Abstract
BioTransformer 3.0 (https://biotransformer.ca) is a freely available web server that supports accurate, rapid and comprehensive in silico metabolism prediction. It combines machine learning ...approaches with a rule-based system to predict small-molecule metabolism in human tissues, the human gut as well as the external environment (soil and water microbiota). Simply stated, BioTransformer takes a molecular structure as input (SMILES or SDF) and outputs an interactively sortable table of the predicted metabolites or transformation products (SMILES, PNG images) along with the enzymes that are predicted to be responsible for those reactions and richly annotated downloadable files (CSV and JSON). The entire process typically takes less than a minute. Previous versions of BioTransformer focused exclusively on predicting the metabolism of xenobiotics (such as plant natural products, drugs, cosmetics and other synthetic compounds) using a limited number of pre-defined steps and somewhat limited rule-based methods. BioTransformer 3.0 uses much more sophisticated methods and incorporates new databases, new constraints and new prediction modules to not only more accurately predict the metabolic transformation products of exogenous xenobiotics but also the transformation products of endogenous metabolites, such as amino acids, peptides, carbohydrates, organic acids, and lipids. BioTransformer 3.0 can also support customized sequential combinations of these transformations along with multiple iterations to simulate multi-step human biotransformation events. Performance tests indicate that BioTransformer 3.0 is 40–50% more accurate, far less prone to combinatorial ‘explosions’ and much more comprehensive in terms of metabolite coverage/capabilities than previous versions of BioTransformer.
Graphical Abstract
Graphical Abstract
Synopsis of BioTransfomer 3.0 functions.
Abstract
The CFM-ID 4.0 web server (https://cfmid.wishartlab.com) is an online tool for predicting, annotating and interpreting tandem mass (MS/MS) spectra of small molecules. It is specifically ...designed to assist researchers pursuing studies in metabolomics, exposomics and analytical chemistry. More specifically, CFM-ID 4.0 supports the: 1) prediction of electrospray ionization quadrupole time-of-flight tandem mass spectra (ESI-QTOF-MS/MS) for small molecules over multiple collision energies (10 eV, 20 eV, and 40 eV); 2) annotation of ESI-QTOF-MS/MS spectra given the structure of the compound; and 3) identification of a small molecule that generated a given ESI-QTOF-MS/MS spectrum at one or more collision energies. The CFM-ID 4.0 web server makes use of a substantially improved MS fragmentation algorithm, a much larger database of experimental and in silico predicted MS/MS spectra and improved scoring methods to offer more accurate MS/MS spectral prediction and MS/MS-based compound identification. Compared to earlier versions of CFM-ID, this new version has an MS/MS spectral prediction performance that is ∼22% better and a compound identification accuracy that is ∼35% better on a standard (CASMI 2016) testing dataset. CFM-ID 4.0 also features a neutral loss function that allows users to identify similar or substituent compounds where no match can be found using CFM-ID’s regular MS/MS-to-compound identification utility. Finally, the CFM-ID 4.0 web server now offers a much more refined user interface that is easier to use, supports molecular formula identification (from MS/MS data), provides more interactively viewable data (including proposed fragment ion structures) and displays MS mirror plots for comparing predicted with observed MS/MS spectra. These improvements should make CFM-ID 4.0 much more useful to the community and should make small molecule identification much easier, faster, and more accurate.
Graphical Abstract
Graphical Abstract
Illustration of the two main functions supported by CFM-ID 4.0. Predicting MS/MS spectra from chemical structures (top) and predicting chemical structures from MS/MS spectra (bottom).
Abstract
The Natural Products Magnetic Resonance Database (NP-MRD) is a comprehensive, freely available electronic resource for the deposition, distribution, searching and retrieval of nuclear ...magnetic resonance (NMR) data on natural products, metabolites and other biologically derived chemicals. NMR spectroscopy has long been viewed as the ‘gold standard’ for the structure determination of novel natural products and novel metabolites. NMR is also widely used in natural product dereplication and the characterization of biofluid mixtures (metabolomics). All of these NMR applications require large collections of high quality, well-annotated, referential NMR spectra of pure compounds. Unfortunately, referential NMR spectral collections for natural products are quite limited. It is because of the critical need for dedicated, open access natural product NMR resources that the NP-MRD was funded by the National Institute of Health (NIH). Since its launch in 2020, the NP-MRD has grown quickly to become the world's largest repository for NMR data on natural products and other biological substances. It currently contains both structural and NMR data for nearly 41,000 natural product compounds from >7400 different living species. All structural, spectroscopic and descriptive data in the NP-MRD is interactively viewable, searchable and fully downloadable in multiple formats. Extensive hyperlinks to other databases of relevance are also provided. The NP-MRD also supports community deposition of NMR assignments and NMR spectra (1D and 2D) of natural products and related meta-data. The deposition system performs extensive data enrichment, automated data format conversion and spectral/assignment evaluation. Details of these database features, how they are implemented and plans for future upgrades are also provided. The NP-MRD is available at https://np-mrd.org.
Background
Road deicing salts are impacting freshwater ecosystems in snowy regions worldwide. Rock salt (typically sodium chloride) is transported to and stored in regional facilities that operate ...year-round and are continuous potential sources of chloride discharge to adjacent water bodies, resulting in different impacts to aquatic ecosystems than chloride pollution from spatially diffuse road networks. The regulatory tools and associated monitoring regimes used by state and federal agencies related to permitting of these facilities is inconsistent. Selection of the regulatory standards and monitoring location in the receiving water body (and how the definition of ‘receiving water body’ is applied) can have a significant influence on the measured or modeled impact of a facility on aquatic ecosystems. Additionally, selection of the monitored media (surface water, soil pore water, shallow ground water, or vegetation) can further influence findings, resulting in inconsistent conclusions of environmental impact and potentially allow exceedances of regulatory thresholds of chloride. This study evaluates chloride pollution from salt loading over two years from a state-permitted salt storage and transport facility in Shelburne, Vermont, USA to an adjacent wetland and river that drains to Lake Champlain. Water quality results and modeled assumptions made by the permittee were compared to monitoring data at two discharge points from the site including a drainage channel downstream of the site’s stormwater pond and at a shallow ground water seep below the rail car unloading area.
Results
Results indicate elevated chloride concentrations (average of 243 and 643 mg L
−1
) at the discharge points to the receiving water body, in conflict with findings from annual permittee assessments. Soil cores taken in the wetland in the vicinity of the control and two discharge points also indicate elevated Cl
−
(p ≤ 0.035) and Na
+
(p ≤ 0.0006). Samples of
Tsuga canadensis
at the discharge points and at the control site indicate elevated chloride in plant tissues.
Conclusions
Determination of exceedances of chronic and acute standards vary based on the sampling location and medium, indicating a need for consistency and outcome-based monitoring point selection criteria and a move away from reliance on self-reporting by permittees.
Objective—To characterize a population of dogs from a tertiary care center with 2 or more endocrine disorders, including the specific disorders and time intervals between diagnosis of each disorder. ...Design—Retrospective case series. Animals—35 dogs with 2 or more endocrine disorders. Procedures—Medical records were reviewed, and the following was recorded: clinical signs, physical examination findings, and the results of CBC, serum biochemical analysis, urinalysis, aerobic bacterial culture of urine samples, endocrine testing, diagnostic imaging, and necropsy. Results—35 dogs with more than 1 endocrine disorder were identified. Seventy-seven percent (27/35) of the dogs were male, and the mean age at the time of diagnosis of the first endocrinopathy was 7.9 years. Miniature Schnauzer was the most common breed. Twenty-eight of 35 (80%) dogs had 2 disorders; 7 (20%) had 3 disorders. The most common combinations of disorders included diabetes mellitus and hyperadrenocorticism in 57.1 % (20/35) of dogs; hypoadrenocorticism and hypothyroidism in 22.9% (8/35) of dogs; and diabetes mellitus and hypothyroidism in 28.6% (10/35) of dogs. A mean of 14.5 months elapsed between diagnosis of the first and second endocrine disorders, whereas there was a mean of 31.1 months between diagnosis of the first and third endocrine disorders. Conclusions and Clinical Relevance—Results suggested that the occurrence of multiple endocrine disorders was uncommon in dogs. The most common combinations of endocrine disorders in this population of dogs were diabetes mellitus and hyperadrenocorticism, followed by hypoadrenocorticism and hypothyroidism.
One year after identifying the first case of the 2019 coronavirus disease (COVID-19) in Canada, federal and provincial governments are still struggling to manage the pandemic. Provincial governments ...across Canada have experimented with widely varying policies in order to limit the burden of COVID-19. However, to date, the effectiveness of these policies has been difficult to ascertain. This is partly due to the lack of a publicly available, high-quality dataset on COVID-19 interventions and outcomes for Canada. The present paper provides a dataset containing important, Canadian-specific data that is known to affect COVID-19 outcomes, including sociodemographic, climatic, mobility and health system related information for all 10 Canadian provinces and their health regions. This dataset also includes longitudinal data on the daily number of COVID-19 cases, deaths, and the constantly changing intervention policies that have been implemented by each province in an attempt to control the pandemic.
To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats.
8 healthy ...sexually intact male cats.
A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period.
Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control-treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia.
Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats.
To identify the normal gastric acid secretion profile in dogs and determine the degree of gastric acid suppression associated with 4 gastric acid suppressants.
12 healthy Beagles.
Intragastric pH was ...measured continuously for 24-hour periods with a digital recording system placed via a gastrostomy tube. Baseline measurements were obtained when food was withheld and when dogs were fed a standard diet. Dogs were then treated with ranitidine (2 mg/kg, IV, q 12 h), famotidine (0.5 mg/kg, IV, q 12 h), pantoprazole (1 mg/kg, IV, q 24 h), omeprazole (1 mg/kg, PO, q 24 h), or saline solution for 7 days; intragastric pH was recorded on days 0, 2, and 6. Subsequently, the effects of administering famotidine (0.5 mg/kg, IV, q 8 h; 6 dogs) and omeprazole as a suspension (1 mg/kg, PO, q 12 h; 6 dogs) were evaluated. Median 24-hour intragastric pH, percentage of time pH was > or = 3, and percentage of time pH was > or = 4 were determined.
Median pH, percentage of time pH was > or = 3, and percentage of time pH was > or = 4 were all significantly higher when food was withheld than when dogs were fed. Famotidine, pantoprazole, and omeprazole significantly suppressed gastric acid secretion, compared with saline solution, as determined on the basis of median 24-hour pH and percentages of time pH was > or = 3 or > or = 4. However, ranitidine did not. Omeprazole suspension suppressed gastric acid secretion.
Results suggest that in healthy dogs, famotidine, pantoprazole, and omeprazole significantly suppress gastric acid secretion. Twice daily administration of a suspension of omeprazole, was the only regimen tested that approached the potential therapeutic efficacy for acid-related disease when assessed by criteria used for human patients.
To determine effects of therapeutic dosages of aspirin, carprofen, deracoxib, and meloxicam on platelet function and systemic prostaglandin concentrations in healthy dogs.
10 hound-crossbred dogs.
...Aspirin (10 mg/kg, PO, q 12 h), carprofen (4.4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), meloxicam (0.1 mg/kg, PO, q 24 h), and a placebo were administered for 7 days in a random order to each of 10 healthy dogs; there was a 21-day washout period between subsequent treatments. One-stage prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, and plasma concentrations of thromboxane (TX)B(2) and 6-keto prostaglandin (PG)F(1alpha) were measured before and after treatment administration. Platelet function was assessed by use of a platelet-function analyzer and aggregation.
Aspirin, carprofen, and meloxicam did not significantly affect platelet function. Deracoxib caused a mild decrease in platelet aggregation induced by 50microM ADP. Platelet number, Hct, PT, aPTT, and plasma TXB(2) and 6-keto PGF(1alpha) concentrations were unchanged after NSAID administration. Meloxicam administration resulted in a significant decrease in fibrinogen concentration, but results remained within the laboratory reference interval.
Oral administration of commonly used NSAIDs at therapeutic dosages in healthy dogs did not alter plasma TXB(2) and 6-keto PGF(1alpha) concentrations. Deracoxib administration resulted in a minor abnormality in platelet aggregation. Anti-inflammatory doses of aspirin did not affect platelet function as measured by use of optical aggregometry and a platelet-function analyzer. Further evaluation of the effects of aspirin and cyclooxygenase-2-selective inhibitors on hemostasis should be performed.
The objective of this retrospective study was to characterize a population of cats from a tertiary care center diagnosed with multiple endocrine disorders, including the specific disorders and time ...intervals between diagnosis of each disorder. Medical records of 15 cats diagnosed with more than one endocrine disorder were reviewed. The majority of cats were domestic shorthairs, and the mean age at the time of diagnosis of the first disorder was 10.3 years. The most common combination of disorders was diabetes mellitus and hyperthyroidism. Two cats had concurrent diabetes mellitus and hyperadrenocorticism, one cat had concurrent central diabetes insipidus and diabetes mellitus. A mean of 25.7 months elapsed between diagnoses of the first and second endocrine disorder, but this was variable. This study suggests the occurrence of multiple endocrine disorders is uncommon in cats.
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