (optodes) to be positioned on selected portion(s) of the scalp. The optodes locations represent an expectation of assessing cortical regions relevant to the experiment's hypothesis. However, this translation process remains a challenge for fNIRS experimental design. In the present study, we propose an approach that automatically decides the location of fNIRS optodes from a set of predefined positions with the aim of maximizing the anatomical specificity to brain regions-of-interest. The implemented method is based on photon transport simulations on two head atlases. The results are compiled into the publicly available "fNIRS Optodes' Location Decider" (fOLD). This toolbox is a first-order approach to bring the achieved advancements of parcellation methods and meta-analyses from functional…

Abstract Clostridium difficile virulence is driven primarily by the processes of toxinogenesis and sporulation, however many in vitro experimental systems for studying C. difficile physiology have arguably limited relevance to the human colonic environment. We therefore created a more physiologically–relevant model of the colonic milieu to study gut pathogen biology, incorporating human faecal water (FW) into growth media and assessing the physiological effects of this on C. difficile strain 630. We identified a novel set of C. difficile–derived metabolites in culture supernatants, including hexanoyl– and pentanoyl–amino acid derivatives by LC-MSn. Growth of C. difficile strain 630 in FW media resulted in increased cell length without altering growth rate and RNA sequencing identified 889 transcripts as differentially expressed (p < 0.001). Significantly, up to 300–fold increases in the expression of sporulation–associated genes were observed in FW media–grown cells, along with reductions in motility and toxin genes’ expression. Moreover, the expression of classical stress–response…

Alzheimer's Disease (AD) is a progressive neurodegenerative disease where biomarkers for disease based on pathophysiology may be able to provide objective measures for disease diagnosis and staging. Neuroimaging scans acquired from MRI and metabolism images obtained by FDG-PET provide in-vivo measurements of structure and function (glucose metabolism) in a living brain. It is hypothesized that combining multiple different image modalities providing complementary information could help improve early diagnosis of AD. In this paper, we propose a novel deep-learning-based framework to discriminate individuals with AD utilizing a multimodal and multiscale deep neural network. Our method delivers 82.4% accuracy in identifying the individuals with mild cognitive impairment (MCI) who will convert to AD at 3 years prior to conversion (86.4% combined accuracy for conversion within 1-3 years), a 94.23% sensitivity in classifying individuals with clinical diagnosis of probable AD, and a 86.3% specificity in classifying non-demented controls improving upon results in published literature.

Alternative methods, including green synthetic approaches for the preparation of various types of nanoparticles are important to maintain sustainable development. Extracellular or intracellular extracts of fungi are perfect candidates for the synthesis of metal nanoparticles due to the scalability and cost efficiency of fungal growth even on industrial scale. There are several methods and techniques that use fungi-originated fractions for synthesis of gold nanoparticles. However, there is less knowledge about the drawbacks and limitations of these techniques. Additionally, identification of components that play key roles in the synthesis is challenging. Here we show and compare the results of three different approaches for the synthesis of gold nanoparticles using either the extracellular fraction, the autolysate of the fungi or the intracellular fraction of 29 thermophilic fungi. We observed the formation of nanoparticles with different sizes (ranging between 6 nm and 40 nm) and size distributions (with standard deviations ranging between 30% and 70%) depending on the fungi strain…

Previous studies suggested a possible gut microbiota dysbiosis in chronic heart failure (CHF). However, direct evidence was lacking. In this study, we investigated the composition and metabolic patterns of gut microbiota in CHF patients to provide direct evidence and comprehensive understanding of gut microbiota dysbiosis in CHF. We enrolled 53 CHF patients and 41 controls. Metagenomic analyses of faecal samples and metabolomic analyses of faecal and plasma samples were then performed. We found that the composition of gut microbiota in CHF was significantly different from controls. Faecalibacterium prausnitzii decrease and Ruminococcus gnavus increase were the essential characteristics in CHF patients' gut microbiota. We also observed an imbalance of gut microbes involved in the metabolism of protective metabolites such as butyrate and harmful metabolites such as trimethylamine N-oxide in CHF patients. Metabolic features of both faecal and plasma samples from CHF patients also significantly changed. Moreover, alterations in faecal and plasma metabolic patterns correlated with gut…

The myocardium behaves like a sophisticated orchestra that expresses its true potential only if each member performs the correct task harmonically. Recapitulating its complexity within engineered 3D functional constructs with tailored biological and mechanical properties, is one of the current scientific priorities in the field of regenerative medicine and tissue engineering. In this study, driven by the necessity of fabricating advanced model of cardiac tissue, we present an innovative approach consisting of heterogeneous, multi-cellular constructs composed of Human Umbilical Vein Endothelial Cells (HUVECs) and induced pluripotent cell-derived cardiomyocytes (iPSC-CMs). Cells were encapsulated within hydrogel strands containing alginate and PEG-Fibrinogen (PF) and extruded through a custom microfluidic printing head (MPH) that allows to precisely tailor their 3D spatial deposition, guaranteeing a high printing fidelity and resolution. We obtained a 3D cardiac tissue compose of iPSC-derived CMs with a high orientation index imposed by the different defined geometries and blood…

Magnetic skyrmions are topological quasiparticles of great interest for data storage applications because of their small size, high stability, and ease of manipulation via electric current. However, although models exist for some limiting cases, there is no universal theory capable of accurately describing the structure and energetics of all skyrmions. The main barrier is the complexity of non-local stray field interactions, which are usually included through crude approximations. Here we present an accurate analytical framework to treat isolated skyrmions in any material, assuming only a circularly-symmetric 360° domain wall profile and a homogeneous magnetization profile in the out-of-plane direction. We establish the first rigorous criteria to distinguish stray field from DMI skyrmions, resolving a major dispute in the community. We discover new phases, such as bi-stability, a phenomenon unknown in magnetism so far. We predict materials for sub-10 nm zero field room temperature stable skyrmions suitable for applications. Finally, we derive analytical equations to describe…

Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer's disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3-7 of the Aβ peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. Direct comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab demonstrate clear differentiation in the binding properties of these antibodies. The crystal structure of the Fab fragment of aducanumab bound to its epitope peptide reveals that aducanumab binds to the N terminus of Aβ in an extended conformation, distinct from those seen in structures with other antibodies that target this immunodominant epitope. Aducanumab recognizes a compact epitope that sits in a shallow pocket on the antibody surface. In silico analyses suggest that aducanumab interacts weakly with the Aβ monomer and may accommodate a variety of peptide…

Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0 mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25 mg/kg clozapine from vehicle, CNO (1.0-20.0 mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine-like…

Abstract Multiferroic materials have attracted considerable attention as possible candidates for a wide variety of future microelectronic and memory devices, although robust magnetoelectric (ME) coupling between electric and magnetic orders at room temperature still remains difficult to achieve. In order to obtain robust ME coupling at room temperature, we studied the Pb(Fe0.5Nb0.5)O3/Ni0.65Zn0.35Fe2O4/Pb(Fe0.5Nb0.5)O3 (PFN/NZFO/PFN) trilayer structure as a representative FE/FM/FE system. We report the ferroelectric, magnetic and ME properties of PFN/NZFO/PFN trilayer nanoscale heterostructure having dimensions 70/20/70 nm, at room temperature. The presence of only (00l) reflection of PFN and NZFO in the X-ray diffraction (XRD) patterns and electron diffraction patterns in Transmission Electron Microscopy (TEM) confirm the epitaxial growth of multilayer heterostructure. The distribution of the ferroelectric loop area in a wide area has been studied, suggesting that spatial variability of ferroelectric switching behavior is low, and film growth is of high quality. The ferroelectric…

Abstract DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5′ UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10 −10 ), ulcerative colitis (p = 2 × 10 −5 ), Crohn’s disease (p = 6 × 10 −8 ) and coronary artery disease (p = 5.5 × 10 −6 )…

Early 21st-century droughts in Europe have been broadly regarded as exceptionally severe, substantially affecting a wide range of socio-economic sectors. These extreme events were linked mainly to increases in temperature and record-breaking heatwaves that have been influencing Europe since 2000, in combination with a lack of precipitation during the summer months. Drought propagated through all respective compartments of the hydrological cycle, involving low runoff and prolonged soil moisture deficits. What if these recent droughts are not as extreme as previously thought? Using reconstructed droughts over the last 250 years, we show that although the 2003 and 2015 droughts may be regarded as the most extreme droughts driven by precipitation deficits during the vegetation period, their spatial extent and severity at a long-term European scale are less uncommon. This conclusion is evident in our concurrent investigation of three major drought types - meteorological (precipitation), agricultural (soil moisture) and hydrological (grid-scale runoff) droughts. Additionally,…

Abstract Magnesium oxide nanoparticle (nMgO) is a light metal based antimicrobial nanoparticle that can be metabolized and fully resorbed in the body. To take advantage of the antimicrobial properties of nMgO for medical use, it is necessary to determine the minimal inhibitory, bactericidal and fungicidal concentrations (MIC, MBC and MFC) of nMgO against prevalent infectious bacteria and yeasts. The objective of this study was to use consistent methods and conditions to reveal and directly compare the efficacy of nMgO against nine prevalent pathogenic microorganisms, including two gram-negative bacteria, three gram-positive bacteria with drug-resistant strains, and four yeasts with drug-resistant strains. The MIC of nMgO varied from 0.5 mg/mL to 1.2 mg/mL and the minimal lethal concentration (MLC) of nMgO at 90% killing varied from 0.7 mg/mL to 1.4 mg/mL against different pathogenic bacteria and yeasts. The most potent concentrations (MPC) of nMgO were 1.4 and/or 1.6 mg/mL, depending on the type of bacteria and yeasts tested. As the concentration of nMgO increased, the adhesion of…

Mesenchymal stem cell (MSC)-derived exosomes mediate tissue regeneration in a variety of diseases including ischemic heart injury, liver fibrosis, and cerebrovascular disease. Despite an increasing number of studies reporting the therapeutic effects of MSC exosomes, the underlying molecular mechanisms and their miRNA complement are poorly characterized. Here we microRNA (miRNA)-profiled MSC exosomes and conducted a network analysis to identify the dominant biological processes and pathways modulated by exosomal miRNAs. At a system level, miRNA-targeted genes were enriched for (cardio)vascular and angiogenesis processes in line with observed cardiovascular regenerative effects. Targeted pathways were related to Wnt signaling, pro-fibrotic signaling via TGF-β and PDGF, proliferation, and apoptosis. When tested, MSC exosomes reduced collagen production by cardiac fibroblasts, protected cardiomyocytes from apoptosis, and increased angiogenesis in HUVECs. The intrinsic beneficial effects were further improved by virus-free enrichment of MSC exosomes with network-informed regenerative…

Angle-resolved photoemission spectroscopy (ARPES) is a powerful experimental technique in materials science, as it can directly probe electronic states inside solids in energy (E) and momentum (k) space. As an advanced technique, spatially-resolved ARPES using a well-focused light source (high-resolution ARPES microscopy) has recently attracted growing interests because of its capability to obtain local electronic information at micro- or nano-metric length scales. However, there exist several technical challenges to guarantee high precision in determining translational and rotational positions in reasonable measurement time. Here we present two methods of obtaining k-space mapping and real-space imaging in high-resolution ARPES microscopy. One method is for k-space mapping measurements that enables us to keep a target position on a sample surface during sample rotation by compensating rotation-induced displacements (tracing acquisition method). Another method is for real-space imaging measurements that significantly reduces total acquisition time (scanning acquisition method). We…

Clinical trials had provided evidence for the benefit effect of antihypertensive treatments in preventing future cardiovascular disease (CVD) events; however, the association between hypertension, whether treated/untreated or controlled/uncontrolled and risk of mortality in US population has been poorly understood. A total of 13,947 US adults aged ≥18 years enrolled in the Third National Health and Nutrition Examination Survey (1988-1994) were used to conduct this study. Mortality outcome events included all-cause, CVD-specific, heart disease-specific and cerebrovascular disease-specific deaths, which were obtained from linked 2011 National Death Index (NDI) files. During a median follow-up of 19.1 years, there were 3,550 all-cause deaths, including 1,027 CVD deaths. Compared with normotensives, treated but uncontrolled hypertensive patients were at higher risk of all-cause (HR = 1.62, 95%CI = 1.35-1.95), CVD-specific (HR = 2.23, 95%CI = 1.66-2.99), heart disease-specific (HR = 2.19, 95%CI = 1.57-3.05) and cerebrovascular disease-specific (HR = 3.01, 95%CI = 1.91-4.73) mortality.…

MALDI time-of-flight mass spectrometry (MALDI-TOF MS) has become a widely used tool for the classification of biological samples. The complex chemical composition of pollen grains leads to highly specific, fingerprint-like mass spectra, with respect to the pollen species. Beyond the species-specific composition, the variances in pollen chemistry can be hierarchically structured, including the level of different populations, of environmental conditions or different genotypes. We demonstrate here the sensitivity of MALDI-TOF MS regarding the adaption of the chemical composition of three Poaceae (grass) pollen for different populations of parent plants by analyzing the mass spectra with partial least squares discriminant analysis (PLS-DA) and principal component analysis (PCA). Thereby, variances in species, population and specific growth conditions of the plants were observed simultaneously. In particular, the chemical pattern revealed by the MALDI spectra enabled discrimination of the different populations of one species. Specifically, the role of environmental changes and their…

Confocal laser endomicroscopy (pCLE) provides real-time histologic imaging of human tissues at a depth of 60-70 μm during endoscopy. pCLE of the extrahepatic bile duct after fluorescein injection demonstrated a reticular pattern within fluorescein-filled sinuses that had no known anatomical correlate. Freezing biopsy tissue before fixation preserved the anatomy of this structure, demonstrating that it is part of the submucosa and a previously unappreciated fluid-filled interstitial space, draining to lymph nodes and supported by a complex network of thick collagen bundles. These bundles are intermittently lined on one side by fibroblast-like cells that stain with endothelial markers and vimentin, although there is a highly unusual and extensive unlined interface between the matrix proteins of the bundles and the surrounding fluid. We observed similar structures in numerous tissues that are subject to intermittent or rhythmic compression, including the submucosae of the entire gastrointestinal tract and urinary bladder, the dermis, the peri-bronchial and peri-arterial soft tissues,…

Plant growth promoting rhizobacteria (PGPR) provide an effective and environmentally sustainable method to protect crops against pathogens. The spore-forming Bacilli are attractive PGPR due to their ease of storage and application. Here, we characterized two rhizosphere-associated Bacillus velezensis isolates (Y6 and F7) that possess strong antagonistic activity against Ralstonia solanacearum and Fusarium oxysporum under both laboratory and greenhouse conditions. We identified three lipopeptide (LP) compounds (surfactin, iturin and fengycin) as responsible for the antimicrobial activity of these two strains. We further dissected the contribution of LPs to various biological processes important for rhizosphere colonization. Although either iturin or fengycin is sufficient for antibacterial activity, cell motility and biofilm formation, only iturin plays a primary role in defense against the fungal pathogen F. oxysporum. Additionally, we found that LP production is significantly stimulated during interaction with R. solanacearum. These results demonstrate the different roles of LPs in…

Abstract Metabolic viability based high throughput assays like MTT and MTS are widely used in assessing the cell viability. However, alteration in both mitochondrial content and metabolism can influence the metabolic viability of cells and radiation is a potential mitochondrial biogenesis inducer. Therefore, we tested if MTT assay is a true measure of radiation induced cell death in widely used cell lines. Radiation induced cellular growth inhibition was performed by enumerating cell numbers and metabolic viability using MTT assay at 24 and 48 hours (hrs) after exposure. The extent of radiation induced reduction in cell number was found to be larger than the decrease in MTT reduction in all the cell lines tested. We demonstrated that radiation induces PGC-1α and TFAM to stimulate mitochondrial biogenesis leading to increased levels of SDH-A and enhanced metabolic viability. Radiation induced disturbance in calcium (Ca 2+ ) homeostasis also plays a crucial role by making the mitochondria hyperactive. These findings suggest that radiation induces mitochondrial biogenesis and…

The gut bacteria producing metabolites like short-chain fatty acids (SCFAs; e.g., acetate, propionate and butyrate), are frequently reduced in Patients with diabetes, obesity, autoimmune disorders, and cancers. Hence, microbiome modulators such as probiotics may be helpful in maintaining or even restoring normal gut microbiome composition to benefit host health. Herein, we developed a human-origin probiotic cocktail with the ability to modulate gut microbiota to increase native SCFA production. Following a robust protocol of isolation, characterization and safety validation of infant gut-origin Lactobacillus and Enterococcus strains with probiotic attributes (tolerance to simulated gastric and intestinal conditions, adherence to intestinal epithelial cells, absence of potential virulence genes, cell-surface hydrophobicity, and susceptibility to common antibiotics), we select 10 strains (5 from each genera) out of total 321 isolates. A single dose (oral gavage) as well as 5 consecutive doses of this 10-strain probiotic cocktail in mice modulates gut microbiome and increases SCFA…

Cytokines are soluble factors that mediate cell-cell communications in multicellular organisms. Recently, another system of cell-cell communication was discovered, which is mediated by extracellular vesicles (EVs). Here, we demonstrate that these two systems are not strictly separated, as many cytokines in vitro, ex vivo, and in vivo are released in EV-encapsulated forms and are capable of eliciting biological effects upon contact with sensitive cells. Association with EVs is not necessarily a property of a particular cytokine but rather of a biological system and can be changed upon system activation. EV-encapsulated cytokines were not detected by standard cytokine assays. Deciphering the regulatory mechanisms of EV-encapsulation will lead to a better understanding of cell-cell communications in health and disease.

Photothermal therapy (PTT) is a promising approach for cancer targeting therapy. However, the temperature-dependent killing of tumor cells in PTT remains unclear. In this study, we report necroptosis plays a role in the anti-tumor effects observed in gold nanorod (GNR)-mediated PTT in melanoma. We first synthesized gold nanorods with a targeting adaptor FA (GNRs-FA), which achieved high efficacy of targeted delivery to melanoma cells. We further demonstrated PTT, precipitated by GNRs-FA under the induction of near-infrared laser, was temperature-dependent. Furthermore, the photothermal killing of melanoma cells showed different patterns of cell death depending on varying temperature in PTT. In a lower temperature at 43 °C, the percentages of apoptosis, necroptosis and necrosis of tumor cells were 10.2%, 18.3%, and 17.6%, respectively, suggesting the cell killing is ineffective at lower temperatures. When the temperature increased to 49 °C, the cell death pattern switched to necrosis dominant (52.8%). Interestingly, when the PTT achieved a moderate temperature of 46 °C, necroptosis…

Acoustic telemetry is a principle tool for observing aquatic animals, but coverage over large spatial scales remains a challenge. To resolve this, Australia has implemented the Integrated Marine Observing System's Animal Tracking Facility which comprises a continental-scale hydrophone array and coordinated data repository. This national acoustic network connects localized projects, enabling simultaneous monitoring of multiple species over scales ranging from 100 s of meters to 1000 s of kilometers. There is a need to evaluate the utility of this national network in monitoring animal movement ecology, and to identify the spatial scales that the network effectively operates over. Cluster analyses assessed movements and residency of 2181 individuals from 92 species, and identified four functional movement classes apparent only through aggregating data across the entire national network. These functional movement classes described movement metrics of individuals rather than species, and highlighted the plasticity of movement patterns across and within populations and species. Network…

The agricultural crops are often affected by the scarcity of fresh water. Seasonal drought is a major constraint on Northeast Indian agriculture. Almost 80% of the agricultural land in this region is acidic and facing severe drought during the winter period. Apart from classical breeding and transgenic approaches, the application of plant-growth-promoting bacteria (PGPB) is an alternative strategy for improving plant fitness under stressful conditions. The 1-aminocyclopropane-1-carboxylate (ACC) deaminase-producing PGPB offer drought stress tolerance by regulating plant ethylene levels. The aim of the present study was to evaluate the consortium effect of three ACC-deaminase producing rhizobacteria - Ochrobactrum pseudogrignonenseRJ12, Pseudomonas sp.RJ15 and Bacillus subtilisRJ46 on drought stress alleviation in Vigna mungo L. and Pisum sativum L. Consortium treatment significantly increase seed germination percentage, root length, shoot length, and dry weight of treated plants. An elevated production of reactive oxygen species scavenging enzymes and cellular osmolytes; higher leaf…

Antimicrobial peptides (AMPs) are promising candidates in the fight against multidrug-resistant pathogens owing to AMPs' broad range of activities and low toxicity. Nonetheless, identification of AMPs through wet-lab experiments is still expensive and time consuming. Here, we propose an accurate computational method for AMP prediction by the random forest algorithm. The prediction model is based on the distribution patterns of amino acid properties along the sequence. Using our collection of large and diverse sets of AMP and non-AMP data (3268 and 166791 sequences, respectively), we evaluated 19 random forest classifiers with different positive:negative data ratios by 10-fold cross-validation. Our optimal model, AmPEP with the 1:3 data ratio, showed high accuracy (96%), Matthew's correlation coefficient (MCC) of 0.9, area under the receiver operating characteristic curve (AUC-ROC) of 0.99, and the Kappa statistic of 0.9. Descriptor analysis of AMP/non-AMP distributions by means of Pearson correlation coefficients revealed that reduced feature sets (from a full-featured set of 105 to…

Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid hydroperoxides. There has been significant research on the pathways leading to the accumulation of oxidized lipids, but the downstream effects and how lipid peroxides cause cell death during ferroptosis remain a major puzzle. We evaluated key features of ferroptosis in newly developed molecular dynamics models of lipid membranes to investigate the biophysical consequences of lipid peroxidation, and generated hypotheses about how lipid peroxides contribute to cell death during ferroptosis.

Abstract The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs) that regulate the energy homeostasis and impact on immune cell function of the host. Recently, innovative approaches based on the oral administration of SCFAs have been discussed for therapeutic modification of inflammatory immune responses in autoimmune diseases. So far, most studies have investigated the SCFA-mediated effects on CD4+ T cells and antigen presenting cells. Here we show that butyrate and, to a lesser degree, propionate directly modulate the gene expression of CD8+ cytotoxic T lymphocytes (CTLs) and Tc17 cells. Increased IFN-γ and granzyme B expression by CTLs as well as the molecular switch of Tc17 cells towards the CTL phenotype was mediated by butyrate independently of its interaction with specific SCFA-receptors GPR41 and GPR43. Our results indicate that butyrate strongly inhibited histone-deacetylases (HDACs) in CD8+ T cells thereby affecting the gene expression of effector molecules. Accordingly, the pan-HDAC inhibitors trichostatin A (TSA) and sodium valproate exerted…

The T7 endonuclease 1 (T7E1) mismatch detection assay is a widely used method for evaluating the activity of site-specific nucleases, such as the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system. To determine the accuracy and sensitivity of this assay, we compared the editing estimates derived by the T7E1 assay with that of targeted next-generation sequencing (NGS) in pools of edited mammalian cells. Here, we report that estimates of nuclease activity determined by T7E1 most often do not accurately reflect the activity observed in edited cells. Editing efficiencies of CRISPR-Cas9 complexes with similar activity by T7E1 can prove dramatically different by NGS. Additionally, we compared editing efficiencies predicted by the Tracking of Indels by Decomposition (TIDE) assay and the Indel Detection by Amplicon Analysis (IDAA) assay to that observed by targeted NGS for both cellular pools and single-cell derived clones. We show that targeted NGS, TIDE, and IDAA assays predict similar editing efficiencies for pools of cells but that TIDE and IDAA can miscall…

Next-generation sequencing (NGS) is the method of choice when large numbers of sequences have to be obtained. While the technique is widely applied, varying error rates have been observed. We analysed millions of reads obtained after sequencing of one single sequence on an Illumina sequencer. According to our analysis, the index-PCR for sample preparation has no effect on the observed error rate, even though PCR is traditionally seen as one of the major contributors to enhanced error rates in NGS. In addition, we observed very persistent pre-phasing effects although the base calling software corrects for these. Removal of shortened sequences abolished these effects and allowed analysis of the actual mutations. The average error rate determined was 0.24 ± 0.06% per base and the percentage of mutated sequences was found to be 6.4 ± 1.24%. Constant regions at the 5'- and 3'-end, e.g., primer binding sites used in in vitro selection procedures seem to have no effect on mutation rates and re-sequencing of samples obtains very reproducible results. As phasing effects and other sequencing…

The effect of the 2-methylimidazole (Hmim)/zinc nitrate hexahydrate (Zn) molar ratio on the physicochemical characteristics of the zeolitic imidazolate framework-8 (ZIF-8) was investigated. ZIF-8 crystals were synthesized by mixing Hmim with Zn at room temperature without any additives in methanol solution. It was found that Hmim/Zn molar ratio had significant influence on the crystallinity, yield, particle size and porosity of ZIF-8. The samples synthesized at low Hmim/Zn molar ratio showed a cubic shape, whereas at higher Hmim/Zn ratios truncated rhombic dodecahedron or rhombic dodecahedron morphologies were obtained. The particle size is decreased upon increasing the Hmim/Zn molar ratio. Besides, higher Hmim/Zn molar ratio in a certain range resulted in improving crystallinity, yield, surface area and micropore volume of ZIF-8. The ZIF-8 crystals produced at Hmim/Zn molar ratio of 8 exhibited the best characteristics. The present work provides new insights in relation to the role of Hmim/Zn molar ratio on the synthesis process of ZIF-8.

It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000 CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2,…

Chitosan nanoparticles, produced by ionic gelation, are among the most intensely studied nanosystems for drug delivery. However, a lack of inter-laboratory reproducibility and a poor physicochemical understanding of the process of particle formation have been slowing their potential market applications. To address these shortcomings, the current study presents a systematic analysis of the main polymer factors affecting the nanoparticle formation driven by an initial screening using systematic statistical Design of Experiments (DoE). In summary, we found that for a given chitosan to TPP molar ratio, the average hydrodynamic diameter of the particles formed is strongly dependent on the initial chitosan concentration. The degree of acetylation of the chitosan was found to be the second most important factor involved in the system's ability to form particles. Interestingly, viscosimetry studies indicated that the particle formation and the average hydrodynamic diameter of the particles formed were highly dependent on the presence or absence of salts in the medium. In conclusion, we…

Abstract Transcranial focused ultrasound is a form of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. The effect of ultrasound on human motor cortical excitability is currently unknown. We apply ultrasound to the primary motor cortex in humans using a novel transcranial ultrasound and magnetic stimulation (TUMS) paradigm that allows for concurrent and concentric ultrasound stimulation with transcranial magnetic stimulation (TMS). This allows for non-invasive inspection of the effect of ultrasound on motor neuronal excitability using the motor evoked potential (MEP) generated by TMS. We test the effect of ultrasound on single pulse MEP recruitment curves and paired pulse protocols including short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We also test the longevity of the effect and the effect of ultrasound on the cortical silent period in a small sub-sample of participants. In addition, we test the effect of ultrasound to motor cortex on a stimulus response reaction time task. Results show ultrasound…