Publications by authors named "A Mark Richards"

2,575 Publications

  • Page 1 of 1

Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.

Nat Commun 2021 Nov 25;12(1):6912. Epub 2021 Nov 25.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a K of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.
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http://dx.doi.org/10.1038/s41467-021-27275-8DOI Listing
November 2021

Differences in biofilm formation of Salmonella serovars on two surfaces under two temperature conditions.

J Appl Microbiol 2021 Nov 25. Epub 2021 Nov 25.

Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.

Aims: Salmonella is extremely diverse, with >2500 serovars that are genetically and phenotypically diverse. The aim of this study was to build a collection of Salmonella isolates that are genetically diverse and to evaluate their ability to form biofilm under different conditions relevant to a processing environment.

Methods And Results: Twenty Salmonella isolates representative of 10 serovars were subtyped using Clustered regularly interspaced short palindromic repeats (CRISPR)-typing to assess the genetic diversity between isolates of each serovar. Biofilm formation of the isolates on both plastic and stainless-steel surfaces at 25°C and 15°C was assessed. At 25°C, 8/20 isolates each produced strong and moderate biofilm on plastic surface compared to stainless-steel (3/20 and 13/20, respectively). At 15°C, 5/20 produced strong biofilm on plastic surface and none on stainless-steel. Several isolates produced weak biofilm on plastic (11/20) and stainless-steel (16/20) surfaces. Serovar Schwarzengrund consistently produced strong biofilm while serovars Heidelberg and Newport produced weak biofilm.

Conclusion: These results suggest that Salmonellae differ in their attachment depending on the surface and temperature conditions encountered, which may influence persistence in the processing environment.

Significance And Impact Of Study: These differences in biofilm formation could provide useful information for mitigation of Salmonella in processing environments.
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http://dx.doi.org/10.1111/jam.15381DOI Listing
November 2021

Interspecies variation in hominid gut microbiota controls host gene regulation.

Cell Rep 2021 Nov;37(8):110057

Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA; Department of Ecology, Evolution and Behavior, University of Minnesota, Minneapolis, MN, USA. Electronic address:

The gut microbiome exhibits extreme compositional variation between hominid hosts. However, it is unclear how this variation impacts host physiology across species and whether this effect can be mediated through microbial regulation of host gene expression in interacting epithelial cells. Here, we characterize the transcriptional response of human colonic epithelial cells in vitro to live microbial communities extracted from humans, chimpanzees, gorillas, and orangutans. We find that most host genes exhibit a conserved response, whereby they respond similarly to the four hominid microbiomes. However, hundreds of host genes exhibit a divergent response, whereby they respond only to microbiomes from specific host species. Such genes are associated with intestinal diseases in humans, including inflammatory bowel disease and Crohn's disease. Last, we find that inflammation-associated microbial species regulate the expression of host genes previously associated with inflammatory bowel disease, suggesting health-related consequences for species-specific host-microbiome interactions across hominids.
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http://dx.doi.org/10.1016/j.celrep.2021.110057DOI Listing
November 2021

An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.

Cell Chem Biol 2021 Nov 22. Epub 2021 Nov 22.

Department of Chemistry, New York University, New York, NY 10003, USA. Electronic address:

DnaK is the bacterial homolog of Hsp70, an ATP-dependent chaperone that helps cofactor proteins to catalyze nascent protein folding and salvage misfolded proteins. In the pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), DnaK and its cofactors are proposed antimycobacterial targets, yet few small-molecule inhibitors or probes exist for these families of proteins. Here, we describe the repurposing of a drug called telaprevir that is able to allosterically inhibit the ATPase activity of DnaK and to prevent chaperone function by mimicking peptide substrates. In mycobacterial cells, telaprevir disrupts DnaK- and cofactor-mediated cellular proteostasis, resulting in enhanced efficacy of aminoglycoside antibiotics and reduced resistance to the frontline TB drug rifampin. Hence, this work contributes to a small but growing collection of protein chaperone inhibitors, and it demonstrates that these molecules disrupt bacterial mechanisms of survival in the presence of different antibiotic classes.
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http://dx.doi.org/10.1016/j.chembiol.2021.11.004DOI Listing
November 2021

Variability of the Plasma Lipidome and Subclinical Coronary Atherosclerosis.

Arterioscler Thromb Vasc Biol 2021 Nov 23:ATVBAHA121316847. Epub 2021 Nov 23.

Cardiovascular Research Institute (S.H.T., H.W.L.K., X.Y., H.C., A.M.R., M.Y.C.).

Objective: While the risk of acute coronary events has been associated with biological variability of circulating cholesterol, the association with variability of other atherogenic lipids remains less understood. We evaluated the longitudinal variability of 284 lipids and investigated their association with asymptomatic coronary atherosclerosis. Approach and Results: Circulating lipids were extracted from fasting blood samples of 83 community-sampled symptom-free participants (age 41-75 years), collected longitudinally over 6 months. Three types of coronary plaque volume (calcified, lipid-rich, and fibrotic) were quantified using computed tomography coronary angiogram. We first deconvoluted between-subject (CV) and within-subject (CV) lipid variabilities. We then tested whether the mean lipid abundance was different across groups categorized by Framingham risk score and plaques phenotypes (lipid-rich, fibrotic, and calcified). Last, we investigated whether visit-to-visit variability of each lipid was associated with plaque burden. Most lipids (72.5%) exhibited higher CV than CV. Among the lipids (N=145) with 1.2-fold higher CV than CV, 26 species including glycerides and ceramides were significantly associated with Framingham risk score and the 3 plaque phenotypes (false discovery rate <0.05). In an exploratory analysis of person-specific visit-to-visit variability without multiple-comparisons testing, high variability of 3 lysophospholipids (lysophosphatidylcholines 16:0, 18:0, and O-18:1) were associated with lipid-rich and fibrotic (noncalcified) plaque volume while high variability of diacylglycerol 18:1_20:0, triacylglycerols 52:2, 52:3, and 52:4, ceramide d18:0/20:0, dihexosylceramide d18:1/16:0, and sphingomyelin 36:3 were associated with calcified plaque volume.

Conclusions: High person-specific longitudinal variation of specific nonsterol lipids are associated with the burden of subclinical coronary atherosclerosis. Larger studies are needed to confirm these exploratory findings.
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http://dx.doi.org/10.1161/ATVBAHA.121.316847DOI Listing
November 2021
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