Biology subjects

Meredith, L. W.

Publications and source records attributed to Meredith, L. W..

5 recordsLinked to original sources

bioRxiv2026

Preserved CETP Activity and Early Serum Amyloid A are Associated with Improved Outcomes in Sepsis-Associated ARDS

Background: Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. It is a leading cause of in-hospital mortality. The multicenter Acute Respiratory Distress Syndrome Network Statins for Acutely Injured Lungs from Sepsis (ARDSNet-SAILS) trial found that rosuvastatin (RS) did not improve clinical outcomes in patients with sepsis-associated ARDS and may increase hepatic and renal dysfunction. We evaluated associations of plasma cholesterol ester transfer protein (CETP) activity and Serum Amyloid A (SAA) levels with survival and clinical outcomes using plasma samples and clinical data from ARDSNet-SAILS trial. Methods: This secondary analysis included clinical data and plasma samples from 471 ARDSNet-SAILS participants, randomized to placebo (PL) or RS. Plasma CETP activities and SAA levels were measured at enrollment (Day 0, n=466) and Days 3 (n=425) and 6 (n=342). Treatment effects were assessed using linear mixed models, and associations with survival and outcomes using Cox, linear, beta-binomial, and zero-inflated negative binomial regression models. Results: CETP activities were significantly higher in the survivors compared to non-survivors on days 0, 3, and 6 of analysis, in both the treatment groups (p<0.01). Higher Day 0 and Day 3 CETP activities in PL patients independently predicted improved survival, with every 3-unit increase in activity associated with 18 to 19% lower mortality risk. In the RS treatment group, higher CETP at Day 0, Day 3, and Day 6 was significantly associated with reduced hazard of mortality (p=0.039, 0.005, and 0.022, and hazard ratios = 0.87, 0.82, and 0.80, respectively, for Days 0, 3, and 6). Higher CETP values on Days 3 and 6 were also significantly negatively associated with APACHE score and positively associated with increased renal dysfunction-free days (p=0.001). Plasma SAA levels decreased significantly over time in both treatment groups (p<0.0001). In the PL group, higher plasma SAA levels were associated with a lower hazard of mortality. Accordingly, survivors had significantly higher plasma SAA levels than non-survivors at Day 0 (p=0.005). Higher SAA levels at Days 0 and 3 were also inversely correlated with APACHE scores, while Day 0 SAA levels were positively associated with overall organ dysfunction-free days (p=0.002). In contrast, in the RS group, higher plasma SAA levels were associated with an increased hazard of mortality, reaching statistical significance at Day 6 (p<0.01). Despite this, higher SAA levels in the RS group were positively associated with renal dysfunction-free days (Day 3, p=0.004; Day 6, p=0.006), hepatic dysfunction-free days (Days 0, 3, and 6; all p[≤]0.001), and overall organ dysfunction-free days (Day 0, p=0.017; Days 3 and 6, both p<0.001). Analysis of SAA levels in FPLC fractions demonstrated higher SAA levels in the HDL fraction among survivors compared with non-survivors in the PL group on Days 0 and 3; however, this difference was not observed in the RS group. Conclusion: Taken together, these findings identify plasma CETP activities and early SAA levels as stable prognostic biomarkers associated with improved survival and reduced disease severity in sepsis. However, while both CETP activity and SAA levels were unaffected by RS treatment, it appeared to modify the association between SAA and mortality.

biochemistry↗

bioRxiv2023

Antisense Oligonucleotide Targeting Hepatic Serum Amyloid A Limits the Progression of Angiotensin II-Induced Abdominal Aortic Aneurysm Formation

Background and aimObesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. We reported that deficiency of SAA significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. The aim of this study is to investigate whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice. MethodsMale C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with AngII until the end of the study. Mice with at least a 25% increase in the luminal diameter of the abdominal aorta after 4 weeks of AngII infusion were stratified into 2 groups. The first group received a control antisense oligonucleotide (Ctr ASO), and the second group received ASO that suppresses SAA (SAA-ASO) until the end of the study. ResultsPlasma SAA levels were significantly reduced by the SAA ASO treatment. While mice that received the control ASO had continued aortic dilation throughout the AngII infusion periods, the mice that received SAA-ASO had a significant reduction in the progression of aortic dilation, which was associated with significant reductions in matrix metalloprotease activities, decreased macrophage infiltration and decreased elastin breaks in the abdominal aortas. ConclusionsWe demonstrate for the first time that suppression of SAA protects obese C57BL/6 mice from the progression of AngII-induced AAA. Suppression of SAA may be a therapeutic approach to limit AAA progression.

pathology↗

bioRxiv2020

Patterns of within-host genetic diversity in SARS-CoV-2

Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around the world. The modest mutation rate and rapid transmission of SARS-CoV-2 prevents the reconstruction of transmission chains from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe the patterns of within-host diversity in 1,181 SARS-CoV-2 samples sequenced to high depth in duplicate. 95% of samples show within-host mutations at detectable allele frequencies. Analyses of the mutational spectra revealed strong strand asymmetries suggestive of damage or RNA editing of the plus strand, rather than replication errors, dominating the accumulation of mutations during the SARS-CoV-2 pandemic. Within and between host diversity show strong purifying selection, particularly against nonsense mutations. Recurrent within-host mutations, many of which coincide with known phylogenetic homoplasies, display a spectrum and patterns of purifying selection more suggestive of mutational hotspots than recombination or convergent evolution. While allele frequencies suggest that most samples result from infection by a single lineage, we identify multiple putative examples of co-infection. Integrating these results into an epidemiological inference framework, we find that while sharing of within-host variants between samples could help the reconstruction of transmission chains, mutational hotspots and rare cases of superinfection can confound these analyses.

genomics↗

bioRxiv2020

A novel antiviral formulation inhibits a range of enveloped viruses.

Some free fatty acids derived from milk and vegetable oils are known to have potent antiviral and antibacterial properties. However, therapeutic applications of short to medium chain fatty acids are limited by physical characteristics such as immiscibility in aqueous solutions. We evaluated a novel proprietary formulation based on an emulsion of short chain caprylic acid, ViroSAL, for its ability to inhibit a range of viral infections in vitro and in vivo. In vitro, ViroSAL inhibited the enveloped viruses Epstein-Barr, measles, herpes simplex, Zika and orf parapoxvirus, together with Ebola, Lassa, vesicular stomatitis and SARS-CoV-1 pseudoviruses, in a concentration- and time-dependent manner. Evaluation of the components of ViroSAL revealed that caprylic acid was the main antiviral component; however, the ViroSAL formulation significantly inhibited viral entry compared with caprylic acid alone. In vivo, ViroSAL significantly inhibited Zika and Semliki Forest Virus replication in mice following the inoculation of these viruses into mosquito bite sites. In agreement with studies investigating other free fatty acids, ViroSAL had no effect on norovirus, a non-enveloped virus, indicating that its mechanism of action may be via surfactant disruption of the viral envelope. We have identified a novel antiviral formulation that is of great interest for prevention and/or treatment of a broad range of enveloped viruses.

microbiology↗

bioRxiv2017

The translational landscape of Zika virus during infection of mammalian and insect cells

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus recently associated with congenital diseases and neurological complications. As for all flaviviruses, the ZIKV RNA genome is expected to encode a single polyprotein with all the enzymatic activities required for viral replication. Here, we report the discovery of multiple non-canonical open reading frames (ORFs) identified by ribosome profiling. In both mammalian and insect cells infected with Asian/American and African ZIKV strains, we observed translation of previously unrecognised upstream ORFs (uORFs) in the 5' region. In the Asian/American ZIKV lineage, ribosomes translated uORF1 and uORF2 that initiated from non-AUG start codons, whereas in the African ZIKV lineage, these two uORFs were fused into a single uORF (African uORF). Using a reverse genetics system, we examined the impact on ZIKV fitness of the expression of single or dual uORFs by analysing a panel of mutant viruses. We found that expression of the African uORF, and more significantly, the Asian/American uORF1, modulated virus growth and tropism in human cortical neurons and 3D organoid tissue, indicating that these novel uORFs contribute to ZIKV neurotropism. Although ZIKV uORFs are expressed in mosquito cells, they did not have a detectable effect on transmission by the mosquito vector in vivo. Our discovery of ZIKV uORFs sheds new light on ZIKV-induced neuropathogenesis and raises the question of their existence in other neurotropic flaviviruses.

microbiology↗