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McIntyre, R.

Publications and source records attributed to McIntyre, R..

9 recordsLinked to original sources

A DNA foundation model predicts osteoporosis risk genes without proximity bias

Targets supported by human genetic associations are more than twice as likely to progress from clinical development to approval. Genome-wide association studies are the largest source of genetic evidence for disease risk but linking non-coding variants to effector genes remains a significant barrier to identifying causal targets. Current gene-mapping approaches suffer from proximity bias, largely ignoring distal genes. Here we introduce Rosalind, a DNA foundation model fine-tuned on human genetic variation from GTEx, that directly predicts variant-gene regulatory relationships from sequence without relying on nearest-gene heuristics. We demonstrate Rosalinds accuracy through extensive benchmarking, apply it to multiple complex traits to establish broad utility, and provide experimental validation in osteoporosis using a translational osteoblast assay. We demonstrate that genes distal to osteoporosis risk variants were significantly more likely to alter a bone formation phenotype than nearest genes. Together, these results highlight deep learning-based regulatory models as a general and scalable framework for translating novel genetic insights to drug discovery.

genetics↗

TRAMFIX: TRavelling Across Melbourne for FIXel-based analysis (a reproducibility study)

Fixel-based analysis (FBA) has gained substantial interest for its ability to probe fibre-specific changes in the brains white matter from diffusion-weighted imaging data. However, the reproducibility and reliability of fixel-based measures across different scanners remains largely unknown. In this work, we present TRAMFIX: a multisite dataset of travelling participants (n=10 healthy adults) scanned across four 3T MRI scanners using a harmonised multi-shell DWI protocol. DWI data were processed using two pipelines that can adopted when performing multi-site FBA studies (site-specific versus pooled processing). We extracted fixel-based measures of fibre density (FD), fibre cross-section (FC), and fibre density and cross-section (FDC), as well as diffusion tensor imaging (DTI)-based fractional anisotropy (FA) and mean diffusivity (MD) from the harmonised protocol. Within-subject coefficients of variation (CVws) and intraclass correlation coefficients (ICC) of FBA and DTI measures were computed at multiple resolutions of computation and analysis: (i) the whole-brain averaged level, (ii) tract-level, and (iii) fixel- or voxel-level. Fixel-based metrics demonstrated high reproducibility and reliability at the whole-brain level (CVws ranging between 0.51% to 1.57% and ICC between 0.93 and 0.996). While reproducibility and reliability remained high for tract-averaged FBA measures (particularly the FC and FDC metrics), some tracts exhibited lower ICC values < 0.8 for the FD measure. When examining fixel-level reliability and reproducibility clear spatial patterns emerged, with lower ICC across subcortical and cerebellar regions, and higher CVws at the cortical boundaries. Across all levels, tensor-based metrics demonstrated slightly lower reproducibility and reliability metrics than FBA measures, suggesting that FBA metrics are just as, if not more, reproducible than DTI metrics across scanners when using identical protocols. Our findings provide support for the reproducibility and reliability of fixel-based measures, highlighting their potential for use in multi-site FBA studies. Future work examining protocol-related differences, as well as appropriate harmonisation strategies when pooling data across sites and scanners, will be valuable.

neuroscience↗

Default mode and motor networks facilitate early learning of implicit motor sequences: a multimodal MR spectroscopy and fMRI study

Learning new motor skills is a fundamental process that involves the sequencing of actions. Skill develops with practice and time, and manifests as performance that is fast and accurate. Although we know that learning can occur through an implicit process in the absence of conscious awareness, and across multiple temporal scales, the precise neural mechanisms mediating implicit motor sequence learning remain poorly understood. Similarly, the capacity for interventions with known influence on learning and memory, such as cardiovascular exercise, to facilitate implicit learning is yet to be clearly established. Here, we investigated the neuroplasticity of implicit motor sequence learning and the effect of acute exercise priming. Healthy adults (39.5% female) aged 22.55 {+/-} 2.69 years were allocated to either a high-intensity exercise (HIIT) group (n = 16) or to a very low-intensity control group (n = 17). Following exercise, participants performed a serial reaction time task. MR spectroscopy estimates of sensorimotor gamma-aminobutyric acid (GABA) were acquired before and after exercise, and during task performance, and resting-state fMRI was acquired at the end of the protocol. We show that early stages of learning are linked to default mode network connectivity, while the overall degree of learning following sustained practice is associated with motor network connectivity. Sensorimotor GABA concentration was linked to the early stages of learning, and GABA concentration was modulated following HIIT, although the two were not related. Overall, via integration of multiple neuroimaging modalities we demonstrate that interactions between hippocampal and motor networks underlie implicit motor sequence learning. Key points summary- Motor learning occurs across different temporal scales and can arise implicitly in the absence of conscious awareness. - Explicit motor learning is linked to the brains primary inhibitory neurotransmitter, GABA, and interactions across motor and hippocampal networks. - Whether these same neural mechanisms are implicated in implicit learning is unclear. Similarly, the capacity to influence learning via priming with cardiovascular exercise is yet to be clearly established. - We show that early implicit learning is underpinned by default mode network connectivity and sensorimotor GABA concentration, while total learning following sustained practice is linked to motor network connectivity. We also found that HIIT exercise elevated sensorimotor GABA concentration, but not the magnitude of implicit learning. - Overall, our results highlight shared involvement of default mode and motor networks in implicit motor sequence learning.

neuroscience↗

The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function: insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation.

Phospholipase C-gamma 2 (PLC{gamma}2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLC{gamma}2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLC{gamma}2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLC{gamma}2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLC{gamma}2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLC{gamma}2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLC{gamma}2 GOF on human microglia. PLC{gamma}2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLC{gamma}2 wild type. Despite the increase in PLC{gamma}2 enzymatic activity, the PLC{gamma}2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLC{gamma}2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLC{gamma}2 in the CNS. Drug candidates targeting PLC{gamma}2 will need to precisely mimic the effects of the PLC{gamma}2 P522R variant on microglial function, but not those of the PLC{gamma}2 S707Y variant. HighlightsO_LIThe impact of strongly hypermorphic variants of PLC{gamma}2 have not been studied in brain and yet PLC{gamma}2 is implicated in modifying risk of CNS disorders including Alzheimers disease C_LIO_LITo address this, we explored the role of the strongly hypermorphic PLC{gamma}2 S707Y variant in hiPSC-derived microglia C_LIO_LIS707Y increases PLC{gamma}2 enzymatic activity and intracellular calcium flux C_LIO_LIPhagocytosis and cytokine production are diminished in PLC{gamma}2 S707Y microglia C_LIO_LIPLC{gamma}2 S707Y downregulates expression of genes related to innate immunity and response C_LIO_LIModulation of PLC{gamma}2 for therapy must recapitulate the positive effects of moderate hypermorphic variants on microglial functions whilst avoiding detrimental effects of strongly hypermorphic variants like PLC{gamma}2 S707Y C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/564579v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@9f0903org.highwire.dtl.DTLVardef@108d26forg.highwire.dtl.DTLVardef@2fb691org.highwire.dtl.DTLVardef@7af80c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Breeding displacement in gray wolves (Canis lupus): Three males usurp breeding position and pup rearing from a neighboring pack in Yellowstone National Park

Gray Wolves (Canis lupus) are territorial, group living carnivores that live in packs typically consisting of a dominant breeding pair and their offspring. Breeding tenures are relatively short and competitive, with vacancies usually occurring following a breeders death, and are often filled by unrelated immigrants or by relatives of the previous breeder. The frequency and conditions of active breeder displacements are poorly understood. Position changes in the dominance hierarchy are common yet rarely documented in detail. We describe a turnover in male breeding position in a wolf pack by males from a neighboring pack in mid-summer 2016 in Yellowstone National Park. Over the course of two months, three males from the Mollies pack displaced the breeding male of the neighboring Wapiti Lake pack, joined the packs two adult females, and subsequently raised the previous males four approximately three-month old pups. In the four years following the displacement (2017 to 2020), at least one of the intruding males has successfully bred with the dominant female and most years with a subordinate female (who was one of the pups at the time of displacement). The pack reared pups to adulthood each year. Male breeding displacements are likely influenced by male-male competition and female mate choice. These changes are the result of individuals competing to improve breeding position and may lead to increased pack stability and greater reproductive success. We report in detail on the behavior of a closely observed breeding displacement and we discuss the adaptive benefits of the change.

animal behavior and cognition↗

Monash DaCRA fPET-fMRI: A DAtaset for Comparison of Radiotracer Administration for high temporal resolution functional FDG-PET

Background Functional [18F]-fluorodeoxyglucose positron emission tomography (FDG-fPET) is a new approach for measuring glucose uptake in the human brain. The goal of FDG-fPET is to maintain a constant plasma supply of radioactive FDG in order to track, with high temporal resolution, the dynamic uptake of glucose during neuronal activity that occurs in response to a task or at rest. FDG-fPET has most often been applied in simultaneous BOLD-fMRI/FDG-fPET (blood oxygenation level dependent functional MRI fluorodeoxyglucose functional positron emission tomography) imaging. BOLD-fMRI/FDG-fPET provides the capability to image the two primary sources of energetic dynamics in the brain, the cerebrovascular haemodynamic response and cerebral glucose uptake. FindingsIn this Data Note, we describe an open access dataset, Monash DaCRA fPET-fMRI, which contrasts three radiotracer administration protocols for FDG-fPET: bolus, constant infusion, and hybrid bolus/infusion. Participants (n=5 in each group) were randomly assigned to each radiotracer administration protocol and underwent simultaneous BOLD-fMRI/FDG-fPET scanning while viewing a flickering checkerboard. The Bolus group received the full FDG dose in a standard bolus administration; the Infusion group received the full FDG dose as a slow infusion over the duration of the scan, and the Bolus-Infusion group received 50% of the FDG dose as bolus and 50% as constant infusion. We validate the dataset by contrasting plasma radioactivity, grey matter mean uptake, and task-related activity in the visual cortex. ConclusionsThe Monash DaCRA fPET-fMRI dataset provides significant re-use value for researchers interested in the comparison of signal dynamics in fPET, and its relationship with fMRI task-evoked activity.

neuroscience↗

Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

Mitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity. SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

cell biology↗

The mutational profile and clonal landscape of the inflammatory bowel disease affected colon

Summary paragraphInflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. Here, we whole-genome sequenced 447 colonic crypts from 46 IBD patients, and compared these to 412 crypts from 41 non-IBD controls. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.

genetics↗

Constant Infusion Radiotracer Administration for High Temporal Resolution Positron Emission Tomography (PET) of the Human Brain: Application to -Fluorodexoyglucose PET (FDG-PET)

Functional Positron Emission Tomography (fPET) provides a method to track molecular dynamics in the human brain. With a radioactively labelled glucose-analogue, [18F]-flurodeoxyglucose (FDG-fPET), it is now possible to index the dynamics of glucose metabolism with temporal resolutions approaching those of functional magnetic resonance imaging (fMRI). This direct measure of glucose uptake has enormous potential for understanding normal and abnormal brain function, and probing the effects of metabolic and neurodegenerative diseases. Further, new advances in hybrid MR-PET hardware makes it possible to capture fluctuations in glucose and blood oxygenation simultaneously using fMRI and FDG-fPET.\n\nThe temporal resolution and signal-to-noise of the FDG-fPET images is critically dependent upon the administration of the radioactive tracer. In this work we present two alternative continuous infusion protocols and compare them to a traditional bolus approach. We detail a method for acquiring blood samples, time-locking PET, MRI and experimental stimulus, and administrating the non-traditional tracer delivery. By applying a visual stimulus, we demonstrate cortical maps of the glucose-response to external stimuli on an individual level with a temporal resolution of 16-seconds.\n\nSummaryRadiotracer infusion protocols for positron emission tomography (PET) provide improved temporal resolution over bolus administration. Here, we describe radiotracer administration for two protocols, constant infusion and bolus plus infusion protocol. We compare this to the standard bolus administration protocol. Using [18-F] fluorodeoxyglucose PET (FDG-PET) as an example, we show that temporal resolutions of approximately 16sec are achievable using these protocols.

neuroscience↗