Integration of metabolomics, lipidomics and clinical data using a machine learning method.

BACKGROUND: The recent pandemic of obesity and the metabolic syndrome (MetS) has led to the realisation that new drug targets are needed to either reduce obesity or the subsequent pathophysiological consequences associated with excess weight gain. Certain nuclear hormone receptors (NRs) play a pivotal role in lipid and carbohydrate metabolism and have been highlighted as potential treatments for obesity. This realisation started a search for NR agonists in order to understand and successfully treat MetS and associated conditions such as insulin resistance, dyslipidaemia, hypertension, hypertriglyceridemia, obesity and cardiovascular disease. The most studied NRs for treating metabolic diseases are the peroxisome proliferator-activated receptors (PPARs), PPAR-α, PPAR-γ, and PPAR-δ. However, prolonged PPAR treatment in animal models has led to adverse side effects including increased risk of a number of cancers, but how these receptors change metabolism long term in terms of pathology, despite many beneficial effects shorter term, is not fully understood. In the current study, changes in male Sprague Dawley rat liver caused by dietary treatment with a PPAR-pan (PPAR-α, -γ, and -δ) agonist were profiled by classical toxicology (clinical chemistry) and high throughput metabolomics and lipidomics approaches using mass spectrometry. RESULTS: In order to integrate an extensive set of nine different multivariate metabolic and lipidomics datasets with classical toxicological parameters we developed a hypotheses free, data driven machine learning approach. From the data analysis, we examined how the nine datasets were able to model dose and clinical chemistry results, with the different datasets having very different information content. CONCLUSIONS: We found lipidomics (Direct Infusion-Mass Spectrometry) data the most predictive for different dose responses. In addition, associations with the metabolic and lipidomic data with aspartate amino transaminase (AST), a hepatic leakage enzyme to assess organ damage, and albumin, indicative of altered liver synthetic function, were established. Furthermore, by establishing correlations and network connections between eicosanoids, phospholipids and triacylglycerols, we provide evidence that these lipids function as a key link between inflammatory processes and intermediary metabolism

Trends of Water Requirements of Major Crops and Cropping Patterns in Bogura and Rajshahi Districts of Bangladesh

Reliable past trends of water requirements of individual crops and cropping patterns at local level, although crucially important for irrigation forecast and agricultural planning, are yet inadequate for the water-scarce Barind region of Bangladesh. This study, therefore, determined water requirements and their trends of eight major crops (aus, aman, boro, vegetables, mustard, sugarcane, wheat and potato) and six cropping patterns (aus–aman–boro, aus–aman–potato, aman–potato–fallow, vegetables–aman, aman–mustard–fallow and aus–fallow–wheat) of Bogura and Rajshahi districts of the Barind region. Water requirements were determined from crop, soil and weather data for the period 1985–2013 by using Soil-Water Balance via CropWat (SWBcropwat) model. Trends of rainfall, crop evapotranspiration (ETc) and irrigation requirement (IR) were determined with MAKESENS statistical tool. Monthly total rainfall revealed increasing trend in January, August and October but decreasing trend in the other months, with significant (p£0.05) trend in July in Bogura. Monthly total ETc decreased except in July and September, with significant trend in October–April/May. Seasonal ETc for the crops decreased significantly except for aman rice and sugarcane in Bogura and for aman rice in Rajshahi. ETc also decreased for the cropping patterns except for aman–mustard–fallow in Rajshahi. While effective rainfall (ER) for the crops and cropping patterns decreased only minimally, IR decreased significantly for boro, potato and vegetables in Bogura and for mustard and vegetables in Rajshahi. IR decreased for all cropping patterns, with significant trend for aus–aman–potato, aman–potato–fallow and vegetables–aman patterns. In response to changing cropping area, total volume of ETc increased gradually from 1985 to 2005 in Bogura and from 1985 to 2010 in Rajshahi for boro rice, but it decreased until 2005 before increasing for aus rice in both districts. After the year 2000, total volume of ETc decreased for wheat but increased for potato, indicating a shift from wheat to potato cultivation. Due to contrasting trends of ER and ETc and self-motivated shift in crop-choice, continuous adjustment of irrigation-based crop planning is necessary. The results of this study can guide future investigation for all other crops and cropping patterns to help planning agriculture of the study areas by choosing appropriate crops and cropping patterns based on available water resources

Effect of Torrefaction on Water Vapor Adsorption Properties and Resistance to Microbial Degradation of Corn Stover

The equilibrium moisture content (EMC) of biomass affects transportation, storage, downstream feedstock processing, and the overall economy of biorenewables production. Torrefaction is a thermochemical process conducted in the temperature regime between 200 and 300 °C under an inert atmosphere that, among other benefits, aims to reduce the innate hydrophilicity and susceptibility to microbial degradation of biomass. The objective of this study was to examine water sorption properties of torrefied corn stover. The EMC of raw corn stover, along with corn stover thermally pretreated at three temperatures, was measured using the static gravimetric method at equilibrium relative humidity (ERH) and temperatures ranging from 10 to 98% and from 10 to 40 °C, respectively. Five isotherms were fitted to the experimental data to obtain the prediction equation that best describes the relationship between the ERH and the EMC of lignocellulosic biomass. Microbial degradation of the samples was tested at 97% ERH and 30 °C. Fiber analyses were conducted on all samples. In general, torrefied biomass showed an EMC lower than that of raw biomass, which implied an increase in hydrophobicity. The modified Oswin model performed best in describing the correlation between ERH and EMC. Corn stover torrefied at 250 and 300 °C had negligible dry matter mass loss due to microbial degradation. Fiber analysis showed a significant decrease in hemicellulose content with the increase in pretreatment temperature, which might be the reason for the hydrophobic nature of the torrefied biomass. The outcomes of this work can be used for torrefaction process optimization, and decision-making regarding raw and torrefied biomass storage and downstream processing

Hypoxia Exacerbates Inflammatory Signaling in Human Coronavirus OC43-Infected Lung Epithelial Cells

Cytokine storm (CS) is associated with poor prognosis in COVID-19 patients. Hypoxic signaling has been proposed to influence proinflammatory pathways and to be involved in the development of CS. Here, for the first time, the role of hypoxia in coronavirus-mediated inflammation has been investigated, using transcriptomic and proteomic approaches. Analysis of the transcriptome of A549 lung epithelial cells using RNA sequencing revealed 191 mRNAs which were synergistically upregulated and 43 mRNAs which were synergistically downregulated by the combination of human Betacoronavirus OC43 (HCoV-OC43) infection and hypoxia. Synergistically upregulated mRNAs were strongly associated with inflammatory pathway activation. Analysis of the expression of 105 cytokines and immune-related proteins using antibody arrays identified five proteins (IGFBP-3, VEGF, CCL20, CD30, and myeloperoxidase) which were markedly upregulated in HCoV-OC43 infection in hypoxia compared to HCoV-OC43 infection in normal oxygen conditions. Our findings show that COVID-19 patients with lung hypoxia may face increased risk of inflammatory complications. Two of the proteins we have identified as synergistically upregulated, the cytokines VEGF and CCL20, represent potential future therapeutic targets. These could be targeted directly or, based on the novel findings described here by inhibiting hypoxia signaling pathways, to reduce excessive inflammatory cytokine responses in patients with severe infections

A causal web between chronotype and metabolic health traits

Observational and experimental evidence has linked chronotype to both psychological and cardiometabolic traits. Recent Mendelian randomization (MR) studies have investigated direct links between chronotype and several of these traits, often in isolation of outside potential mediating or moderating traits. We mined the EpiGraphDB MR database for calculated chronotype–trait associations (p-value < 5 × 10−8). We then re-analyzed those relevant to metabolic or mental health and investigated for statistical evidence of horizontal pleiotropy. Analyses passing multiple testing correction were then investigated for confounders, colliders, intermediates, and reverse intermediates using the EpiGraphDB database, creating multiple chronotype–trait interactions among each of the the traits studied. We revealed 10 significant chronotype–exposure associations (false discovery rate < 0.05) exposed to 111 potential previously known confounders, 52 intermediates, 18 reverse intermediates, and 31 colliders. Chronotype–lipid causal associations collided with treatment and diabetes effects; chronotype–bipolar associations were mediated by breast cancer; and chronotype–alcohol intake associations were impacted by confounders and intermediate variables including known zeitgebers and molecular traits. We have reported the influence of chronotype on several cardiometabolic and behavioural traits, and identified potential confounding variables not reported on in studies while discovering new associations to drugs and disease

Defected Ground Structure toward Cross Polarization Reduction of Microstrip Patch Antenna with Improved Impedance Matching

A new approach based on the incorporation of Z-shaped defected ground structure (DGS) in microstrip antenna (MSA) for improving impedance matching and cross polarization (XP) performances is proposed in this paper. Through detail analysis of the surface current densities, and input impedance, the proposed DGS is integrated into a rectangular MSA (RMSA) to realize flat relative XP reduction of 22 dB in the H-plane around broadside angular range of ±60 degrees. Further, an equivalent circuit model (ECM) for the proposed antenna is introduced by considering the mutual coupling in between the DGS and patch and the model is verified using circuit-system-EM co-simulation software, Advanced Design System (ADS). A prototype has been fabricated and tested for the validation of simulated results and it shows good agreement with each other. The antenna operates over 2.32-2.58 GHz with good far-field radiation characteristics and a peak gain of 2.8 dBi at the resonating frequency 2.4 GHz. Hence, the proposed design can be useful for the IEEE 802.11b applications

Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence

<p>Abstract</p> <p>Background</p> <p>Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1's biology and pathogenicity. Despite the increasing availability of antiretroviral therapy, HIV-associated dementia (HAD) continues to be a devastating consequence of HIV-1 infection of the brain although the underlying disease mechanisms remain uncertain. Herein, molecular diversity within the HIV-1 non-structural gene, Vpr, was examined in RNA sequences derived from brain and blood of HIV/AIDS patients with or without HIV-associated dementia (HAD) together with the ensuing pathobiological effects.</p> <p>Results</p> <p>Cloned brain- and blood-derived full length <it>vpr </it>alleles revealed that amino acid residue 77 within the brain-derived alleles distinguished HAD (77Q) from non-demented (ND) HIV/AIDS patients (77R) (<it>p </it>< 0.05) although <it>vpr </it>transcripts were more frequently detected in HAD brains (<it>p </it>< 0.05). Full length HIV-1 clones encoding the 77R-ND residue induced higher <it>IFN-α</it>, <it>MX1 </it>and <it>BST-2 </it>transcript levels in human glia relative to the 77Q-HAD encoding virus (<it>p </it>< 0.05) but both viruses exhibited similar levels of gene expression and replication. Myeloid cells transfected with 77Q-(p<it>Vpr77Q-HAD</it>), 77R (p<it>Vpr77R-ND</it>) or Vpr null (p<it>Vpr</it>^<it>(-)</it>)-containing vectors showed that the p<it>Vpr77R-ND </it>vector induced higher levels of immune gene expression (<it>p </it>< 0.05) and increased neurotoxicity (<it>p </it>< 0.05). Vpr peptides (amino acids 70-96) containing the 77Q-HAD or 77R-ND motifs induced similar levels of cytosolic calcium activation when exposed to human neurons. Human glia exposed to the 77R-ND peptide activated higher transcript levels of <it>IFN-α</it>, <it>MX1</it>, <it>PRKRA </it>and <it>BST-2 </it>relative to 77Q-HAD peptide (<it>p </it>< 0.05). The Vpr 77R-ND peptide was also more neurotoxic in a concentration-dependent manner when exposed to human neurons (<it>p </it>< 0.05). Stereotaxic implantation of full length Vpr, 77Q-HAD or 77R-ND peptides into the basal ganglia of mice revealed that full length Vpr and the 77R-ND peptide caused greater neurobehavioral deficits and neuronal injury compared with 77Q-HAD peptide-implanted animals (<it>p </it>< 0.05).</p> <p>Conclusions</p> <p>These observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.</p

Case Report Common Iliac Artery Thrombosis following Pelvic Surgery Resulting in Kidney Allograft Failure Successfully Treated by Percutaneous Transluminal Angioplasty with Balloon-Expandable Covered Stent

We report the case of a 66-year-old woman who developed acute kidney allograft failure due to thrombotic occlusion of the common iliac artery after hysterectomy requiring emergent allograft rescue. She underwent percutaneous transluminal angioplasty with endovascular balloon expandable covered stent graft placement in the right common iliac artery. Although there are a handful of case reports of acute limb ischemia secondary to acute common iliac artery thrombosis, this is the first case reported in the literature resulting in successful kidney allograft rescue following pelvic surgery. Background Arterial thrombosis causing late acute kidney allograft failure is extremely rare. Pelvic or abdominal surgeries may place kidney allografts implanted in the pelvis at risk for injury Case Presentation A 66-year-old woman with end-stage renal disease in the setting of type-2 diabetes mellitus, hypertension, kidney stones, and renal artery stenosis had received an unrelated living-donor kidney transplant 7 years earlier. She also had a history of chronic obstructive pulmonary disease, coronary artery disease, heart failure with preserved left ventricular ejection fraction, and atrial fibrillation (on rivaroxaban, an orally active direct factor Xa inhibitor) for which she had undergone atrioventricular nodal ablation and insertion of a permanent pacemaker. She presented with excessive uterine bleeding. The workup demonstrated a pelvic mass and fluidfilled uterus. She underwent an elective hysteroscopy with dilation and curettage, which revealed pyometra. The intraoperative course was complicated by bleeding and uterine perforation requiring total abdominal hysterectomy and bilateral salpingooophorectomy. She lost 300 mL of blood and received intraoperatively 3.2 liters of crystalloids. There was no documented intraoperative hypotension. Pulses were equally palpable in both lower extremities before and after surgery. The patient developed anuria in the immediate postoperative period, and furosemide (40 mg) was administered intravenously with no response. The patient was reintubated for acute respiratory failure, and her anuria persisted. Investigations The urology service was initially consulted, and the patient underwent a cystoscopy with retrograde ureterogram, which revealed normal iodinated contrast filling and caliber o

Metabolomics and Lipidomics Study of Mouse Models of Type 1 Diabetes Highlights Divergent Metabolism in Purine and Tryptophan Metabolism Prior to Disease Onset.

With the increase in incidence of type 1 diabetes (T1DM), there is an urgent need to understand the early molecular and metabolic alterations that accompany the autoimmune disease. This is not least because in murine models early intervention can prevent the development of disease. We have applied a liquid chromatography (LC-) and gas chromatography (GC-) mass spectrometry (MS) metabolomics and lipidomics analysis of blood plasma and pancreas tissue to follow the progression of disease in three models related to autoimmune diabetes: the nonobese diabetic (NOD) mouse, susceptible to the development of autoimmune diabetes, and the NOD-E (transgenic NOD mice that express the I-E heterodimer of the major histocompatibility complex II) and NOD-severe combined immunodeficiency (SCID) mouse strains, two models protected from the development of diabetes. All three analyses highlighted the metabolic differences between the NOD-SCID mouse and the other two strains, regardless of diabetic status indicating that NOD-SCID mice are poor controls for metabolic changes in NOD mice. By comparing NOD and NOD-E mice, we show the development of T1DM in NOD mice is associated with changes in lipid, purine, and tryptophan metabolism, including an increase in kynurenic acid and a decrease in lysophospholipids, metabolites previously associated with inflammation