Biology subjects

Davidson, M.

Publications and source records attributed to Davidson, M..

12 recordsLinked to original sources

bioRxiv2026

Specific F1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo, a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F1-selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

cancer biology↗

bioRxiv2025

Hippocampal grey matter changes across scales in Alzheimer's Disease

Alzheimers disease (AD) is a progressive and debilitating neurodegenerative disease of the central nervous system, characterized by deterioration in cognitive function including extensive memory impairment. The hippocampus, a medial temporal lobe region, is a key orchestrator in the encoding and retrieval of memory and is believed to be one of the first regions to deteriorate in AD. In this work we examined hippocampal macrostructure (specifically gyrification and thickness) and microstructure in Alzheimers disease (AD) and mild cognitive impairment (MCI) relative to healthy aged controls in the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. We first utilized an iterative training paradigm to adapt an existing deep learning approach for capturing hippocampal topology to elderly individuals as well as individuals with potential hippocampal degeneration. Using this new model, we found notable decreases in both thickness and gyrification in AD and MCI across both the subfields and anterior-posterior axis. Using the diffusion tensor representation derived from diffusion MRI data, we found significant increases in the mean diffusivity across the extent of the hippocampus in AD and MCI, which may be related to a number of changes such as loss of neuronal cells, decreased fiber density, demyelination, and increased presence of CSF. Examining the primary direction of diffusion relative to canonical hippocampal axes, we found distinct diffusion orientation shifts in AD and MCI throughout the anterior-posterior extent of the subiculum and CA1. Specifically, we found a decrease in diffusion oriented tangentially, and an increase in diffusion oriented along the long-axis. This could potentially be related to the known degeneration of the perforant path, which is greatly affected in AD and is a largely tangential oriented pathway. The AD-related changes in diffusion orientations were found to not have significant spatial overlap with AD-related changes in mean diffusivity, suggesting that they may be capturing distinct spatially-localized disease processes. Finally, we showed that the macro- and microstructure of the hippocampus in AD changed less across age relative to MCI and controls. As well, the age-related hippocampal macrostructure changes in MCI appeared indistinguishable from healthy aging.

neuroscience↗

bioRxiv2024

The effect of circulating neutralizing antibodies on the replication of SARS-CoV-2 variants following post-vaccination infections.

The impact of pre-existing neutralizing antibodies (NAbs) titers on SARS-CoV-2 viral shedding dynamics in post-vaccination infection (PVI) are not well understood. We characterized viral shedding longitudinally in nasal specimens in relation to baseline (pre/peri-infection) serum neutralizing antibody titers in 125 participants infected with distinct SARS-CoV-2 variants. Among 68 participants who had received vaccinations, we quantified the effect of baseline serum NAb titers on maximum viral RNA titers and on the duration of infectivity. Baseline NAb titers were higher and efficiently targeted a broader range of variants in participants who received one or two monovalent ancestral booster vaccinations compared to those with a full primary vaccine series. In participants with Delta variant infections, baseline NAb titers targeting Delta were negatively correlated with maximum viral RNA copies. Per log10 increase in baseline NAb IC50, maximum viral load was reduced -2.43 (95% confidence interval [CI] -3.76, -1.11) log10 N copies and days of infectious viral shedding were reduced -2.79 [95% CI: -4.99, -0.60] days. By contrast, in those with Omicron infections (BA.1, BA.2, BA.4 or BA.5 lineages) baseline NAb responses against Omicron lineages did not predict viral outcomes. Our results provide robust estimates of the effect of baseline NAbs on the magnitude and duration of nasal viral replication after PVI (albeit with an unclear effect on transmission) and show how immune escape variants efficiently evade these modulating effects.

immunology↗

bioRxiv2022

Genetic architecture and evolution of color variation in American black bears

Color variation is a frequent evolutionary substrate for camouflage in small mammals but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus, exhibits a range of colors including the cinnamon morph which has a similar color to the brown bear, U. arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U. arctos and cinnamon U. americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U. americanus individuals and identified a single major locus (P < 10-13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that impaired protein localization and decreased pigment production. Population genetic analyses and demographic modeling indicated that the R153C variant arose 9.36kya in a southwestern population where it likely provided a selective advantage, spreading both northwards and eastwards by gene flow. A different TYRP1 allele, R114C, contributes to the characteristic brown color of U. arctos, but is not fixed across the range. HIGHLIGHTSO_LIThe cinnamon morph of American black bears and brown bears have different missense mutations in TYRP1 that account for their similar coloration C_LIO_LITYRP1 variants in American black bears and brown bears are loss-of-function alleles associated with impaired protein localization to melanosomes C_LIO_LIIn American black bears, the variant causing the cinnamon morph arose 9,360 years ago in the western lineage where it provides an adaptive advantage, and has spread northwards and eastwards by migration C_LI

evolutionary biology↗

bioRxiv2022

Tension anisotropy drives phenotypic transitions of cells via two-way cell-ECM feedback

Mechanical factors such as stress in the extracellular environment are known to affect phenotypic commitment of cells. However, the stress fields experienced by cells in tissues are multiaxial, and the ways that cells integrate this multiaxial information are largely unknown. Here, we report that the anisotropy of these stress fields is a critical factor triggering phenotypic transition in fibroblast cells, outweighing the previously reported role of stress amplitude. Using a combined experimental and computational approach, we discovered a self-reinforcing mechanism in which cellular protrusions interact with collagen fibers to develop tension anisotropy, which in turn stabilizes protrusions and amplifies their contractile forces. Disruption of this self-reinforcing process, either by reducing tension anisotropy or by inhibiting contractile protrusions, prevented phenotypic conversion of fibroblasts to contractile myofibroblasts.

biophysics↗

bioRxiv2021

Microstructured hydrogels to guide self-assembly and function of lung alveolospheres

Epithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current protocols to grow these organoids almost exclusively depend on culture within three-dimensional (3D) Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, we describe a method that relies on polymeric hydrogel substrates for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human induced pluripotent stem cell (iPSC)-derived alveolar type 2 cells (iAT2s) self-assemble into alveolospheres and propagate in Matrigel-free conditions. By engineering pre-defined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure was reduced when compared to 3D culture while maintaining alveolar type 2 cell fate of human iAT2 and primary mouse tissue-derived progenitor cells. This hydrogel system is a facile and accessible culture system for the culture of primary and iPSC-derived lung progenitors and the method could be expanded to the culture of other epithelial progenitor and stem cell aggregates.

bioengineering↗

bioRxiv2020

A single-cell atlas of Plasmodium falciparum transmission through the mosquito

Malaria parasites have a complex life cycle featuring diverse developmental strategies, each uniquely adapted to navigate specific host environments. Here we use single-cell transcriptomics to illuminate gene usage across the transmission cycle of the most virulent agent of human malaria - Plasmodium falciparum. We reveal developmental trajectories associated with the colonisation of the mosquito midgut and salivary glands and elucidate the transcriptional signatures of each transmissible stage. Additionally, we identify both conserved and nonconserved gene usage between human and rodent parasites, which point to both essential mechanisms in malaria transmission and species-specific adaptations potentially linked to host tropism. Together, the data presented here, which are made freely available via an interactive website, establish the most complete atlas of the P. falciparum transcriptional journey to date. One sentence summarySingle-cell transcriptomics of P. falciparum transmission stages highlights developmental trajectories and gene usage.

genomics↗

bioRxiv2020

Factors Influencing Precision Medicine Knowledge and Attitudes

Precision medicine holds great promise for improving health and reducing health disparities that can be most fully realized by advancing diversity and inclusion in research participants. Without engaging underrepresented groups, precision medicine could not only fail to achieve its promise but also further exacerbate the health disparities already burdening the most vulnerable. Yet underrepresentation by people of non-European ancestry continues in precision medicine research and there are disparities across racial groups in the uptake of precision medicine applications and services. Studies have explored possible explanations for population differences in precision medicine participation, but full appreciation of the factors involved is still developing. To better inform the potential for addressing health disparities through PM, we assessed the relationship of precision medicine knowledge and trust in biomedical research with sociodemographic variables. Using a series of linear regression models applied to survey data collected in a diverse sample, we analyzed variation in both precision medicine knowledge and trust in biomedical research with socioeconomic factors as a way to understand the range of precision medicine knowledge (PMK) in a broadly representative group and its relationship to trust in research and demographic characteristics. Our results demonstrate that identifying as Black, while significantly PMK, explains only 1.5% of the PMK variance in unadjusted models and 7% of overall variance in models adjusted for meaningful covariates such as age, marital status, employment, and education. We also found a positive association between PMK and trust in biomedical research. These results indicate that race is a factor affecting PMK, even after accounting for differences in sociodemographic variables. Additional work is needed, however, to identify other factors contributing to variation in PMK as we work to increase diversity and inclusion in precision medicine applications.

genetics↗

bioRxiv2020

Interrupting reactivation of immunological memory reprograms allergy and averts anaphylaxis

IgE production against innocuous antigens can lead to life-threatening reactions such as anaphylaxis. While IgE levels drastically decline with strict allergen avoidance, the ability to regenerate IgE can persist for a lifetime, as is the case for peanut allergy. The mechanism by which IgE regenerates remains unresolved. A novel culture system and application of single-cell RNA-sequencing, elucidated the transcriptomic signature of human peanut-reactive B and T cells and revealed IL-4/IL-13 as a signaling pathway critical for the IgE recall response. Indeed, interruption of this pathway not only prevented IgE production and anaphylaxis, but also reprogrammed the pathogenic response against peanut. This investigation advances our understanding of the mechanism that regenerates IgE in food allergy and spotlights IL-4/IL-13 blockade as a therapeutic with disease-transforming potential. One Sentence SummarySingle-cell transcriptomics of allergic memory responses reveals how to teach the immune system to forget.

immunology↗

bioRxiv2019

Intermittent Starvation Extends the Functional Lifetime of Primary Human Hepatocyte Cultures

Primary human hepatocyte (PHH) cultures have become indispensable to mitigate the risk of adverse drug reactions in human patients. In contrast to de-differentiating monocultures, co-culture with non-parenchymal cells maintains PHH functions for 2-4 weeks. However, since the functional lifespan of PHHs in vivo is 200-400 days, it is desirable to further prolong PHH functions in vitro towards modeling chronic drug exposure and disease progression. Fasting has benefits on the longevity of organisms and the health of tissues such as the liver. We hypothesized that a culturing protocol that mimics dynamic fasting/starvation could activate starvation pathways and prolong PHH functional lifetime. To mimic starvation, serum and hormones were intermittently removed from the culture medium of micropatterned co-cultures (MPCC) containing PHHs organized onto collagen domains and surrounded by 3T3-J2 murine fibroblasts. A weekly 2-day starvation optimally prolonged PHH functional lifetime for 6+ weeks in MPCCs versus a decline after 3 weeks in non-starved controls. The 2-day starvation also enhanced the functions of PHH monocultures for 2 weeks, suggesting direct effects on PHHs. In MPCCs, starvation activated adenosine monophosphate activated protein kinase and restricted fibroblast overgrowth onto PHH islands, thereby maintaining hepatic polarity. The effects of starvation on MPCCs were partially recapitulated by activating adenosine monophosphate activated protein kinase using metformin or growth-arresting fibroblasts via mitomycin-C. Lastly, starved MPCCs demonstrated lower false positives for drug toxicity tests and higher drug-induced cytochrome-P450 activities versus non-starved controls even after 5 weeks. In conclusion, intermittent serum/hormone starvation extends PHH functional lifetime towards enabling clinically-relevant drug screening.

cell biology↗

bioRxiv2019

Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma

B-cell non-Hodgkins lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

genomics↗

bioRxiv2017

Ultra-sensitive mutation detection and genome-wide DNA copy number reconstruction by error corrected circulating tumour DNA sequencing

Minimally invasive circulating free DNA (cfDNA) analysis can portray cancer genome landscapes but highly sensitive and specific genetic approaches are necessary to accurately detect mutations with often low variant frequencies. We developed a targeted cfDNA sequencing technology using novel off-the-shelf molecular barcodes for error correction, in combination with custom solution hybrid capture enrichment. Modelling based on cfDNA yields from 58 patients shows that our assay, which requires 25ng of cfDNA input, should be applicable to >95% of patients with metastatic colorectal cancer. Sequencing of a 163.3 kb target region including 32 genes detected 100% of single nucleotide variants with 0.15% variant frequency in cfDNA spike-in experiments. Molecular barcode error correction reduced false positive mutation calls by 98.6%. In a series of 28 patients with metastatic colorectal cancers, 80 out of 91 (88%) mutations previously detected by tumour tissue sequencing were called in the cfDNA. Call rates were similar for single nucleotide variants and small insertions/deletions. Mutations only called in cfDNA but not detectable in matched tumour tissue included, among others, a subclonal resistance driver mutation to anti-EGFR antibodies in the KRAS gene, multiple activating PIK3CA mutations in each of two patients (indicative of parallel evolution), and TP53 mutations originating from clonal haematopoiesis. Furthermore, we demonstrate that cfDNA off-target read analysis allows the reconstruction of genome wide copy number aberration profiles from 71% of these 28 cases. This error-corrected ultra-deep cfDNA sequencing assay with a target region that can be readily customized enables broad insights into cancer genomes and evolution.

genomics↗