Biology subjects

Steele, J.

Publications and source records attributed to Steele, J..

12 recordsLinked to original sources

bioRxiv2026

Dynamic thermodynamic-informational entropic relationship (TIER) models of selective vulnerability to neurodegeneration

BACKGROUNDNeurodegenerative diseases share selective vulnerability patterns suggesting common physical mechanisms. We apply unified mechanics theory to neural systems, predicting that brain regions accumulate structural damage proportional to computational workload. METHODSWe simulated a hierarchical neural network implementing relationships between mechanical work (W = F x D), proportional thermodynamic entropy accumulation ({Delta}s {propto} W), and structural failure thresholds. Neural architectures at three hierarchical levels employed Hebbian learning across 2000 simulation sets, tracking thermodynamic entropy generation and dynamic stability. A coupled "siphon" model simulated cortical and subcortical support populations under constant cognitive demand. RESULTSHeteromodal integration nodes consistently exhibited elevated work, accelerated entropy accumulation, and dynamic instability across architectures. Support systems reached 50% population loss before cortical systems despite lower absolute work, demonstrating accelerated compensatory failure. DISCUSSIONThese thermodynamic-informational entropic relationship (TIER) models depict mechanisms underlying selective vulnerability across neurodegeneration, reframing neurodegeneration as the physical consequence of evolutionary trade-offs optimizing cognitive performance over longevity.

neuroscience↗

bioRxiv2026

Tabular foundation model predicts alternative lengthening of telomeres (ALT) and identifies SMARCAL1 as a target in ALT-driven cancers

Alternative lengthening of telomeres (ALT) is a telomerase-independent pathway used by aggressive cancers to maintain their replicative immortality. Because ALT is absent from normal human cells, it is an appealing target for cancer therapy, but the lack of ability to determine ALT status at scale has hindered discovery. Here, we developed ALTitude, a machine learning method from a tabular foundation model that infers ALT from cell line whole genome sequencing data, without need for paired germline analysis. We deployed ALTitude across the DepMap, doubling the number of known ALT+ cancer models. Systematic integration of ALTitude with CRISPR-Cas9 screens yielded the selective dependency on SMARCAL1 in ALT+ cell lines, where we show it stabilizes the ALT phenotype. Acute depletion of SMARCAL1 leads to G2/M arrest, mitotic catastrophe, and cell death. These data provide a valuable resource for studying ALT-related genomic features and present SMARCAL1 as a therapeutic target for ALT+ malignancies.

cancer biology↗

bioRxiv2026

Heterologous Rieske non-heme iron monooxygenases enable efficient microbial conversion of lignin guaiacol to adipic acid

Adipic acid (1,6-hexanedioic acid) is a key building block for nylon-6,6, a widely used polymer in the global chemical industry. Current industrial production relies on petrochemical feedstocks and nitric acid oxidation of cyclohexane/cyclohexanol mixtures, releasing nitrous oxide, a potent greenhouse gas. Biotechnological routes offer sustainable alternatives but have been limited by low yields or reliance on multi-strain systems. Here we report a one-pot, single-strain microbial process for the efficient conversion of guaiacol - a lignin derived aromatic - into adipic acid. By integrating heterologous Rieske non-heme iron monooxygenases from Cupriavidus necator N-1 with systematic process optimisations in engineered Escherichia coli, we achieve near-quantitative conversion with 97% yield and titres of 1.5 g/L in aqueous, lab-scale reactions. This work demonstrates a novel and efficient strategy for lignin valorisation through engineered microbial synthesis, providing a new sustainable and scalable route to adipic acid.

synthetic biology↗

bioRxiv2025

Corylus avellana disease management: using metagenomics to illuminate the rhizosphere microbiome of Corylus

The European hazelnut, Corylus avellana, is one of the most economically important tree nut crops globally. The biotrophic ascomycete pathogen Anisogramma anomala, found naturally associated with wild C. americana, continues to pose a significant threat to European hazelnut production across North America. Here, metagenomics was used to examine the taxonomic and functional features of the rhizosphere microbial communities of hazelnut trees differing in their levels of resistance to A. anomala: highly tolerant Corylus americana, and resistant and susceptible Corylus avellana. No statistically significant differences in microbial alpha diversity or beta diversity were noted between the three rhizosphere groups. Compared to bulk soil, all three rhizosphere groups were enriched for the fungal phylum Basidiomycota and bacterial phylum "Candidatus Rokubacteriota". At the genus level, the bacterial genera Actinospica, Occallatibacter, and "Candidatus Sulfotelmatobacter" were under-represented, while the genus Rhizobacter was over-represented, in the resistant and susceptible C. avellana rhizosphere samples compared to the bulk soil. A total of 45 dereplicated, high-quality metagenome-assembled genomes (MAGs) were generated, corresponding to 41 bacteria and 4 archaea. Many of the MAGs carried multiple biosynthetic gene clusters, including MAGs corresponding to the genera Lysobacter and Actinospica. Overall, the low differentiation of the rhizosphere microbiomes suggest that differences in A. anomala disease expression are likely not associated with differences in the rhizosphere microbiome. Nevertheless, the results shed new light on the rhizosphere communities of two species of hazelnut, and woody perennials more broadly, and identify potential avenues for future research into the development of microbial inoculants for Corylus spp..

microbiology↗

bioRxiv2025

The Effect of Resistance Training Volume on Individual-Level Skeletal Muscle Adaptations: A Novel Replicated Within-Participant Unilateral Trial

PurposeThere is growing emphasis on investigating heterogeneity in resistance training (RT) outcomes, likely motivated by observations of substantial gross variability in training effects. However, gross variability does not necessarily represent true inter-individual response variation (IRV) and can be obscured by measurement error, sampling variance, and biological variability. Appropriate study design and statistical analysis are required to distinguish IRV from these confounding sources of within-participant variation. Methods16 recreationally trained participants completed a novel replicated within-participant unilateral design across two 11-week training phases separated by a 6-8 week washout. Lower limbs were randomized to a low volume ([~]8 sets/week) or high volume ([~]16 sets/week) training protocol in each phase. We assessed both general (GEN; average response across conditions) and condition-specific (CON; difference between volumes) IRV for vastus lateralis cross-sectional area and leg press one-repetition maximum using a multi-stage statistical approach. ResultsHigher weekly set volumes demonstrated a detectable advantage for muscle hypertrophy (1.8 cm{superscript 2} [95% HDI: 0.29, 3.41]; 98.77% posterior probability) but not maximal strength (3.48 kg [95% HDI: -5.1, 12.15]; 80.01% posterior probability). Despite substantial gross variability, we failed to detect irrefutable evidence of meaningful IRV. Integrated methods revealed stronger evidence for GEN versus CON IRV, with correlation coefficients ranging from 0.67 to 0.7 for GEN versus 0.04 to 0.06 for CON. ConclusionsOur findings clearly illustrate that gross variability in training outcomes does not necessarily indicate true inter-individual differences, a distinction critical for both research and practice. KEY POINTSO_LIGross variability in resistance training outcomes is commonly interpreted as evidence of meaningful inter-individual response variation (IRV), but this variability often reflects confounding sources of within-participant variation rather than true inter-individual differences. C_LIO_LIUsing a novel replicated within-participant unilateral design, we investigated the effects of different weekly set volumes on changes in muscle size and maximal strength, as well as the inter-individual variation thereof. C_LIO_LIAt the group level, higher weekly set volumes produced modest but detectable benefits for muscle hypertrophy but not maximal strength. At the individual level, we failed to reveal irrefutable evidence of true IRV for either primary outcome, though there was stronger support for variability in training responses independent of weekly set volume (i.e., general IRV) compared to differential responses between volume conditions (i.e., condition-specific IRV). C_LIO_LIWhile this study has limitations, it highlights that appropriate study design and statistical analysis are essential for investigating IRV in resistance training. Our findings, along with the broader research in multiple disciplines (i.e., medicine, nutrition science, and exercise physiology), demonstrate that gross variability can purely reflect confounding sources of within-participant variation (e.g., sampling variance, measurement error, biological variability) rather than true inter-individual differences--a distinction critical for both research and practice. C_LI

physiology↗

bioRxiv2024

Haptoglobin and glutamine synthetase may biomark cachexia induced by anti-acute myeloid leukemia chemotherapy

BackgroundAnti-cancer chemotherapy is an underappreciated contributor to cancer cachexia, an often irreversible body-wasting condition that causes 20-30% of cancer-related deaths. An obstacle to predicting, monitoring and understanding the mechanisms underlying chemotherapy cachexia is that each cancer (and sub-type) is assigned different chemotherapeutic compounds, typically in multi-agent regimens. Here, we investigate the chemotherapy induction regimen (CIR) used in the haematological cancer, acute myeloid leukemia (AML). We hypothesized that the AML CIR would induce cachexia, including loss of lean tissue mass and skeletal muscle atrophy. MethodsUsing an unbiased proteomics approach we interrogated the underlying molecular mechanisms. 3-month-old male Balb/c mice were treated with the AML CIR via intraperitoneal injections of daunorubicin (1.7 mg/kg) on days 1-3, and cytarabine (33.2 mg/kg) administered on days 1-7 or vehicle. Mice were assessed 24 hours after the last treatment, on day 8, or allowed to recover for 2 weeks and assessed on day 22. A third cohort was given access to running wheels in cages. We assessed body composition, whole body metabolism and assessed the muscle proteome using quantitative tandem mass tag labelling LC-MS/MS analysis. ResultsThe AML CIR-induced acute cachexia involved a [~]10% loss of body mass, [~]10% loss of lean mass and [~]20% reduction in skeletal muscle fibre size. Whole body metabolism and ambulatory activity declined. This cachexic phenotype did not recover over the 2-week post-CIR period (lean mass loss post-CIR: 1 week [~]7% vs 2 weeks [~]9%). In voluntarily active CIR-treated mice, body wasting was exacerbated due to unchecked loss of fat mass (CIR sedentary: [~]31% vs CIR active: [~]51%). Muscle proteome studies revealed upregulation of haptoglobin (Hp) and glutamine synthetase (Glul), which were positively correlated with body and lean mass loss. Hp was sensitive to the conditional induction, recovery and exacerbation of AML CIR-mediated cachexia, suggestive of biomarker potential. ConclusionsThe AML CIR induces an acute reduction of body, lean and fat mass underpinned by skeletal muscle atrophy, hypermetabolism and catabolism. Our data uncovered a conditionally sensitive muscle biomarker in Hp, which may be useful as a prognostic tool across other scenarios of chemotherapy-induced myopathy and cachexia or as a target for therapeutic discovery in follow-up studies.

physiology↗

bioRxiv2024

Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid.

Retinoic acid (RA) is a standard-of-care neuroblastoma drug thought to be effective by inducing differentiation. Curiously, RA has little effect on primary human tumors during upfront treatment but can eliminate neuroblastoma cells from the bone marrow during post-chemo consolidation therapy--a discrepancy that has never been explained. To investigate this, we treated a large cohort of neuroblastoma cell lines with RA and observed that the most RA-sensitive cells predominantly undergo apoptosis or senescence, rather than differentiation. We conducted genome-wide CRISPR knockout screens under RA treatment, which identified BMP signaling as controlling the apoptosis/senescence vs differentiation cell fate decision and determining RAs overall potency. We then discovered that BMP signaling activity is markedly higher in neuroblastoma patient samples at bone marrow metastatic sites, providing a plausible explanation for RAs ability to clear neuroblastoma cells specifically from the bone marrow, seemingly mimicking interactions between BMP and RA during normal development.

cancer biology↗

bioRxiv2024

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

cancer biology↗

bioRxiv2024

Multi-Channel smFRET study reveals a Compact conformation of EF-G on the Ribosome

While elongation factor G (EF-G) is crucial for ribosome translocation, the role of its GTP hydrolysis remains ambiguous. EF-Gs indispensability is further exemplified by the phosphorylation of human eukaryotic elongation factor 2 (eEF2) at Thr56, which inhibits protein synthesis globally, but its exact mechanism is not clear. In this study, we developed a multi-channel single-molecule FRET (smFRET) microscopy methodology to examine the conformational changes of E. coli EF-G induced by mutations that closely aligned with eEF2s Thr56 residue. We utilized Alexa 488/594 double-labeled EF-G to catalyze the translocation of fMet-Phe-tRNAPhe-Cy3 inside Cy5-L27 labeled ribosomes, allowing us to probe both processes within the same complex. Our findings indicate that in the presence of either GTP or GDPCP, wild-type EF-G undergoes a conformational extension upon binding to the ribosome to promote normal translocation. On the other hand, T48E and T48V mutations did not affect GTP/GDP binding or GTP hydrolysis, but impeded Poly(Phe) synthesis and caused EF-G to adopt a unique compact conformation, which wasnt observed when the mutants interact solely with the sarcin/ricin loop. This study provides new insights into EF-Gs adaptability and sheds light on the modification mechanism of human eEF2.

biophysics↗

bioRxiv2023

Aberrant tissue stiffness impairs neural tube development in Mthfd1l mutant mouse embryos

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy, and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos was significantly lower compared to that of wild-type embryos, while exogenous formate supplementation improved tissue stiffness and gross embryonic morphology in both nullizygous and heterozygous embryos. Our results demonstrate the significance of proper tissue stiffness for normal NTC and pave the way for future studies on the mechanobiology of normal and abnormal embryonic development.

developmental biology↗

bioRxiv2021

Pharmacological blockade of muscle afferents and perception of effort: a systematic review with meta-analysis

BackgroundThe perception of effort (PE) provides information on task difficulty and influences physical exercise regulation and human behavior. This perception differs from other-exercise related perceptions such as pain. There is no consensus on the role of group III-IV muscle afferents as a signal processed by the brain to generate PE. ObjectiveThe aim of this meta-analysis was to investigate the effect of pharmacologically blocking muscle afferents on the PE. MethodsSix databases were searched to identify studies measuring the ratings of perceived effort (RPE) during physical exercise, with and without pharmacological blockade of muscle afferents. Articles were coded based on the operational measurement used to distinguish studies in which PE was assessed specifically (effort dissociated) or as a composite experience including other exercise-related perceptions (effort not dissociated). Articles that did not provide enough information for coding were assigned to the unclear group. ResultsThe effort dissociated group (n=6) demonstrated a slight RPE increase with reduced muscle afferents feedback (standard mean change raw (SMCR), 0.39; 95%CI, 0.13 to 0.64). The group effort not dissociated (n=2) did not reveal conclusive results (SMCR, -0.29; 95%CI, -2.39 to 1.8). The group unclear (n=8) revealed a slight RPE decrease with reduced muscle afferents feedback (SMCR, -0.27; 95%CI, -0.50 to -0.04). ConclusionsThe heterogeneity in results between groups reveals that the inclusion of perceptions other than effort in its rating influences the RPE scores reported by the participants. The absence of decreased RPE in the effort dissociated group suggests that muscle afferents feedback is not a sensory signal of PE. Key pointsO_LITo date, there is no consensus on the neurophysiological signal processed by the brain to generate the perception of effort. C_LIO_LIFollowing a systematic search in six databases, this meta-analysis suggests that reducing afferent feedback from the working muscles via epidural anesthesia does not reduce perception of effort. C_LIO_LIThis systematic review suggests that afferent feedback from the working muscles is not the neurophysiological signal processed by the brain to generate the perception of effort. C_LI

neuroscience↗

bioRxiv2021

Motor unit recruitment patterns of the quadriceps differ between continuous high- and low-torque isometric knee extension to momentary failure

The size principle is a theory of motor unit (MU) recruitment that suggests MUs are recruited in an orderly manner from the smallest (lower threshold) to the largest (higher threshold) MUs. A consequence of this biophysical theory is that, for isometric contractions, recruitment is dependent on the intensity of actual effort required to meet task demands. This concept has been supported by modelling work demonstrating that, in tasks performed to momentary failure, full MU recruitment will have occurred upon reaching failure irrespective of the force requirements of the task. However, in vivo studies examining this are limited. Therefore, the aim of the current study was to examine MU recruitment of the quadriceps under both higher- and lower-torque (70% and 30% of MVC, respectively) isometric knee extension, performed to momentary failure. Specifically, we compared surface electromyography (sEMG) frequency characteristics, determined by wavelet analysis, across the two continuous isometric knee extension tasks to identify potential differences in recruitment patterns. A convenience sample of 10 recreationally active adult males (height: 179.6{+/-}6.0 cm; mass: 76.8{+/-}7.3 kg; age: 26{+/-}7 years) with previous resistance training experience (6{+/-}3 years) were recruited. Using a within-session, repeated-measures, randomised crossover design participants performed the knee extension tasks whilst sEMG was collected from the vastus medialis (VM), rectus femoris (RF) and vastus lateralis (VL). Myoelectric signals were decomposed into intensities as a function of time and frequency using an EMG-specific wavelet transformation. Our first analysis compared the mean frequency at momentary failure; second, we investigated the effects of load on relative changes in wavelet intensities; finally, we quantified the degree of wavelet similarity over time. Wavelet-based calculation of the mean signal frequency appeared to show similar mean frequency characteristics occurring when reaching momentary failure. However, individual wavelets revealed that different changes in frequency components occurred between the two tasks, suggesting that patterns of recruitment differed. Low-torque conditions resulted in an increase in intensity of all frequency components across the trials for each muscle whereas high-torque conditions resulted in a wider range of frequency components contained within the myoelectric signals at the beginning of the trials. However, as the low-torque trial neared momentary failure there was an increased agreement between conditions across wavelets. Our results corroborate modelling studies as well as recent biopsy evidence, suggesting overall MU recruitment may largely be similar for isometric tasks performed to momentary failure with the highest threshold MUs likely recruited, despite being achieved with differences in the pattern of recruitment over time utilised.

physiology↗