Biology subjects

Fuhrmann, D.

Publications and source records attributed to Fuhrmann, D..

10 recordsLinked to original sources

bioRxiv2026

Extracellular protein catabolism drives regulated nitrogen handling and ammonia buffering in acute myeloid leukemia

Acute myeloid leukemia (AML) cells exhibit pronounced metabolic plasticity, yet how amino acid supply is coordinated to sustain leukemic metabolism remains poorly understood. Here, we show that AML cells catabolize extracellular proteins as a major source of amino acids through lysosomal degradation of albumin. This proteocatabolic activity supports anabolic processes and mitochondrial energy production and establishes a regulated, high-throughput regime of primary nitrogen-containing metabolites (nitrogen regimen). Sustained proteocatabolism inevitably generates ammonia, and we find elevated ammonia concentrations in bone marrow plasma from newly diagnosed AML patients that decline with effective induction therapy. Using metabolomics, isotope tracing and targeted genetic and pharmacological manipulations, we identify glutamate-ammonia ligase (GS/GLUL) as a central enzyme that buffers proteocatabolism-derived ammonia by stabilizing intracellular nitrogen homeostasis. Loss of GS function limits sustainable nitrogen handling capacity, thereby impairing leukemic proliferation and delaying disease progression in vivo. Together, our findings define extracellular protein catabolism as a regulating nitrogen management strategy in AML and reveal GS as a capacity-defining vulnerability of proteocatabolic growth.

cancer biology↗

bioRxiv2026

Adversity and adolescent brain development: differential associations with grey and white matter across two longitudinal cohorts

Globally, 60% of the population has experienced at least one type of adversity (e.g., emotional abuse, bullying) across infancy, childhood, and adolescence. Such experiences have been linked to an increased risk for mental health disorders. Changes in brain structure following experiences of childhood adversity have been hypothesised to be a mechanistic pathway explaining later mental health issues. However, to understand how changes in brain structure might mediate the effects of adversity, it is essential to identify which underlying neuronal processes may be affected by different types of adverse experiences. A key open question is whether grey or white matter is more vulnerable to adversity, as these two structures reflect distinct neurobiological mechanisms. This study investigated whether differences in trajectories of grey and white matter development during adolescence can be explained by exposure to different types of adversity. We applied the Adverse Adolescent Experiences Framework (Pollmann et al., 2025) categorising adversity into four levels: Intrapersonal (e.g., accidents), Caregiver (e.g., emotional neglect), Peer (e.g., bullying), and Community (e.g., neighbourhood safety). Exposure to each of the four factors was estimated through principal components analyses. We analysed two large longitudinal datasets: the Adolescent Brain Cognitive Development study ([~]12,000 adolescents measured at ages 10, 12, and 14) and the IMAGEN study ([~]1,400 adolescents measured at ages 14, 19, and 22). Using latent growth curve models, we captured individual differences in brain development by estimating baseline levels (intercepts) and rates of change (slopes) for total grey matter volume and mean white matter fractional anisotropy. In both cohorts, we found significant interindividual variability in baseline levels and rates of change for both grey matter volume and fractional anisotropy. Caregiver, Peer, and Community adversities were negatively associated only with the intercepts of grey matter volume and white matter fractional anisotropy. Importantly, associations differed between grey and white matter. In ABCD, Peer and Community adversities were more strongly associated with grey matter volume intercepts. In contrast, in IMAGEN, Caregiver, Peer and Community adversities were more strongly linked to white matter fractional anisotropy intercepts. This suggests that adversity has unique associations with grey and white matter, rather than exerting a uniform influence on brain structure. By demonstrating that different environments generate distinct biological associations with brain maturation, this work underscores the need to consider both grey and white matter when assessing the neurodevelopmental pathways to outcomes across the lifespan.

neuroscience↗

bioRxiv2022

The midpoint of cortical thinning between late childhood and early adulthood differs across individuals and regions: Evidence from longitudinal modelling in a 12-wave sample

Charting human brain maturation between childhood and adulthood is a fundamental prerequisite for understanding the rapid biological and psychological changes during human development. Two barriers have precluded the quantification of maturational trajectories: demands on data and demands on estimation. Using high-temporal resolution neuroimaging data of up to 12-waves in the HUBU cohort (N = 90, aged 7-21 years) we investigate changes in apparent cortical thickness across childhood and adolescence. Fitting a four-parameter logistic nonlinear random effects mixed model, we quantified the characteristic, s-shaped, trajectory of cortical thinning in adolescence. This approach yields biologically meaningful parameters, including the midpoint of cortical thinning (MCT), which corresponds to the age at which the cortex shows most rapid thinning - in our sample occurring, on average, at 14 years of age. These results show that, given suitable data and models, cortical maturation can be quantified with precision for each individual and brain region.

neuroscience↗

bioRxiv2021

HIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex

DNA:DNA:RNA triplexes that are formed through Hoogsteen base-pairing have been observed in vitro, but the extent to which these interactions occur in cells and how they impact cellular functions remains elusive. Using a combination of bioinformatic techniques, RNA/DNA pulldown and biophysical studies, we set out to identify functionally important DNA:DNA:RNA triplex-forming long non-coding RNAs (lncRNA) in human endothelial cells. The lncRNA HIF1-AS1 was retrieved as a top hit. Endogenous HIF1-AS1 reduced the expression of numerous genes, including EPH Receptor A2 and Adrenomedullin through DNA:DNA:RNA triplex formation by acting as an adapter for the repressive human silencing hub complex (HUSH). Moreover, the oxygen-sensitive HIF1-AS1 was down-regulated in pulmonary hypertension and loss-of-function approaches not only resulted in gene de-repression but also enhanced angiogenic capacity. As exemplified here with HIF1-AS1, DNA:DNA:RNA triplex formation is a functionally important mechanism of trans-acting gene expression control.

molecular biology↗

bioRxiv2021

A morphometric double dissociation: cortical thickness is more related to aging; surface area is more related to cognition

The thickness and surface area of cortex are genetically distinct aspects of brain structure, and may be affected differently by age. However, their potential to differentially predict age and cognitive abilities has been largely overlooked, likely because they are typically aggregated into the commonly used measure of volume. In a large sample of healthy adults (N=647, aged 18-88), we investigated the brain-age and brain-cognition relationships of thickness, surface area, and volume, plus five additional morphological shape metrics. Cortical thickness was the metric most strongly associated with age cross-sectionally, as well as exhibiting the steepest longitudinal change over time (subsample N=261, aged 25-84). In contrast, surface area was the best single predictor of age-residualized cognitive abilities (fluid intelligence), and changes in surface area were most strongly associated with cognitive change over time. These findings were replicated in an independent dataset (N=1345, aged 18-93). Our results suggest that cortical thickness and surface area make complementary contributions the age-brain-cognition triangle, and highlight the importance of considering these volumetric components separately.

neuroscience↗

bioRxiv2019

The effects of age on resting-state BOLD signal variability is explained by cardiovascular and neurovascular factors

Accurate identification of brain function is necessary to understand neurocognitive ageing, and thereby promote health and well-being. Many studies of neurocognitive aging have investigated brain function with the blood-oxygen level-dependent (BOLD) signal measured by functional magnetic resonance imaging. However, the BOLD signal is a composite of neural and vascular signals, which are differentially affected by aging. It is therefore essential to distinguish the age effects on vascular versus neural function. The BOLD signal variability at rest (known as resting state fluctuation amplitude, RSFA), is a safe, scalable and robust means to calibrate vascular responsivity, as an alternative to breath-holding and hypercapnia. However, the use of RSFA for normalization of BOLD imaging assumes that age differences in RSFA reflecting only vascular factors, rather than age-related differences in neural function (activity) or neuronal loss (atrophy). Previous studies indicate that two vascular factors, cardiovascular health and cerebrovascular function, are insufficient when used alone to fully explain age-related differences in RSFA. It remains possible that their joint consideration is required to fully capture age differences in RSFA. We tested the hypothesis that RSFA no longer varies with age after adjusting for a combination of cardiovascular and cerebrovascular measures. We also tested the hypothesis that RSFA variation with age is not associated with atrophy. We used data from the population-based, lifespan Cam-CAN cohort. After controlling for cardiovascular and cerebrovascular estimates alone, the residual variance in RSFA across individuals was significantly associated with age. However, when controlling for both cardiovascular and cerebrovascular estimates, the variance in RSFA was no longer associated with age. Grey matter volumes did not explain age-differences in RSFA, after controlling for cardiovascular health. The results were consistent between voxel-level analysis and independent component analysis. Our findings indicate that cardiovascular and cerebrovascular signals are together sufficient predictors of age differences in RSFA. We suggest that RSFA can be used to separate vascular from neuronal factors, to characterise neurocognitive aging. We discuss the implications and make recommendations for the use of RSFA in the research of aging.

neuroscience↗

bioRxiv2019

Neurocognitive reorganization between crystallized intelligence, fluid intelligence and white matter microstructure in two age-heterogeneous developmental cohorts

Despite the reliability of intelligence measures in predicting important life outcomes such as educational achievement and mortality, the exact configuration and neural correlates of cognitive abilities remain poorly understood, especially in childhood and adolescence. Therefore, we sought to elucidate the factorial structure and neural substrates of child and adolescent intelligence using two cross-sectional, developmental samples (CALM: N=551 (N=165 imaging), age range: 5-18 years, NKI-Rockland: N=337 (N=65 imaging), age range: 6-18 years). In a preregistered analysis, we used structural equation modelling (SEM) to examine the neurocognitive architecture of individual differences in childhood and adolescent cognitive ability. In both samples, we found that cognitive ability in lower and typical-ability cohorts is best understood as two separable constructs, crystallized and fluid intelligence, which became more distinct across development, in line with the age differentiation hypothesis. Further analyses revealed that white matter microstructure, most prominently the superior longitudinal fasciculus, was strongly associated with crystallized (gc) and fluid (gf) abilities. Finally, we used SEM trees to demonstrate evidence for developmental reorganization of gc and gf and their white matter substrates such that the relationships among these factors dropped between 7-8 years before increasing around age 10. Together, our results suggest that shortly before puberty marks a pivotal phase of change in the neurocognitive architecture of intelligence.

neuroscience↗

bioRxiv2018

The neurocognitive architecture of fluid ability in children and adolescents

Fluid intelligence is the capacity to solve novel problems in the absence of task-specific knowledge, and is highly predictive of outcomes like educational attainment and psychopathology. Here, we modelled the neurocognitive architecture of fluid intelligence in two cohorts: CALM (N = 551, aged 5 - 17 years) and NKI-RS (N = 335, aged 6 - 17 years). We used multivariate Structural Equation Modelling to test a preregistered watershed model of fluid intelligence. This model predicts that white matter contributes to intermediate cognitive phenotypes, like working memory and processing speed, which, in turn, contribute to fluid intelligence. We found that this model performed well for both samples and explained large amounts of variance in fluid intelligence (R2CALM = 51.2%, R2NKI-RS = 78.3%). The relationship between cognitive abilities and white matter differed with age, showing a dip in strength around ages 7 - 12 years. This age-effect may reflect a reorganization of the neurocognitive architecture around pre- and early puberty. Overall, these findings highlight that intelligence is part of a complex hierarchical system of partially independent effects.

neuroscience↗

bioRxiv2018

Multimodal integration and vividness in the angular gyrus during episodic encoding and retrieval

Much evidence suggests that the angular gyrus (AnG) is involved in episodic memory, but its precise role is yet to be determined. We examined two possible accounts, within the same experimental paradigm: the CoBRA account (Shimamura, 2011), which suggests that the AnG acts as a convergence zone that binds multimodal episodic features; and the Subjectivity account (Yazar et al., 2012), which implicates AnG involvement in subjective mnemonic experience (such as vividness or confidence). fMRI was employed during both encoding and retrieval of paired-associates. During study, female and male human participants memorised picture-pairs of common objects (in the unimodal task) or of an object-picture and an environmental sound (in the crossmodal task). At test, they performed a cued-recall task, and further indicated the vividness of their memory. During retrieval, BOLD activation in the AnG was greatest for vividly remembered associates, consistent with the Subjectivity account. During encoding, the same effect of vividness was found, but this was further modulated by task: Greater activations were associated with subsequent recall in the crossmodal than the unimodal task. Thus, encoding data suggests an additional role to the AnG in cross-modal integration, consistent with its role at retrieval proposed by CoBRA. These results resolve some of the puzzles in the literature and indicate that the AnG can play different roles during encoding and retrieval, determined by the cognitive demands posed by different mnemonic tasks.\n\nSignificance StatementWe offer new insights into the multiplicity of processes that are associated with angular gyrus (AnG) activation during encoding and retrieval of newly formed memories. We used fMRI while human participants learned and subsequently recalled pairs of objects presented to the same sensory modality or to different modalities. We were able to show that the AnG is involved when vivid memories are created and retrieved, as well as when encoded information is integrated across different sensory modalities. These findings provide novel evidence for the contribution of the AnG to our subjective experience of remembering, alongside its role in integrative processes that promote subsequent memory.

neuroscience↗

bioRxiv2018

Cardiovascular risk factors for micro- and macro-structural brain changes in healthy ageing

Cardiovascular health declines with age, increasing the risk of hypertension and elevated heart rate in middle- and old age. Here, we used multivariate techniques to investigate the associations between cardiovascular health (diastolic blood pressure, systolic blood pressure and heart rate) and white matter macrostructure (lesion volume and number), and microstructure (as measured by Diffusion Weighted Imaging) in the cross-sectional, population-based Cam-CAN cohort (N = 667, aged 18 to 88). We found that cardiovascular health and age made approximately similar contributions to white matter health and explained up to 56% of variance. Lower diastolic blood pressure, higher systolic blood pressure and higher heart rate were each strongly, and independently, associated with white matter abnormalities on all indices. Body mass and exercise were associated with white matter health, both directly and indirectly via cardiovascular health. These results highlight the importance of cardiovascular risk factors for white matter health across the adult lifespan and suggest that systolic blood pressure, diastolic blood pressure and heart rate affect white matter via separate mechanisms.

neuroscience↗