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Anal Chem 2021 Apr 12. Epub 2021 Apr 12.

Department of Engineering and Chemical Sciences, Karlstad University, Karlstad SE-651 88, Sweden.

A strategy to match any retention shifts due to increased or decreased pressure drop during supercritical fluid chromatography (SFC) method transfer is presented. The strategy relies on adjusting the co-solvent molarity without the need to adjust the back-pressure regulator. Exact matching can be obtained with minimal changes in separation selectivity. Read More

Org Lett 2021 Apr 8. Epub 2021 Apr 8.

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India.

An oxa-[2,3] sigmatropic rearrangement involving arynes is reported featuring the umpolung of ketones, where the C═O bond polarity is reversed. The in situ-generated sulfur ylides from β-keto thioethers and arynes undergo efficient rearrangement allowing the facile and robust synthesis of functionalized enol ethers in high yields and excellent functional group compatibility. Preliminary mechanistic studies rule out the possibility of Pummerer-type rearrangement operating in this case. Read More

J Am Chem Soc 2021 Mar 24. Epub 2021 Mar 24.

Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48103, United States.

Methyl-coenzyme M reductase (MCR) catalyzes both the synthesis and the anaerobic oxidation of methane (AOM). Its catalytic site contains Ni at the core of cofactor F. The Ni ion, in its low-valent Ni(I) state, lights the fuse leading to homolysis of the C-S bond of methyl-coenzyme M (methyl-SCoM) to generate a methyl radical, which abstracts a hydrogen atom from coenzyme B (HSCoB) to generate methane and the mixed disulfide CoMSSCoB. Read More

J Phys Chem B 2021 03 26;125(9):2212-2221. Epub 2021 Feb 26.

Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Understanding and describing the dynamics of proteins is one of the major challenges in biology. Here, we use multifield variable-temperature NMR longitudinal relaxation (R) measurements to determine the hierarchical activation energies of motions of four different proteins: two small globular proteins (GB1 and the SH3 domain of α-spectrin), an intrinsically disordered protein (the C-terminus of the nucleoprotein of the Sendai virus, Sendai Ntail), and an outer membrane protein (OmpG). The activation energies map the motions occurring in the side chains, in the backbone, and in the hydration shells of the proteins. Read More

FEBS J 2021 Feb 11. Epub 2021 Feb 11.

Department of Cell & Systems Biology, University of Toronto, ON, Canada.

Although the quantity and quality of single-cell data have progressed rapidly, making quantitative predictions with single-cell stochastic models remains challenging. The stochastic nature of cellular processes leads to at least three challenges in building models with single-cell data: (a) because variability in single-cell data can be attributed to multiple different sources, it is difficult to rule out conflicting mechanistic models that explain the same data equally well; (b) the distinction between interesting biological variability and experimental variability is sometimes ambiguous; (c) the nonstandard distributions of single-cell data can lead to violations of the assumption of symmetric errors in least-squares fitting. In this review, we first discuss recent studies that overcome some of the challenges or set up a promising direction and then introduce some powerful statistical approaches utilized in these studies. Read More

Adv Exp Med Biol 2021 ;1295:29-48

Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

Tumor-homing peptides are widely used for improving tumor selectivity of anticancer drugs and imaging agents. The goal is to increase tumor uptake and reduce accumulation at nontarget sites. Here, we describe current approaches for tumor-homing peptide identification and validation, and provide comprehensive overview of classes of tumor-homing peptides undergoing preclinical and clinical development. Read More

Am J Physiol Heart Circ Physiol 2021 04 22;320(4):H1321-H1336. Epub 2021 Jan 22.

Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Arsenic exposure though drinking water is widespread and well associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which iAS induces these effects are largely unknown. Recently, an epidemiological study in an American population with a low burden of cardiovascular risk factors found that iAS exposure was associated with altered left ventricular geometry. Considering the possibility that iAS directly induces cardiac remodeling independently of hypertension, we investigated the impact of an environmentally relevant iAS exposure on the structure and function of male and female hearts. Read More

Curr Top Med Chem 2021 Jan 14. Epub 2021 Jan 14.

Laboratory of BioInformatics, bioMathematics and bioStatistics (BIMS), Institut Pasteur de Tunis, 1002, Université de Tunis El Manar, Tunis. Tunisia.

Background: Saponin metabolism shows high structural variability due to diversity of aglycones and glycosylations (Gly). Although they represent potential source of drug design, their metabolism suffers yet from a misunderstanding due to insufficient investments in analytical methods.

Aim: Bibliographic structural data offer a wide field for extensive statistical analysis helping for highlighting mechanistic orders governing metabolic diversity. Read More

Saudi Pharm J 2020 Dec 29;28(12):1507-1513. Epub 2020 Sep 29.

Department of Information Technology, Faculty of Computing and Information Technology, King Abdulaziz University, Jeddah 80221, Saudi Arabia.

Drug-drug interactions (DDIs) are a potentially distressing corollary of drug interventions, and may result in discomfort, debilitating illness, or even death. Existing research predominantly considers only a single level of interaction; however, serious health complications may result from multi-pathway DDIs, and so new methods are needed to enable predicting and preventing complex DDIs. This article introduces a novel method for the prediction of DDIs at two pharmacological levels (metabolic and transporter interactions) by means of a rule-based model implemented with Semantic Web technologies. Read More

Microb Genom 2021 01;7(1)

David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.

Diagnosing antimicrobial resistance (AMR) in the clinic is based on empirical evidence and current gold standard laboratory phenotypic methods. Genotypic methods have the potential advantages of being faster and cheaper, and having improved mechanistic resolution over phenotypic methods. We generated and applied rule-based and logistic regression models to predict the AMR phenotype from and multidrug-resistant clinical isolate genomes. Read More

Am J Hum Genet 2021 01 18;108(1):134-147. Epub 2020 Dec 18.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences ("N-end rule"). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Read More

Biochemistry 2020 12 4;59(50):4775-4786. Epub 2020 Dec 4.

Discovery Biology, Discovery Sciences, BioPharmaceuticals, R&D, AstraZeneca, Cambridge CB4 0WG, U.K.

Protein arginine methyltransferases (PRMTs) are of great interest for the development of therapeutics due to their involvement in a number of malignancies, such as lung and colon cancer. PRMT5 catalyzes the formation of symmetrical dimethylarginine of a wide variety of substrates and is responsible for the majority of this mark within cells. To gain insight into the mechanism of PRMT5 inhibition, we co-expressed the human PRMT5:MEP50 complex (hPRMT5:MEP50) in insect cells for a detailed mechanistic study. Read More

Acad Emerg Med 2020 Nov 20. Epub 2020 Nov 20.

Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, USA.

Background: The risk for cervical spine injury (CSI) must be assessed in children who sustain blunt trauma. The Pediatric Emergency Care Applied Research Network (PECARN) retrospectively derived CSI model identifies CSI risk in children based on emergency department (ED) provider observations. The objective of this pilot study was to determine the univariate association of emergency medical services (EMS) provider-observed historical, mechanistic, and physical examination factors with CSI in injured children. Read More

Am J Hum Genet 2020 12 12;107(6):1011-1028. Epub 2020 Nov 12.

The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK. Electronic address:

Resolving the molecular processes that mediate genetic risk remains a challenge because most disease-associated variants are non-coding and functional characterization of these signals requires knowledge of the specific tissues and cell-types in which they operate. To address this challenge, we developed a framework for integrating tissue-specific gene expression and epigenomic maps to obtain "tissue-of-action" (TOA) scores for each association signal by systematically partitioning posterior probabilities from Bayesian fine-mapping. We applied this scheme to credible set variants for 380 association signals from a recent GWAS meta-analysis of type 2 diabetes (T2D) in Europeans. Read More

J Neurosci 2020 12 9;40(50):9634-9649. Epub 2020 Nov 9.

Centre for Neural Circuits and Behaviour, University of Oxford, Oxford, OX1 3SR, United Kingdom.

Cortical areas comprise multiple types of inhibitory interneurons, with stereotypical connectivity motifs that may follow specific plasticity rules. Yet, their combined effect on postsynaptic dynamics has been largely unexplored. Here, we analyze the response of a single postsynaptic model neuron receiving tuned excitatory connections alongside inhibition from two plastic populations. Read More

J Enzyme Inhib Med Chem 2021 Dec;36(1):15-33

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.

In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC = 0. Read More

Ecol Lett 2021 Jan 6;24(1):27-37. Epub 2020 Oct 6.

Wildlife Health Ghent, Department of Pathology, Bacteriology and Avian Diseases, Ghent University, Salisburylaan 133, Merelbeke, 9820, Belgium.

While epizootics increasingly affect wildlife, it remains poorly understood how the environment shapes most host-pathogen systems. Here, we employ a three-step framework to study microclimate influence on ectotherm host thermal behaviour, focusing on amphibian chytridiomycosis in fire salamanders (Salamandra salamandra) infected with the fungal pathogen Batrachochytrium salamandrivorans (Bsal). Laboratory trials reveal that innate variation in thermal preference, rather than behavioural fever, can inhibit infection and facilitate salamander recovery under humidity-saturated conditions. Read More

Commun Biol 2020 Sep 30;3(1):540. Epub 2020 Sep 30.

Department of Entomology, University of Maryland, Collage Park, MD, USA.

Regulatory genes are often multifunctional and constrained, which results in evolutionary conservation. It is difficult to understand how a regulatory gene could be lost from one species' genome when it is essential for viability in closely related species. The gene paired is a classic Drosophila pair-rule gene, required for formation of alternate body segments in diverse insect species. Read More

Elife 2020 09 23;9. Epub 2020 Sep 23.

Department of Molecular and Cellular Biology and School of Engineering and Applied Sciences, Harvard University, Cambridge, United States.

The spindle shows remarkable diversity, and changes in an integrated fashion, as cells vary over evolution. Here, we provide a mechanistic explanation for variations in the first mitotic spindle in nematodes. We used a combination of quantitative genetics and biophysics to rule out broad classes of models of the regulation of spindle length and dynamics, and to establish the importance of a balance of cortical pulling forces acting in different directions. Read More

PLoS One 2020 11;15(9):e0238838. Epub 2020 Sep 11.

Systems Biology Laboratory, Masaryk University, Brno, Czech Republic.

Computational systems biology provides multiple formalisms for modelling of biochemical processes among which the rule-based approach is one of the most suitable. Its main advantage is a compact and precise mechanistic description of complex processes. However, state-of-the-art rule-based languages still suffer several shortcomings that limit their use in practice. Read More

NAR Cancer 2020 Jun 29;2(2):zcaa010. Epub 2020 Jun 29.

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA.

Mechanistic understanding of hypoxia-responsive signaling pathways provides important insights into oxygen- and metabolism-dependent cellular phenotypes in diseases. Using SILAC-based quantitative proteomics, we provided a quantitative map identifying over 6300 protein groups in response to hypoxia in prostate cancer cells and identified both canonical and novel cellular networks dynamically regulated under hypoxia. Particularly, we identified SDE2, a DNA stress response modulator, that was significantly downregulated by hypoxia, independent of HIF (hypoxia-inducible factor) transcriptional activity. Read More

ChemSusChem 2020 Sep 17;13(18):4929-4936. Epub 2020 Aug 17.

School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. China.

Electrosynthesis as a potential means of introducing heteroatoms into the carbon framework is rarely studied. Herein, the electrochemical Beckmann rearrangement, i. e. Read More

Nucleus 2020 12;11(1):132-148

Department of Biological Engineering, Massachusetts Institute of Technology , Cambridge, MA, USA.

Mammalian genome structure is closely linked to function. At the scale of kilobases to megabases, CTCF and cohesin organize the genome into chromatin loops. Mechanistically, cohesin is proposed to extrude chromatin loops bidirectionally until it encounters occupied CTCF DNA-binding sites. Read More

Bioorg Chem 2020 08 1;101:103987. Epub 2020 Jun 1.

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.

New series of compounds bearing 2-thioquinazolinone scaffold were designed, synthesized as HSP90 inhibitors. Anti-proliferative activity of the synthesized compounds was evaluated against HCT-116, Hela and MCF-7 cell lines and compound 5k was found to be the most active member of the entire study with IC of 4.47, 7. Read More

Proc Natl Acad Sci U S A 2020 06 3;117(24):13800-13809. Epub 2020 Jun 3.

Department of Metabolic Biology, John Innes Centre, NR4 7UH Norwich, United Kingdom.

While colocalization within a bacterial operon enables coexpression of the constituent genes, the mechanistic logic of clustering of nonhomologous monocistronic genes in eukaryotes is not immediately obvious. Biosynthetic gene clusters that encode pathways for specialized metabolites are an exception to the classical eukaryote rule of random gene location and provide paradigmatic exemplars with which to understand eukaryotic cluster dynamics and regulation. Here, using 3C, Hi-C, and Capture Hi-C (CHi-C) organ-specific chromosome conformation capture techniques along with high-resolution microscopy, we investigate how chromosome topology relates to transcriptional activity of clustered biosynthetic pathway genes in Our analyses reveal that biosynthetic gene clusters are embedded in local hot spots of 3D contacts that segregate cluster regions from the surrounding chromosome environment. Read More

Sci Stud Read 2020 24;24(1):7-13. Epub 2019 Dec 24.

Department of Psychology, University of Denver, Denver CO.

The multiple deficit model (MDM) was proposed because the prevailing single-deficit model provided an inadequate account of atypical neuropsychological development. Across methods and levels of analysis, there has been support for the two fundamental tenets of the MDM, that multiple predictors contribute probabilistically to neurodevelopmental disorders and shared risk factors contribute to comorbidity. Diagnostically, the multiplicity of factors means that no single cognitive deficit or combination of deficits can be used to rule in or out most neurodevelopmental disorders. Read More

Radiol Case Rep 2020 Jun 7;15(6):705-708. Epub 2020 Apr 7.

Department of Radiology, King Faisal Specialist Hospital & Research Center, MBC#28 P.O. Box 3354, Riyadh, Saudi Arabia.

Cardiac amyloidosis (CA) is an important cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). At present, 3 bone-seeking tracers, Tc-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD), Tc-pyrophosphate (Tc-PYP), and Tc-hydroxymethylene diphosphonate (Tc-HMDP), have been evaluated for detecting CA, but they are not widely available. In contrast, methylene diphosphate (MDP) is widely available. Read More

Sci Total Environ 2020 May 8;717:137167. Epub 2020 Feb 8.

Sydney Institute of Agriculture, The University of Sydney, 2006 Sydney, NSW, Australia. Electronic address:

Agricultural pesticides can become persistent environmental pollutants. Among many, glyphosate (GLP) is under particular scrutiny because of its extensive use and its alleged threats to the ecosystem and human health. Here, we introduce the first global environmental contamination analysis of GLP and its metabolite, AMPA, conducted with a mechanistic dynamic model at 0. Read More

Ann N Y Acad Sci 2020 08 24;1474(1):15-26. Epub 2020 Mar 24.

Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.

Bisphosphonates (BPs) are widely prescribed drugs used to treat osteoporosis, commonly arising in postmenopausal women and in chronic glucocorticoid use. Their mechanism of action is through inhibiting osteoclast-induced bone remodeling, and they also possess calcium sequestering properties. Common side effects involve the gastrointestinal system and rare but serious side effects, including osteonecrosis of the jaw. Read More

ACS Omega 2020 Mar 5;5(10):5306-5317. Epub 2020 Mar 5.

Department of Materials Science and Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.

The microstructural, thermomechanical, and quasistatic mechanical properties of biobased polyamide 410 (PA410)/poly(octane--ethylene)--maleic anhydride (POE--MA) blends with the impact toughener in the composition range of 0-20 wt % have been investigated, with an aim to overcome the poor notch and strain sensitivity of PA410. The crystallinity of the blends obtained from enthalpic measurements and initial degradation temperature indicating thermal stability remained mostly unaffected. A remarkably substantial increase, i. Read More