Biology subjects

Plummer, M.

Publications and source records attributed to Plummer, M..

3 recordsLinked to original sources

bioRxiv2024

Subendothelial Calcification Increases Surface Roughness and Promotes Lipid Deposition into the Arterial Wall

ObjectiveWe have previously demonstrated that subendothelial calcification accelerates atherosclerosis in mice. This study addresses a mechanism by which subendothelial calcifications can increase low-density lipoprotein (LDL) uptake into the arterial wall. MethodsMice overexpressing tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells (eTNAP mice) were used as a model of calcification. Calcification and atherosclerosis were detected by micro-computed tomography (micro-CT) and histology. The endothelial roughness was characterized by surface metrology. A fluid-structure interaction model was used to calculate wall shear stress (WSS). The uptake of fluorescent LDL was traced in vitro and in vivo. Human arteries were assessed for the prevalence of internal elastic lamina (IEL) calcification. ResultseTNAP mice developed more severe aortic atherosclerosis than controls on the LDL receptor mutant background (p<0.01). Subendothelial calcifications in eTNAP mice were confirmed by micro-CT. An increase in aortic surface area roughness, including the height, volume, and steepness parameters, was observed in eTNAP mice compared to controls (p<0.01). Calcifications affected near-wall hemodynamics, creating pockets of reduced WSS. Endothelial cells cultured on rough surfaces showed increased LDL uptake compared to cells cultured on smooth collagen (p<0.0001). Fluorescent LDLs were traced to subendothelial calcifications in eTNAP mice but not in controls. In humans, IEL calcification was prevalent in older adults and inversely correlated with arterial diameter (p<0.05). ConclusionSubendothelial calcification is sufficient to perturb near-wall hemodynamics, creating localized areas of reduced WSS, consistent with increased LDL uptake near calcified lesions. Subendothelial calcification may represent an alternative or concurrent mechanism for the initiation of atherosclerosis. Research perspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIWe tested a novel hypothesis that subendothelial microcalcification can initiate atherosclerosis. C_LIO_LIThe study demonstrated that micron-sized subendothelial calcifications, induced by the overexpression of tissue-nonspecific alkaline phosphatase in the endothelium, are sufficient to perturb local hemodynamics, creating pockets of low wall shear stress, consistent with an increase in low-density lipoprotein uptake and deposition into the arterial wall in juxtaposition to calcified lesions. C_LI What are the clinical implications?O_LIWe suggest that calcification of internal elastic lamina of medium-sized arteries may represent early lesions initiating atherosclerosis; however, the epidemiologic evidence for this theory is currently unavailable. C_LI

physiology↗

bioRxiv2023

Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam against Mycobacterium abscessus

Mycobacterium abscessus (Mab) affects patients with immunosuppression, Cystic Fibrosis (CF), or underlying structural lung diseases. Additionally, Mab poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual {beta}-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with a {beta}-lactamase inhibitors [BLI; avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration MIC values for 54 clinical Mab isolates and ATCC19977 (MIC50 and MIC90 [≤] 0.25 g/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding [~]1.5 Log10 CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in additional reduction of CFUs ([~]3 Log10 for sulopenem-CXM and AVI and [~]4 Log10 for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (LDTs; LDTMab1-LDTMab4), Penicillin-Binding-Protein B (PBP-B), and D,D-Carboxypeptidase (DDC). Acyl complexes identified via mass spectrometry analysis, demonstrated the binding of sulopenem with LdtMab2-LdtMab4, DDC, and PBP B, and CXM with LdtMab2 and PBP-B. Molecular docking suggested formation of a covalent adduct between sulopenem and LdtMab2 after the nucleophilic attack of the cysteine residue at the {beta}-lactam carbonyl carbon, leading to the cleavage of the {beta}-lactam ring, and the establishment of a thioester bond linking the LdtMab2 with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLI. These findings potentially broaden selection of oral therapeutic agents to combat Mab.

microbiology↗

bioRxiv2022

Selective retrieval revealed by electroencephalographic (EEG) neural pattern reinstatement

1.For past experiences to guide our actions we need to retrieve the relevant memories. Here, we used electroencephalography (EEG) to investigate how memories are selected for retrieval, and to test how current goals and external retrieval cues drive selection during the retrieval cascade. We analysed data from two studies in which people studied objects in picture or auditory word formats and later recalled them using either written words (Experiment 1, n = 28) or line drawings (Experiment 2, n = 28) as retrieval cues. We used multivariate decoding to quantify the reinstatement of study phase neural patterns when people successfully identified items that had been studied in a format currently designated as targeted, compared with non-targeted items. Neural reinstatement emerged at around 500 ms post-stimulus, like the established left parietal event-related potential (ERP) signature of recollection. Reinstatement was target-selective (greater for targets than non-targets) when test cues overlapped more with targets, a pattern previously shown for the left parietal ERP (Moccia & Morcom, 2021). In contrast, when cues overlapped more with non-targets, neural reinstatement was reversed - greater for non-targets - unlike the left parietal ERP. We also tested for goal-directed mental reinstatement proposed to guide selection prior to retrieval cues. When words were cues there was strong evidence of this proactive reinstatement, but it was not detected when pictures were cues. Together, the data suggest that selection can act at multiple stages of memory retrieval and depends on both external cues and goal-directed control.

neuroscience↗