Biology subjects

Peters, S.

Publications and source records attributed to Peters, S..

30 records · Page 2Linked to original sources

bioRxiv2022

Development of a yeast whole-cell biocatalyst for MHET conversion into terephthalic acid and ethylene glycol

BackgroundOver the 70 years since the introduction of plastic into everyday items, plastic waste has become an increasing problem. With over 360 million tonnes of plastics produced every year, solutions for plastic recycling and plastic waste reduction are sorely needed. Recently, multiple enzymes capable of degrading PET (polyethylene teraphthalate) plastic have been identified and engineered. In particular, the enzymes PETase and MHETase from Ideonella sakaiensis depolymerize PET into the two building blocks used for its synthesis, ethylene glycol (EG) and terephthalic acid (TPA). Importantly, EG and TPA can be re-used for PET synthesis allowing complete and sustainable PET recycling. ResultsIn this study, we used Saccharomyces cerevisiae as a platform to develop a whole-cell catalyst expressing the MHETase enzyme, which converts MHET (monohydroxyethyl terephthalate) into TPA and EG. We assessed six expression architectures and identified those resulting in efficient MHETase expression on the yeast cell surface. We show that the MHETase whole-cell catalyst has activity comparable to recombinant MHETase purified from Escherichia coli. Finally, we demonstrate that surface displayed MHETase is stable to pH, temperature, and for at least 12 days at room temperature. ConclusionsWe demonstrate the feasibility of using S. cerevisiae as a platform for the expression and surface display of PET degrading enzymes and predict that the whole-cell catalyst will viable alternatives to protein purification-based approaches for plastic degradation.

synthetic biology↗

bioRxiv2022

The genome of Lactuca saligna, a wild relative of lettuce, provides insight into non-host resistance to the downy mildew Bremia lactucae

Lactuca saligna L. is a wild relative of cultivated lettuce (Lactuca sativa L.), with which it is partially interfertile. Hybrid progeny suffer from hybrid incompatibilities (HI), resulting in reduced fertility and distorted transmission ratios. Lactuca saligna displays broad spectrum resistance against lettuce downy mildew caused by Bremia lactucae Regel and is considered a non-host species. This phenomenon of resistance in L. saligna is called non-host resistance (NHR). One possible mechanism behind this NHR is through the plant-pathogen interaction triggered by pathogen-recognition receptors, including nucleotide-binding leucin-rich repeats (NLRs) and receptor-like kinases (RLKs). We report a chromosome-level genome assembly of L. saligna (accession CGN05327), leading to the identification of two large paracentric inversions (>50 Mb) between L. saligna and L. sativa. Genome-wide searches delineated the major resistance clusters as regions enriched in NLRs and RLKs. Three of the enriched regions co-locate with previously identified NHR intervals. RNA-seq analysis of Bremia infected lettuce identified several differentially expressed RLKs in NHR regions. Three tandem wall-associated kinase-encoding genes (WAKs) in the NHR8 interval display particularly high expression changes at an early stage of infection. We propose RLKs as strong candidate(s) for determinants for the NHR phenotype of L. saligna.

genomics↗

bioRxiv2022

Validation that human microbiome phages use alternative genetic coding with TAG stop read as Q

Metagenomic findings suggesting that bacteriophages (phages) can use genetic codes different from those of their host bacteria reveal a new dimension of phage-host interaction dynamics. Whereas reassignment of stop codons to code for amino acids has been predicted, there has been no proteomic validation of alternative coding in phages. In fact, one code where the stop codon TAG is reassigned to glutamine (code 15) has never been experimentally validated in any biological system. Here, we characterized stop codon reassignment in two crAss-like phages found in the human gut microbiome using LC-MS/MS-based metaproteomics. The proteome data from several phage structural proteins clearly demonstrates reassignment of the TAG stop codon to glutamine, establishing for the first time the expression of genetic code 15. One-Sentence SummaryMass spectrometry confirms protein expression of predicted alternate genetic coding in phage genomes from human microbiomes.

systems biology↗

bioRxiv2020

Longitudinal Network Re-organization Across Learning and Development

While it is well understood that the brain experiences changes across short-term experience/learning and long-term development, it is unclear how these two mechanisms interact to produce developmental outcomes. Here we test an interactive model of learning and development where certain learning-related changes are constrained by developmental changes in the brain against an alternative development-as-practice model where outcomes are determined primarily by the accumulation of experience regardless of age. Participants (8-29 years) participated in a three-wave, accelerated longitudinal study during which they completed a feedback learning task during an fMRI scan. Adopting a novel longitudinal modeling approach, we probed the unique and moderated effects of learning, experience, and development simultaneously on behavioral performance and network modularity during the task. We found nonlinear patterns of development for both behavior and brain, and that greater experience supported increased learning and network modularity relative to naive subjects. We also found changing brain-behavior relationships across adolescent development, where heightened network modularity predicted improved learning, but only following the transition from adolescence to young adulthood. These results present compelling support for an interactive view of experience and development, where changes in the brain impact behavior in context-specific fashion based on developmental goals.

neuroscience↗

bioRxiv2020

Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety

Recently, oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including general anxiety disorder or autism spectrum disorder. Therefore, knowledge on the involved molecular processes downstream of OXT receptor (OXTR) activation is indispensable. We reveal that alternative splicing of corticotropin releasing factor receptor 2 (CRFR2) parallels increased anxiety-like behavior following chronic OXT treatment, contrasting the well-known anxiolysis of acute OXT. In detail, chronic OXT shifts the splicing ratio between membrane-bound (mCRFR2) and soluble CRFR2 (sCRFR2) in favor of the latter via ERK1/2-MEF2A signaling. Targeted manipulations of Crfr2 splicing mimic the effect of chronic OXT, confirming its role in the regulation of anxiety-like behavior. Furthermore, chronic OXT triggers cytoplasmic distribution and extracellular release of sCRFR2 into the cerebrospinal fluid, with sCRFR2 levels positively correlating with anxiety-like behavior. Concluding, the dichotomy between anxiolytic mCRFR2 and anxiogenic sCRFR2 is the basis for the deleterious effects of chronic OXT on anxiety. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/255844v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1b50691org.highwire.dtl.DTLVardef@1c22efborg.highwire.dtl.DTLVardef@19a772eorg.highwire.dtl.DTLVardef@69af7_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2020

C/EBPB-dependent Adaptation to Palmitic Acid Promotes Stemness in Hormone Receptor Negative Breast Cancer

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network. SignificanceCellular adaptation to obesity-induced palmitic acid drives tumor initiation through activation of a C/EBPB-dependent transcriptional network. This highlights a cell-autonomous mechanistic connection between obesity and postmenopausal hormone receptor negative breast cancer.

cancer biology↗

bioRxiv2019

An improved de novo assembly and annotation of the tomato reference genome using single-molecule sequencing, Hi-C proximity ligation and optical maps

The original Heinz 1706 reference genome was produced by a large team of scientists from across the globe from a variety of input sources that included 454 sequences in addition to full-length BACs, BAC and fosmid ends sequenced with Sanger technology. We present here the latest tomato reference genome (SL4.0) assembled de novo from PacBio long reads and scaffolded using Hi-C contact maps. The assembly was validated using Bionano optical maps and 10X linked-read sequences. This assembly is highly contiguous with fewer gaps compared to previous genome builds and almost all scaffolds have been anchored and oriented to the 12 tomato chromosomes. We have found more repeats compared to the previous versions and one of the largest repeat classes identified are the LTR retrotransposons. We also describe updates to the reference genome and annotation since the last publication. The corresponding ITAG4.0 annotation has 4,794 novel genes along with 29,281 genes preserved from ITAG2.4. Most of the updated genes have extensions in the 5 and 3 UTRs resulting in doubling of annotated UTRs per gene. The genome and annotation can be accessed using SGN through BLAST database, Pathway database (SolCyc), Apollo, JBrowse genome browser and FTP available at https://solgenomics.net.

genomics↗

bioRxiv2018

Developmental maturation of the precuneus as a functional core of the default-mode network

Efforts to map the functional architecture of the developing human brain have shown that connectivity between and within functional neural networks changes from childhood to adulthood. While prior work has established that the adult precuneus distinctively modifies its connectivity during task versus rest states (Utevsky, Smith, & Huettel, 2014), it remains unknown how these connectivity patterns emerge over development. Here, we use functional magnetic resonance imaging (fMRI) data collected at two longitudinal timepoints from over 250 participants between the ages of 8 and 26 engaging in two cognitive tasks and a resting-state scan. By applying independent component analysis (ICA) to both task and rest data, we identified three canonical networks of interest - the rest-based default mode network (DMN) and the task-based left and right frontoparietal networks (LFPN, RFPN) - which we explored for developmental changes using dual-regression analyses. We found systematic state-dependent functional connectivity in the precuneus, such that engaging in a task (compared to rest) resulted in greater precuneus-LFPN and precuneus-RFPN connectivity, whereas being at rest (compared to task) resulted in greater precuneus-DMN connectivity. These cross-sectional results replicated across both tasks and at both developmental timepoints. Finally, we used longitudinal mixed models to show that the degree to which precuneus distinguishes between task and rest states increases with age, due to age-related increasing segregation between precuneus and LFPN at rest. Our results highlight the distinct role of the precuneus in tracking processing state, in a manner that is both present throughout and strengthened across development.

neuroscience↗

bioRxiv2018

Qoala-T: A supervised-learning tool for quality control of automatic segmented MRI data

Performing quality control to detect image artifacts and data-processing errors is crucial in structural magnetic resonance imaging, especially in developmental studies. Currently, many studies rely on visual inspection by trained raters for quality control. The subjectivity of these manual procedures lessens comparability between studies, and with growing study sizes quality control is increasingly time consuming. In addition, both inter-rater as well as intra-rater variability of manual quality control is high and may lead to inclusion of poor quality scans and exclusion of scans of usable quality. In the current study we present the Qoala-T tool, which is an easy and free to use supervised-learning model to reduce rater bias and misclassification in manual quality control procedures. First, we manually rated quality of N = 784 FreeSurfer-processed T1-weighted scans. Different supervised-learning models were then compared to predict manual quality ratings. Results show that the Qoala-T tool using random forests is able to predict scan quality with both high sensitivity and specificity (mean area under the curve (AUC) = 0.98). In addition, the Qoala-T tool was also able to adequately predict the quality of a novel unseen dataset (N = 112; mean AUC = 0.95). These outcomes indicate that using Qoala-T in other datasets could greatly reduce the time needed for quality control. More importantly, this procedure could further help to reduce variability related to manual quality control, thereby benefiting the comparability of data quality between studies.

neuroscience↗

bioRxiv2017

Longitudinal development of hippocampal subregions from childhood to adulthood

Detailed descriptions of the development of the hippocampus promise to shed light on the neural foundation of development of memory and other cognitive functions, as well as the emergence of major mental disorders. Hippocampus is a heterogeneous structure with a well characterized internal complexity, but development of its distinct subregions in humans has remained poorly described. We analyzed magnetic resonance imaging (MRI) data from a large longitudinal sample (270 participants, 678 scans) using an automated segmentation tool and mixed models to delineate the development of hippocampal subregion volumes from childhood to adulthood. We also examined sex differences in subregion volumes and their development, and associations between hippocampal subregions and general cognitive ability. Nonlinear developmental trajectories with early volume increases were observed for subiculum, cornu ammonis (CA) 1, molecular layer (ML) and fimbria. In contrast, parasubiculum, presubiculum, CA2/3, CA4 and the granule cell layer of the dentate gyrus (GC-DG) showed linear volume decreases. No sex differences were found in hippocampal subregion development. Finally, general cognitive ability was positively associated with CA2/3 and CA4 volumes, as well as with ML development. In conclusion, hippocampal subregions appear to develop in diversified ways across adolescence, and specific subregions may link to general cognitive level.\n\nHighlightsO_LIHippocampal subregions develop in differential ways from childhood to adulthood\nC_LIO_LISubiculum, CA1, ML and fimbria showed nonlinear trajectories with initial increases\nC_LIO_LIParasubiculum, presubiculum, CA2/3, CA4 and GC-DG showed linear volume decreases\nC_LIO_LIThere were no sex differences in hippocampal subregion development\nC_LIO_LIGeneral cognitive ability associated with CA2/3 and CA4 volumes and ML development\nC_LI

neuroscience↗

bioRxiv2017

RANKL Signaling Sustains Primary Tumor Growth In Genetically Engineered Mouse Models Of Lung Adenocarcinoma

HypothesisNon-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-{kappa}B (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy.\n\nMethodsRANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial.\n\nResultsIn human lung adenocarcinoma datasets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and LKB1 mutations. In KrasLSL-G12D/WT, KrasLSL-G12D/WT; Lkb1Flox/Flox and KrasLSL-G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK-Fc with cisplatin revealed increased efficacy compared to single agents.\n\nConclusionsRANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma, and suggest that patients with KRAS mutant lung tumors will benefit from such treatments.

cancer biology↗

bioRxiv2016

A Canonical Neural Mechanism for Behavioral Variability

The ability to generate variable movements is essential for learning and adjusting complex behaviors. This variability has been linked to the temporal irregularity of neuronal activity in the central nervous system. However, how neuronal irregularity actually translates into behavioral variability is unclear. Here we combine modeling, electrophysiological and behavioral studies to address this issue. We demonstrate that a model circuit comprising topographically organized and strongly recurrent neural networks can autonomously generate irregular motor behaviors. Simultaneous recordings of neurons in singing finches reveal that neural correlations increase across the circuit driving song variability, in agreement with the model predictions. Analyzing behavioral data, we find remarkable similarities in the babbling statistics of 5-6 month-old human infants and juveniles from three songbird species, and show that our model naturally accounts for these universal statistics.

neuroscience↗