Biology subjects

Hoffmann, J.

Publications and source records attributed to Hoffmann, J..

23 records · Page 2Linked to original sources

bioRxiv2020

Effects of Post-Myocardial Infarction Heart Failure on the Bone Vascular Niche

Bone vasculature provides protection and signals necessary to control stem cell quiescence and renewal1. Specifically, type H capillaries, which highly express Endomucin, constitute the endothelial niche supporting a microenvironment of osteoprogenitors and long-term hematopoietic stem cells2-4. The age-dependent decline in type H endothelial cells was shown to be associated with bone dysregulation and accumulation of hematopoietic stem cells, which display cell-intrinsic alterations and reduced functionality3. The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the vascular bone cell composition. We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Inhibition of NLRP3-dependent IL-1{beta} production partially prevents the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of vascular bone function in ischemic heart disease.

cell biology↗

bioRxiv2020

Mycobacterium tuberculosis micro-diversity promotes intra-macrophagic persistence and antibiotic tolerance

Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptive response during the course of tuberculosis (TB) and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in a cohort of patients with delayed Mtb culture conversion. We captured the genetic diversity of both the initial and the last Mtb isolate obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed the last Mtb isolate to rifampicin (RIF) prior to whole genome sequencing analysis. We were able to detect unfixed SNPs within the Mtb isolates for 9/12 patients, and non-synonymous (ns) SNPs in 6/12 patients. Furthermore, RIF exposure revealed 8 additional unfixed nsSNP unlinked to drug resistance. To better understand the dynamics of Mtb micro-diversity during the course of TB, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments chosen to mimic the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants, not necessarily linked to canonical drug-resistance and which may be able to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management. Author summaryTuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), bacteria that are able to persist inside the patient for many months or years, thus requiring long antibiotic treatments. Here we focused on TB patients with delayed response to treatment and we performed genetic characterization of Mtb isolates to search for sub-populations that may tolerate anti-TB drugs. We found that Mtb cultured from 9/12 patients contained different sub-populations, and in vitro drug exposure revealed 8 other sub-populations, none related to known drug-resistance mechanisms. Furthermore, we characterized a Mtb variant isolated from a sub-population growing in the presence of rifampicin (RIF), a major anti-TB drug. We found that this variant featured a modified lipidic envelope, and that it was able to develop in the presence of RIF and inside human macrophage cells. We performed pharmacological modelling and found that this kind of variant may be related to a poor response to treatment. In conclusion, searching for particular Mtb sub-populations may help to detect patients at risk of treatment failure and provide additional guidance for TB management.

microbiology↗

bioRxiv2020

Light-driven formation of high-valent manganese oxide by photosystem II supports evolutionary role in early bioenergetics

Water oxidation and concomitant O2-formation by the Mn4Ca cluster of oxygenic photosynthesis has shaped the biosphere, atmosphere, and geosphere. It has been hypothesized that at an early stage of evolution, before photosynthetic water oxidation became prominent, photosynthetic formation of Mn oxides from dissolved Mn(2+) ions may have played a key role in bioenergetics and possibly facilitated early geological manganese deposits. The biochemical evidence for the ability of photosystems to form extended Mn oxide particles, lacking until now, is provided herein. We tracked the light-driven redox processes in spinach photosystem II (PSII) particles devoid of the Mn4Ca clusters by UV-vis and X-ray spectroscopy. We find that oxidation of aqueous Mn(2+) ions results in PSII-bound Mn(III,IV)-oxide nanoparticles of the birnessite type comprising 50-100 Mn ions per PSII. Having shown that even todays photosystem-II can form birnessite-type oxide particles efficiently, we propose an evolutionary scenario, which involves Mn-oxide production by ancestral photosystems, later followed by down-sizing of protein-bound Mn-oxide nanoparticles to finally yield todays Mn4CaO5 cluster of photosynthetic water oxidation.

biophysics↗

bioRxiv2019

Dietary vs non-dietary fatty acid profiles of lake trout morphs from Lake Superior and Great Bear Lake: Are fish really what they eat?

Fatty acids are well-established biomarkers used to characterize trophic ecology, food-web linkages, and the ecological niche of many different taxa. Most often, fatty acids that are examined include only those previously identified as "dietary" or "extended dietary" biomarkers. Fatty acids considered as non-dietary biomarkers, however, represent numerous fatty acids that can be extracted. Some studies may include non-dietary fatty acids (i.e., combined with dietary fatty acids), but do not specifically assess them, whereas in other studies, these data are discarded. In this study, we explored whether non-dietary biomarkers fatty acids can provide worthwhile information by assessing their ability to discriminate intraspecific diversity within and between lakes. Non-dietary fatty acids used as biomarkers delineated variation among regions, among locations within a lake, and among ecotypes within a species. Physiological differences that arise from differences in energy processing can be adaptive and linked to habitat use by a species ecotypes, and likely explains why non-dietary fatty acids biomarkers can be a relevant tool to delineate intraspecific diversity. Little is known about the non-dietary-mediated differences in fatty acid composition, but our results showed that non-dietary fatty acids biomarkers can be useful tool in identifying variation.

ecology↗

bioRxiv2018

Size, shape and structure of insect wings

The size, shape and structure of insect wings are intimately linked to their ability to fly. However, there are few systematic studies of the variability of the natural patterns in wing morphology across insects. We assemble a comprehensive dataset of insect wings and analyze their morphology using topological and geometric notions in terms of i) wing size and contour shape, ii) vein geometry and topology, and iii) shape and distribution of wing membrane domains. These morphospaces are a first-step in defining the diversity of wing patterns across insect orders and set the stage for investigating their functional consequences.

evolutionary biology↗