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Bosch, R.

Publications and source records attributed to Bosch, R..

7 recordsLinked to original sources

Metabolic redundancy is required for microbial polyethylene assimilation

Polyethylene (PE) is amongst the most recalcitrant synthetic polymers, and only a limited number of microbes have been shown to utilise it as their sole carbon and energy source. Here, we investigated the metabolic basis enabling the efficient assimilation of PE oxidised scission products and its prevalence in microbial communities naturally colonising plastic surfaces. Metabolomic profiling of weathered PE (W-PE) leachates revealed a highly diverse pool of oxidised aliphatic compounds varying in chain length and oxidation state. Different plastic-degrading bacteria consumed this complex mix of metabolites to distinct extents, with consumption efficiency positively correlating with the number of redundant genes associated with the {beta}-oxidation pathway in their genomes. Comparative proteomic analysis of two Alcanivorax species exhibiting contrasting PE-leachate consumption capabilities confirmed that this functional redundancy was fully activated in response to the chemically complex PE-derived substrate pool. In contrast, it remained largely uninduced in the presence of the single, structurally simple alkane hexadecane. Hence, our results indicate that efficient PE assimilation requires a broad and redundant enzymatic repertoire capable of funnelling structurally diverse oxidised aliphatic intermediates through {beta}-oxidation. Metagenomic analysis of plastisphere communities further revealed enrichment of fatty acid degradation genes in biofilms colonising both pristine and weathered PE--as expected more strongly in W-PE--compared with wood and surrounding water controls, supporting the ecological relevance of this mechanism for PE biodegradation. Together, these findings identify {beta}-oxidation metabolic redundancy as a key trait underpinning microbial PE assimilation and suggest that plastic degradation may be occurring under natural environmental conditions.

microbiology↗

Inflammatory Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia

The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16++ monocytes with increased anti-viral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.

immunology↗

Lack of functional polyester-biodegrading potential in marine versus terrestrial environments evidenced by an innovative airbrushing technique

Biodegradable plastics, primarily aliphatic polyesters, degrade to varying extents in different environments. However, the absence of easily implementable techniques for screening microbial biodegradation potential --coupled with the limitations of non-functional omics analyses-- has restricted comparative studies across diverse polymer types and ecosystems. In this study, we optimized a novel airbrushing method that facilitates functional analyses by simplifying the preparation of polyester-coated plates for biodegradation screening. By repurposing an airbrush kit, polyester microparticles (MPs) could be evenly sprayed onto solid media, enabling rapid detection of extracellular depolymerizing activity via clearing zone halos. This technique was effective in screening both isolated microbial cultures and natural environmental samples, demonstrating its versatility. The method was successfully applied across multiple environments, ranking the biodegradability of six polyesters, from most to least biodegradable: polycaprolactone (PCL), poly[(R)-3-hydroxybutyrate] (PHB), poly(butylene succinate) (PBS), poly(ethylene succinate) (PES), poly(lactic acid) (PLA), and poly(butylene adipate-co-terephthalate) (PBAT). Most notably, it revealed a consistent 1,000-fold higher biodegradation potential in terrestrial compared to marine environments. This approach offers a valuable tool for isolating novel polyester-degrading microbes with significant biotechnological potential, paving the way for improved plastic waste management solutions. SYNOPSISScreening polyester-degrading microbes has traditionally been challenging due to the difficulty of incorporating polyesters into solid media. This study introduces an innovative airbrush spraying method that simplifies the preparation of polyester MPs on solid media plates, making the screening process significantly more efficient. Using this method, we demonstrated the differential biodegradability of aliphatic polyesters across environments. The results revealed a stark contrast in biodegrading potential, with terrestrial ecosystems exhibiting substantially higher activity compared to marine environments. Abstract graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/622231v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@176883eorg.highwire.dtl.DTLVardef@eab2aforg.highwire.dtl.DTLVardef@792bbdorg.highwire.dtl.DTLVardef@126ab7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

HIV-specific T-cell responses reflect substantive in vivo interactions with infected cells despite long-term therapy

Antiretroviral therapies (ART) durably suppress HIV replication to undetectable levels - however, infection persists in the form of long-lived reservoirs of infected cells with integrated proviruses, that re-seed systemic replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in driving reductions in viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle, by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. We show that T-cell responses to autologous reservoir viruses persist over years, and that the maintenance of HIV-Nef-specific responses was uniquely associated with residual frequencies of infected cells. These responses disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV-infected cells. These results indicate substantial visibility of the HIV reservoir to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing HIV infection.

immunology↗

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells.

Uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic uveal melanoma, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012) and overall survival (p = 0.011). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05), but significantly upregulated IL-10, IL-1{beta}, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

cancer biology↗

Genetic Association Study of Childhood Aggression across raters, instruments and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data - i.e. within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE=0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P=1.6E-06), PCDH7 (P=2.0E-06) and IPO13 (P=2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg =0.46 between self- and teacher-assessment to rg =0.81 between mother- and teacher-assessment. We obtained moderate to strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg| : 0.19 - 1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg =~ -0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46 - 0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

genomics↗

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

genetics↗