Biology subjects

Cooper, D.

Publications and source records attributed to Cooper, D..

25 records · Page 2Linked to original sources

bioRxiv2021

The Immunomodulatory Effects of Social Isolation in Mice are Linked to Temperature Control

Living in isolation is considered an emerging societal problem that negatively affects the physical wellbeing of its sufferers in ways that we are just starting to appreciate. This study investigates the immunomodulatory effects of social isolation in mice, utilising a two-week program of sole cage occupancy followed by the testing of immune-inflammatory resilience to bacterial sepsis. Our results revealed that mice housed in social isolation showed an increased ability to clear bacterial infection compared to control socially housed animals. These effects were associated with specific changes in whole blood gene expression profile and an increased production of classical pro-inflammatory cytokines. Interestingly, equipping socially isolated mice with artificial nests as a substitute for their natural huddling behaviour reversed the increased resistance to bacterial sepsis. These results further highlight the ability of the immune system to act as a sensor of our living conditions and to respond in a compensatory fashion to external challenges that might threaten the survival of the host.

immunology↗

bioRxiv2021

Neutralization of spike 69/70 deletion, E484K, and N501Y SARS-CoV-2 by BNT162b2 vaccine-elicited sera

We engineered three SARS-CoV-2 viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion+N501Y+D614G from UK; and E484K+N501Y+D614G from SA. Neutralization geometric mean titers (GMTs) of twenty BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.

microbiology↗

bioRxiv2021

Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera

Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.

microbiology↗

bioRxiv2020

Physiologic RNA Targets and Refined Sequence Specificity of Coronavirus EndoU

Coronavirus EndoU inhibits dsRNA-activated antiviral responses; however, the physiologic RNA substrates of EndoU are unknown. In this study, we used mouse hepatitis virus (MHV)-infected bone-marrow-derived macrophage (BMM) and cyclic phosphate cDNA sequencing to identify the RNA targets of EndoU. EndoU targeted viral RNA, cleaving the 3' side of pyrimidines with a strong preference for UA and CA sequences (endoYA). EndoU-dependent cleavage was detected in every region of MHV RNA, from the 5' NTR to the 3' NTR, including transcriptional regulatory sequences (TRS). Cleavage at two CA dinucleotides immediately adjacent to the MHV poly(A) tail suggest a mechanism to suppress negative-strand RNA synthesis and the accumulation of viral dsRNA. MHV with EndoU (EndoUmut) or 2'-5' phosphodiesterase (PDEmut) mutations provoked the activation of RNase L in BMM, with corresponding cleavage of RNAs by RNase L. The physiologic targets of EndoU are viral RNA templates required for negative-strand RNA synthesis and dsRNA accumulation. ImpactCoronavirus EndoU cleaves UA and CA sequences (endoYA) within viral (+) strand RNA to evade dsRNA-activated host responses.

microbiology↗

bioRxiv2019

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

ABSTRACTThe carbon source for catabolism in vivo is a fundamental question in metabolic physiology. Limited by data and rigorous mathematical analysis, controversy exists over the nutritional sources for carbon in the tricarboxylic acid (TCA) cycle under physiological settings. Using isotope-labeling data in vivo across several experimental conditions, we construct multiple models of central carbon metabolism and develop methods based on metabolic flux analysis (MFA) to solve for the preferences of glucose, lactate, and other nutrients used in the TCA cycle across many tissues. We show that in nearly all circumstances, glucose contributes more than lactate as a nutrient source for the TCA cycle. This conclusion is verified in different animal strains from different studies, different administrations of 13C glucose, and is extended to multiple tissue types. Thus, this quantitative analysis of organismal metabolism defines the relative contributions of nutrient fluxes in physiology, provides a resource for analysis of in vivo isotope tracing data, and concludes that glucose is the major nutrient used for catabolism in mammals.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

bioRxiv2019

Extracellular vesicles from monocyte/platelet aggregates modulate human atherosclerotic plaque responses

In atherosclerosis, a chronic disease characterized by lipid accumulation, fibrosis and vascular inflammation, extracellular vesicles (EVs) are emerging as key players in different stages of disease development. Here we provide evidence that EVs released by mixed aggregates of monocytes and platelets in response to TNF- are both CD14+ and CD41+. Tempering platelet activation with Iloprost impacted the quality and quantity of EV produced. Proteomics of EVs from cells activated with TNF- alone or in presence Iloprost revealed distinct proteome, with selective hits like gelsolin. EVs from TNF- stimulated monocytes augmented release of cytokines, and modulated more than 500 proteins by proteomics, when added to human atherosclerotic plaques. In contrast, EVs generated by TNF- and Iloprost produced minimal plaque activation. In conclusion, attenuating platelet activation has an effect on EV composition released from monocyte/platelet aggregates with downstream modulation of their pro-inflammatory actions and contribution to the development and progression of atherosclerosis.

immunology↗

bioRxiv2019

Measurement of organ-specific and acute-phase blood protein levels in early Lyme disease

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that 1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or 2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2 and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

systems biology↗