Biology subjects

Peters, H.

Publications and source records attributed to Peters, H..

8 recordsLinked to original sources

bioRxiv2026

Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma

In advanced stages, lung adenocarcinoma obstructs airways and disrupts ventilation-perfusion relationships in the lung, causing systemic hypoxemia and enabling a feed-forward loop that accelerates malignancy. Systemic hypoxemia is also experienced due to common respiratory comorbidities such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), potentially accelerating malignancy. In a statewide electronic health record network, pre-existing COPD (598 matched pairs) or sleep apnea (235 matched pairs) independently predicted worse survival following incident lung cancer diagnosis. Since the mechanistic basis of the link between malignancy and hypoxia is not well understood, we created systemic hypoxia in KrasLSL-G12D/+;Trp53fl/fl (KP) mice by delivering low inspired oxygen concentrations (8% inspired oxygen; 8 h daily). Hypoxia nearly doubled tumor multiplicity and selectively remodeled cancer central carbon metabolism. Spatially resolved metabolomics revealed marked tumor-compartment glycogen accumulation, elevated tricarboxylic-acid cycle intermediates, and depleted glycolytic pools. Quantitative proteomics across cellular models and autochthonous tumors demonstrated that systemic hypoxia drives glycogen mobilization selectively through the lysosomal enzyme acid -glucosidase (GAA). Tumor-cell-autonomous deletion of GAA eliminated the hypoxia-driven growth advantage and disrupted downstream anabolic biosynthetic pathways. Thus, systemic hypoxia drives lung adenocarcinoma expansion by mobilizing lysosomal glycogen reserves through GAA to sustain proliferative growth.

cancer biology↗

bioRxiv2026

Comparison of HDO production from Glucose as a marker of Glucose metabolism

PURPOSEGlycolytic production of HDO from the metabolism of perdeuterated glucose provides a means for metabolic imaging with 2H MRI. The present study compared HDO production from a cost-efficient [2,3,4,6,6-2H5]glucose with [2H7]glucose in vitro and in vivo. METHODS2H NMR spectroscopy was performed to measure glucose consumption, lactate, and HDO production in the SFxL glioblastoma cell line. In vivo studies in healthy mice using 2H magnetic resonance spectroscopy were performed at 11.1 T after administering a bolus of either metabolic contrast agent. In vivo metabolite levels were quantified using unlocalized and slice-selective localized spectra. RESULTSOur in vitro results demonstrated similar glucose consumption and HDO production kinetics, although significant differences in lactate labeling were observed. The in vivo study showed comparable glucose consumption and HDO production kinetics following tail-vein bolus administration of either metabolic contrast agent, while lactate was not detected in the brain. CONCLUSION[2,3,4,6,6-2H5]glucose shows comparable HDO production to [2H7]glucose, while offering lower cost and reduced spectral complexity. These findings place [2,3,4,6,6-2H5]glucose as an alternative to [2H7]glucose for HDO-based DMI studies.

neuroscience↗

bioRxiv2026

CAIX-targeted α therapy directed against hypoxic tumor cells in combination with immune checkpoint inhibitors in a syngeneic mouse tumor model

Tumor hypoxia is a major factor in therapy resistance. A potential strategy to treat hypoxic tumors is targeted therapy (TAT), since particles can cause complex DNA damage independent of oxygen levels. Here, we investigate the potential of TAT as monotherapy and in combination with immune checkpoint inhibitors (ICI) to treat hypoxic tumors. MethodsMonoclonal anti-CAIX antibody DOTA-MSC3 was labeled with indium-111 (111In) or actinium-225 (225Ac), and binding to CAIX-expressing hypoxic tumor cells was determined in vitro. Subsequently, the in vivo biodistribution and dosimetry of radiolabeled DOTA-MSC3 was assessed in B16F10-OVA tumor-bearing mice, and its spatial distribution in the tumor (autoradiography) was correlated to CAIX expression measured by immunofluorescence. Finally, tumor growth and survival were determined upon treatment with [225Ac]Ac-DOTA-MSC3 with and without ICI. Results111In- and 225Ac-labeled DOTA-MSC3 bound specifically to CAIX-expressing hypoxic tumor cells. In vivo, uptake of both radiopharmaceuticals in B16F10-OVA tumors was spatially correlated with CAIX-positive hypoxic tumor regions. [225Ac]Ac-DOTA-MSC3 significantly prolonged survival of mice compared with PBS control (p=0.0032). Furthermore, the combination of [225Ac]Ac-DOTA-MSC3 and ICI significantly delayed tumor growth and prolonged survival compared with PBS control (p=0.0022 and p=0.0019, respectively). ConclusionOverall, these results demonstrate first proof-of-concept of the potential of CAIX-TAT to treat hypoxic tumors by targeting CAIX-positive hypoxic tumor regions. CAIX-TAT combined with ICI was most effective in inhibiting tumor growth and prolonging survival of tumor-bearing mice. Future studies are required to investigate the radiobiological and immunological effects of CAIX-TAT, to guide optimization of this treatment in combination with ICI.

cancer biology↗

bioRxiv2024

Natural Language Processing Applied to Spontaneous Recall of Famous Faces Reveals Memory Dysfunction in Temporal Lobe Epilepsy Patients

Objective and BackgroundEpilepsy patients rank memory problems as their most significant cognitive comorbidity. Current clinical assessments are laborious to administer and score and may not always detect subtle memory decline. The Famous Faces Task (FF) has robustly demonstrated that left temporal lobe epilepsy (LTLE) patients remember fewer names and biographical details compared to right TLE (RTLE) patients and healthy controls (HCs). We adapted the FF task to capture subjects entire spontaneous spoken recall, then scored responses using manual and natural language processing (NLP) methods. We expected to replicate previous group level differences using spontaneous speech and semi-automated analysis. MethodsSeventy-three (N=73) adults (28 LTLE, 18 RTLE, and 27 HCs) were included in a case-control prospective study design. Twenty FF in politics, sports, and entertainment (active 2008-2017) were shown to subjects, who were asked if they could recognize and spontaneously recall as much biographical detail as possible. We created human-generated and automatically-generated keyword dictionaries for each celebrity, based on a randomly selected training set of half of the HC transcripts. To control for speech output, we measured the speech duration, total word count and content word count for the FF task and a Cookie Theft Control Task (CTT), in which subjects were merely asked to describe a visual scene. Subjects responses to FF and CTT tasks were recorded, transcribed, and analyzed in a blinded manner with a combination of manual and automated NLP approaches. ResultsFamous face recognition accuracy was similar between groups. LTLE patients recalled fewer biographical details compared to HCs and RTLEs using both the gold-standard human-generated dictionary (24%{+/-}12% vs. 31%{+/-}12% and 30%{+/-}12%, p=0.007) and the automated dictionary (24%{+/-}12% vs. 31%{+/-}12% and 32%{+/-}13%, p=0.007). There were no group level differences in speech duration, total word count, or content word count for either the FF and CTT to explain difference in recall performance. There was a positive, statistically significant relationship between MOCA score and FF recall performance as scored by the human-generated ({rho}= .327, p= .029) and automatically-generated dictionaries ({rho}= .422, p= .004) for TLE subjects, but not HCs, an effect that was driven by LTLE subjects. DiscussionLTLE patients remember fewer details of famous people than HCs or RTLE patients, as discovered by NLP analysis of spontaneous recall. Decreased biographical memory was not due to decreased speech output and correlated with lower MOCA scores. NLP analysis of spontaneous recall can detect memory dysfunction in clinical populations in a semi-automated, objective, and sensitive manner.

neuroscience↗

bioRxiv2024

Cell and Transcriptomic Diversity of Infrapatellar Fat Pad during Knee Osteoarthritis

ObjectivesIn this study, we employ a multi-omic approach to identify major cell types and subsets, and their transcriptomic profiles within the infrapatellar fat pad (IFP), and to determine differences in the IFP based on knee osteoarthritis (KOA), sex, and obesity status. MethodsSingle-nucleus RNA sequencing of 82,924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analysis were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex, and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status. ResultsWe identified multiple subclusters of fibroblasts, macrophages, adipocytes, and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles, and computationally identified putative cell-cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs, and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of naive, profibrotic- and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFP. ConclusionsOverall, by employing a multi-omic approach, this study provides the first comprehensive map of cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as a key cell type contributing to transcriptomic and metabolic differences related to KOA disease, sex, or obesity.

cell biology↗

bioRxiv2023

Learning when to learn: hummingbirds adjust their exploration behaviour to match the value of information

Exploration is a key part of an animals ability to learn. The exploration-exploitation dilemma predicts that individuals should adjust their exploration behaviour according to changes in the value of information. Here, we test this prediction by tracking ruby-throated hummingbirds as they foraged repeatedly from a large array of artificial flowers, wherein 25% of the flowers contained a sucrose reward. Similar to real-world floral dynamics, the reward locations were consistent in the short-term, but varied from day to day. Thus, the value of information about the flower contents would be greatest at the beginning of a daily foraging session, and decay toward the end of each session. We tracked five individual hummingbirds in repeated foraging sessions, comprising more than 3,400 floral probes. We analyzed two metrics of their exploration behaviour: (1) the probability that a bird would shift from probing one flower to another, and (2) the Shannon information entropy of a sequence of flowers probed. We show that initially, the hummingbirds increased their exploration behaviour as time elapsed within a session. As they performed more sessions and learned the rules of the environment, the hummingbirds switched to explore more diverse choices at the beginning of a foraging session, when the value of information was high, and less diverse choices toward the end of a session. Our results suggest that foraging hummingbirds can learn when to learn, highlighting the importance of plasticity in exploration behaviour. HighlightsO_LIExploration is a necessary part of learning C_LIO_LIForagers must balance sampling for information with the use of known rewards C_LIO_LIHummingbirds learned to explore more when the value of new information was high C_LIO_LIApparent mistakes may actually represent an information-seeking strategy C_LI

animal behavior and cognition↗

bioRxiv2019

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity of TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9 deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared to Tbx1 heterozygous mice. Using a novel Pax9Cre allele we demonstrated that the site of this Tbx1-Pax9 genetic interaction is in the pharyngeal endoderm, therefore revealing that a Tbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.\n\nSummary statementPax9 is required for outflow tract and aortic arch development, and functions together with Tbx1 in the pharyngeal endoderm for 4th arch artery formation.

developmental biology↗

bioRxiv2019

Coupled fast and slow feedbacks lead to continual evolution: A general modeling approach

The Red Queen Hypothesis, which suggests that continual evolution can result from solely biotic interactions, has been studied in macroevolutionary and microevolutionary contexts. While microevolutionary studies have described examples in which evolution does not cease, understanding which general conditions lead to continual evolution or to stasis remains a major challenge. In many cases, it is unclear which experimental features or model assumptions are necessary for the observed continual evolution to emerge, and whether the described behavior is robust to variations in the given setup. Here, we aim to find the minimal set of conditions under which continual evolution occurs. To this end, we present a theoretical framework that does not assume any specific functional form and, therefore, can be applied to a wide variety of systems. Our framework is also general enough to cast predictions about both monomorphic and polymorphic populations. We show that the combination of a fast positive and a slow negative feedback causes continual evolution to emerge even from the evolution of one single evolving trait, provided that the ecological timescale is sufficiently separated from the timescales of mutation and the negative feedback. Our approach and results thus contribute to a deeper understanding of the evolutionary dynamics resulting from biotic interactions.

evolutionary biology↗