Biology subjects

Jensen, S.

Publications and source records attributed to Jensen, S..

11 recordsLinked to original sources

bioRxiv2026

Autonomous sampling and eDNA metabarcoding for offshore biodiversity monitoring: a pilot study around an FPSO in the Southwestern Atlantic

Characterizing biodiversity around offshore infrastructure is necessary to assess possible influences of industrial activities on marine communities and distinguish persistent ecological change from short-term variability. Combining environmental DNA (eDNA) metabarcoding with autonomous sampling offers a way to expand biological, spatial and temporal coverage while reducing dependence on crewed field operations. We evaluated this approach around a floating production, storage and offloading unit (FPSO) in the Santos Basin, Brazil, to establish an initial biodiversity reference and inform subsequent monitoring. A third-generation Environmental Sample Processor integrated into the W Tupan II uncrewed surface vessel enabled autonomous water sampling at coastal sites, transit locations and the FPSO area, yielding 64 biological samples. We used mitochondrial 12S and 16S metabarcoding to assess taxonomic diversity, sampling completeness and spatial and short-term temporal variation. Around the FPSO, 47 samples from 21 points detected 34 species with 12S and 28 with 16S, representing 74.3% and 65.4% of the respective estimated species richness. Local analyses showed weak radial differentiation across 300-1,500 m around the FPSO, with no near-far taxonomic indicators remaining significant after multiple-testing corrections. Samples collected at the same point approximately 1-2 h apart were almost as dissimilar as samples from different points, whereas technical replicates of post-extraction processing closely matched their source DNA profiles. Taxon turnover accounted for approximately 73% and 80% of temporal Jaccard dissimilarity for 12S and 16S, respectively. Regional analyses recovered a coastal-offshore compositional contrast, with geography and sampling date jointly represented. This pilot supports autonomous eDNA sampling as an operational approach to offshore biodiversity monitoring. The findings favour repeated sampling across campaigns to distinguish transient detections from recurrent patterns and persistent compositional changes.

molecular biology↗

bioRxiv2023

Timp2 loss-of-function mutation and TIMP2 treatment in murine model of NSCLC: modulation of immunosuppression and oncogenic signaling

Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly downregulates the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC. One Sentence SummaryTIMP2 treatment compensates for TIMP2 mutation to reveal immunomodulatory and oncogene regulation that inhibits tumor growth and metastatic niche formation.

cancer biology↗

bioRxiv2023

Isolation and characterization of persisters of the pathogenic microorganism Staphylococcus aureus

Staphylococcus aureus is a notorious pathogen responsible for significant morbidity and mortality in both human society and animal husbandry. The presence of S. aureus persisters is also one of the leading causes of recurrent and chronic diseases. Persisters are a subset of growth-arrested bacteria within a susceptible bacterial population that are able to tolerate antibiotic treatment and resuscitate after stress removal. Consequently, investigating their formation and characteristics is of crucial importance to provide mechanism-based options for their eradication. However, one challenge in mechanistic research on persisters is the enrichment of pure persisters. In this work, we validated a proposed method to isolate persisters from vancomycin and enrofloxacin generated persistent populations. With this, we analyzed the proteome profile of pure persisters and revealed the distinct mechanisms associated with vancomycin and enrofloxacin induced persisters. Furthermore, morphological and metabolic characterizations were performed, indicating further differences between these two persister populations. Finally, we assessed the effect of ATP repression, protein synthesis inhibition and reactive oxygen species (ROS) level on persister formation. In conclusion, this work provides a comprehensive understanding of S. aureus vancomycin and enrofloxacin induced persisters at the molecular, single cell and population levels, facilitating a better understanding of persisters and the development of effective strategies to combat them.

microbiology↗

bioRxiv2023

Molecular physiological characterization of the dynamics of persister formation in Staphylococcus aureus.

Bacteria possess the ability to enter a growth arrested state known as persistence in order to survive antibiotic exposure. Clinically, persisters are regarded as the main causative agents for chronic and recurrent infectious diseases. To combat this antibiotic-tolerant population, a better understanding of the molecular physiology of persisters is required. In this study, we collected samples at different stages of the biphasic kill curve to reveal the dynamics of the cellular molecular changes that occur in the process of persister formation. After exposure to antibiotics with different modes of action, namely vancomycin and enrofloxacin, similar persister levels were obtained. Both shared and distinct stress responses were enriched for the respective persister populations. However, the dynamics of the presence of proteins linked to the persister phenotype throughout the biphasic kill curve and the molecular profiles in a stable persistent population did show large differences depending on the antibiotic used. This suggests that persisters at the molecular level are highly stress specific, emphasizing the importance of characterizing persisters generated under different stress conditions. Additionally, although generated persisters exhibited cross-tolerance toward tested antibiotics, combined therapies were demonstrated to be a promising approach to reduce persister levels. In conclusion, this investigation sheds light on the stress-specific nature of persisters, highlighting the necessity of tailored treatment approaches and the potential of combined therapy. ImportanceBy monitoring proteome and metabolites during Staphylococcus aureus persister formation under vancomycin and enrofloxacin exposure, we revealed the dynamic information of the molecular physiology of persister formation upon exposure to two different antibiotics with different modes of action. The data shows that cells that phenotypically are similarly classified as persisters, do have several molecular characteristics in common but, remarkably so, differ substantially in a significant number of other aspects of their molecular makeup. These contrasts provided valuable insights into persister eradication, which holds considerable clinical relevance.

microbiology↗

bioRxiv2023

Human Dermal Fibroblast Subpopulations and Epithelial Mesenchymal Transition Signals in Hidradenitis Suppurativa Tunnels are Normalized by Spleen Tyrosine Kinase Antagonism in Vivo

Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology. Gene signatures of SFRP2+ fibroblast subsets were increased in lesional tissue, with gene signatures of SFRP1+ fibroblast subsets decreased. SFRP2+ and CXCL12+ fibroblast numbers, measured by IHC, were increased in HS tissue, with greater numbers associated with epithelialized tunnels and Hurley Stage 3 disease. Pro-inflammatory CXCL12+ fibroblasts were also increased, with reductions in SFRP1+ fibroblasts compared to healthy controls. Evidence of Epithelial Mesenchymal Transition was seen via altered gene expression of SNAI2 and altered protein expression of ZEB1, TWIST1, Snail/Slug, E-Cadherin and N-Cadherin in HS lesional tissue. The greatest dysregulation of EMT associated proteins was seen in biopsies containing epithelialized tunnels. The use of the oral Spleen tyrosine Kinase inhibitor Fostamatinib significantly reduced expression of genes associated with chronic inflammation, fibroblast proliferation and migration suggesting a potential role for targeting fibroblast activity in HS.

immunology↗

bioRxiv2023

FcyRIIB is a novel immune checkpoint in the tumor microenvironment limiting activity of Treg-targeting antibodies

Despite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology. Highlights- Fully human anti-CTLA-4 antibodies are limited in their capacity to deplete T regulatory cells and drive durable anti-tumor immunity in humanized FcyR/hCTLA-4 mice - The inhibitory Fcy receptor, FcyRIIB, is upregulated in the tumor microenvironment in patients and in humanized FcyR/hCTLA-4 mice - Blocking FcyRIIB leads to rescue of Treg depletion in humanized murine models - Fc engineering can improve the depleting capacity and in vivo anti-tumor activity of anti-CTLA and anti-CCR8 antibodies targeting tumor infiltrating Tregs

immunology↗

bioRxiv2022

Germline piRNAs counteract endogenous retrovirus invasion from somatic cells.

Most Drosophila transposable elements (TEs) are LTR retrotransposons, some of which belong to the genus Errantivirus and share structural and functional characteristics with vertebrate endogenous retroviruses (ERVs). These virus-derived elements occupy a large part of the genome, but it is unclear whether and how they can be reactivated and if they retain their replication capacity. We created conditions where control of the Drosophila ZAM errantivirus through the piRNA pathway was abolished leading to its reactivation in real time in somatic gonadal cells. We show that ZAM may remain active in these cells indicating that errantiviruses may hide from the efficient germline piRNA pathway by being expressed exclusively in somatic cells. After reactivation, ZAM invaded the oocytes and severe fertility defects were observed. The germline then set up its own adaptive genomic immune response against the constantly invading errantivirus, restricting invasion and restoring fertility. Our results not only highlight how errantiviruses and their host adapt to each other but also reveal a time window during oogenesis that may be favourable for viral germline invasion and endogenization.

genetics↗

bioRxiv2022

Not all seed transfer zones are created equal: Using fire history to identify seed needs in the Cold Deserts of the Western US

Restoration planning requires a reliable seed supply, yet many projects occur in response to unplanned events. Identifying regions of greater risk could help guide seed procurement. Using fire perimeters (2000-2019), we investigated differences in fire occurrence (frequency, area burned, percent of area burned) among seed transfer zones within Cold Deserts of the US. We considered both provisional seed transfer zones (PSTZs), created using climate and stratified by ecoregion, and empirical seed transfer zones (ESTZs) for two species commonly used in restoration. Finally, we present a case study on fire occurrence within Northern Basin and Range greater sage-grouse Priority Areas for Conservation (PACs). Historic fire was effective for prioritizing seed zones: 23 of 132 PSTZs burned every year, and, within each ecoregion, two PSTZs comprised [greater double equals] 50% of the total area burned across all years. Similarly, fire disproportionately occurred in some ESTZs; in the Northern Basin and Range, one (Artemisia tridentata - 83%) or two zones (Pseudoroegneria spicata - 65%) made up a majority of total area burned. Fire occurrence within PACs largely reflected the PSTZ and ESTZ priorities found for the ecoregion, with small exceptions. Imperiled PSTZs (high proportion burned) in PACs largely reflected the patterns found across the ecoregion, while imperiled ESTZs departed from ecoregional patterns. Considering historic disturbance can focus seed procurement efforts on regions that encounter regular disturbance, experience large disturbances, or have particular conservation value. This information can guide seed production, purchase, and storage, create more certainty for growers and managers, and ultimately increase restoration success. IMPLICATIONS FOR PRACTICEO_LIAvailable data on past disturbance patterns may inform strategies for prioritizing seed procurement decisions, especially as geospatial information becomes more widely available C_LIO_LIThe methods presented here illustrate an approach for using historic disturbance data to identify regions that are of greatest need for seed collection and conservation, using seed transfer zones within US Cold Desert ecoregions as an example C_LIO_LIIdentifying regions that experience disturbance over large areas or are likely to be imperiled due to disturbance at a high proportion can guide the collection and conservation of plant materials and better align available plant material with future restoration needs C_LI

ecology↗

bioRxiv2020

Conserved small nucleotidic elements at the origin of concerted piRNA biogenesis from genes and lncRNAs

PIWI-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing in animal germ cells. The piRNA pathway is increasingly recognized as critical for essential cellular functions such as germline development and reproduction. In the Anopheles gambiae ovary, as much as 11% of piRNAs map to protein-coding genes. Here we show that ovarian mRNAs and long non-coding RNAs (lncRNAs) are processed into piRNAs that can direct other transcripts into the piRNA biogenesis pathway. Targeting piRNAs fuel transcripts either into the ping-pong cycle of piRNA amplification or into the machinery of phased piRNA biogenesis, thereby creating networks of inter-regulating transcripts. RNAs of the same network share related genomic repeats. These repeats give rise to piRNAs, which target other transcripts and lead to a cascade of concerted RNA slicing. While ping-pong networks are based on repeats of several hundred nucleotides, networks that rely on phased piRNA biogenesis operate through short [~]40-nucleotides long repeats, which we named snetDNAs. Interestingly, snetDNAs are recurring in evolution from insects to mammals. Our study brings to light a new type of a conserved regulatory pathway, the snetDNA-pathway, by which short sequences can include independent genes and lncRNAs in the same biological pathway. AUTHOR SUMMARYSmall RNA molecules are essential actors in silencing mobile genetic elements in animal germ cells. The 24-29-nucleotide-long Piwi-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing. Mosquitoes of the Anopheles gambiae species complex are the principal vectors of malaria, and research on their germline is essential to develop new strategies of vector control by acting on reproduction. In the Anopheles gambiae ovary as much as 11% of piRNAs originate from protein-coding genes. We identified piRNAs which are able to target transcripts from several distinct genes or long non-coding RNAs (lncRNAs), bringing together genic transcripts and lncRNAs in a same regulation network. piRNA targeting induces transcript slicing and production of novel piRNAs, which then target other mRNAs and lncRNAs leading again to piRNA processing, thus resulting in a cascade of RNA slicing and piRNA production. Each network relies on piRNAs originating from repeated genetic elements, present in all transcripts of the same network. Some of these repeats are very short, only [~]40-nucleotides long. We identified similar repeats in all 43 animal species that we analysed, including mosquitoes, flies, arachnidae, snail, mouse, rat and human, suggesting that such regulation networks are recurrent, possibly conserved, in evolutionary history.

bioinformatics↗

bioRxiv2019

Trapping a somatic endogenous retrovirus into a germline piRNA cluster immunizes the germline against further invasion

BackgroundFor species survival, the germline must faithfully transmit the genetic information to the progeny. Transposable elements (TEs), which are major components of eukaryotic genomes, constitute a significant threat to genome stability due to their mobility. In the metazoan germline, their mobilization is limited by a class of small RNAs that are called PIWI-interacting RNAs (piRNAs) and are produced by dedicated genomic loci called piRNA clusters. Although the piRNA pathway is an adaptive genomic immunity system, it remains unclear how the germline is protected from transposon invasion. To address this question, we used Drosophila melanogaster lines harboring a deletion within flamenco, a major piRNA cluster that is specifically expressed in somatic follicular cells. This deletion leads to derepression of the retrotransposon ZAM and to germline genome invasion.\n\nResultsIn this mutant line that express ZAM in somatic follicular cells, we identified de novo production of sense and antisense ZAM-derived piRNAs that displayed a germinal molecular signature. These piRNAs originated from a new ZAM insertion into a germline dual-strand piRNA cluster and silenced ZAM expression specifically in germ cells. Finally, we found that ZAM trapping in a germinal piRNA cluster is a frequent event that occurs early during the isolation of the mutant line.\n\nConclusionsTransposons can hijack the host developmental process to propagate whenever their silencing is lost. Here, we show that the germline can protect itself by trapping invading somatic-specific TEs into germline piRNA clusters. This is the first demonstration of \"auto-immunization\" of the germline endangered by mobilization of a surrounding somatic TE.

genetics↗

bioRxiv2018

Child Growth Predicts Brain Functional Connectivity and Future Cognitive Outcomes in Urban Bangladeshi Children Exposed to Early Adversities

BackgroundFaltered growth has been shown to affect 161 million children worldwide and derail cognitive development from early childhood. The neural pathways by which growth faltering in early childhood affects future cognitive outcomes remain unclear, which is partially due to the scarcity of research using both neuroimaging and sensitive behavioral techniques in low-income settings. We employed EEG to examine the association between growth faltering and brain functional connectivity and whether brain functional connectivity mediates the effect of early adversity on cognitive development.\n\nMethodsWe recruited participants from an urban impoverished neighborhood in Dhaka, Bangladesh. One sample consisted of 85 children whose EEG and growth measures (height for age, weight for age, and weight to height) were collected at 6 months and cognitive outcomes were assessed at 27 months. Another sample consisted of 115 children whose EEG and growth measures were collected at 36 months and IQ scores were assessed at 48 months. Path analysis was used to test the effect of growth measures on cognitive outcomes through brain functional connectivity.\n\nFindingsFaltered growth was found to be accompanied by overall increased functional connectivity in the theta and low-beta frequency bands for the 36-month-old cohort. For both cohorts, brain functional connectivity was negatively predictive of later cognitive outcomes at 27 and 48 months, respectively. Faltered growth was found to have a negative impact on childrens IQ scores in the older cohort, and this effect was found to be mediated by brain functional connectivity in the low-beta band.\n\nInterpretationThe association found between growth measures and brain functional connectivity may reflect a broad deleterious effect of malnutrition on childrens brain development. The mediation effect of functional connectivity on the relation between physical growth and later IQ scores provides the first experimental evidence that brain functional connectivity may mediate the effect of biological adversity on cognitive development.\n\nFundingBill and Melinda Gates Foundation (OPP1111625)

neuroscience↗